WO2021175432A1

WO2021175432A1 - Method for administration of an anti cancer agent

Info

Publication number: WO2021175432A1
Application number: PCT/EP2020/055904
Authority: WO
Inventors: Shaonan Wang; Kristell MARZIN; Hanny MUSA; Ulrike Tontsch-Grunt; Eleftherios ZOGRAFOS
Original assignee: Boehringer Ingelheim International Gmbh
Priority date: 2020-03-04
Filing date: 2020-03-05
Publication date: 2021-09-10
Also published as: WO2021175824A1; TW202146016A

Abstract

The present invention relates to improved methods for the treatment of cancer comprising the administration of a BET inhibitor to a patient.

Description

METHOD FOR ADMINISTRATION OF AN ANTI CANCER AGENT

Field of the invention

The present invention relates to improved methods of administration of inhibitors of the bromodomain and extra terminal (BET) family of proteins (= BET inhibitors) in the treatment of cancer. In particular, the invention relates to improved methods of administration of BET inhibitors that provide desirable antineoplastic effects with a tolerable level of toxicity.

Background of the invention

The BET family proteins control diverse transcriptional programs that are important for cancer pathogenesis. In particular, the BET family protein bromodomain-containing protein 4 (BRD4) is highly enriched in regions known as “super enhancers”, which are very large enhancer regions that contain extensive binding sites for transcription factors. Genes associated with super enhancers are often highly expressed and very sensitive to BET inhibitors. In addition, BRD4 is associated with mitotic chromosomes and controls the post-mitotic transcription program that enables Gl/S transition during the cell cycle. Inhibition of BRD4 in vitro has been shown to result in pervasive Gl cell cycle arrest across a number of different cancer cell lines. Inhibition of BET bromodomains, e.g. BRD4, may impair the tumor microenvironment, thus inhibiting tumor growth. For example, inhibition of BRD4 has been shown to inhibit MYC expression, which may result in the collapse of the tumor microenvironment.

Although BET inhibitors have been shown to have encouraging preclinical efficacy in in vivo animal models and clinical efficacy in patients, there remains an urgent need to identify a suitable therapeutic window for the administration of BET inhibitors for the treatment of cancers in patients. WO 2019/222331 is also concerned with methods for the administration of BET inhibitors.

Summary of Invention

The present disclosure relates to the treatment of cancers in patients in need thereof comprising administering to the patients effective amounts of a BET inhibitor. The methods and treatments of the invention are characterized by administering the BET inhibitor in an intermittent dosing schedule (one week on (= treatment period)/one week off (= rest period)) in combination with differing individual amounts of the BET inhibitor to be administered during the first part of the treatment period (/.e. the loading period) in relation to the second part of the treatment period (/.e. the maintenance period). These protocols are expected to be safer and at least as effective as, possibly more effective than, administering more frequent doses at lower concentrations or larger but constant doses at intermittent periods. Accordingly, in a first aspect, the present disclosure is directed to a BET inhibitor for use in the treatment of a patient suffering from cancer, wherein the treatment comprises

• daily administration of the BET inhibitor to the patient during a treatment period on consecutive days 1 to 7 of a 14 day cycle;

• no administration of the BET inhibitor to the patient during a rest period on consecutive days 8 to 14 of the 14 day cycle; wherein the treatment period consists of

(a) a loading period on day 1 and a maintenance period on days 2 to 7, or

(b) a loading period on days 1 and 2 and a maintenance period on days 3 to 7; each individual daily amount of the BET inhibitor administered to the patient during the loading period is higher than each individual daily amount of the BET inhibitor administered to the patient during the maintenance period; and

• optionally, start of a new 14 day cycle on day 1 after the end of the previous 14 day cycle.

In a second aspect, the present disclosure is directed to a method for the treatment of a patient suffering from cancer, comprising administering to the patient a BET inhibitor, wherein

• the BET inhibitor is daily administered to the patient during a treatment period on consecutive days 1 to 7 of a 14 day cycle;

• the BET inhibitor is not administered to the patient during a rest period on consecutive days 8 to 14 of the 14 day cycle; wherein the treatment period consists of

(a) a loading period on day 1 and a maintenance period on days 2 to 7, or

• optionally, a new 14 day cycle is started on day 1 after the end of the previous 14 day cycle.

In a third aspect, the present disclosure is directed to the use of a BET inhibitor for the preparation of medicament for the treatment of a patient suffering from cancer, wherein the treatment comprises • daily administration of the BET inhibitor to the patient during a treatment period on consecutive days 1 to 7 of a 14 day cycle;

(a) a loading period on day 1 and a maintenance period on days 2 to 7, or

(b) a loading period on days 1 and 2 and a maintenance period on days 3 to 7; each individual daily amount of the BET inhibitor to be administered to the patient during the loading period is higher than each individual daily amount of the BET inhibitor to be administered to the patient during the maintenance period; and

In a fourth aspect, the present disclosure is directed to a method of reducing the size of a solid tumor in a patient comprising contacting the solid tumor with a BET inhibitor, wherein

(a) a loading period on day 1 and a maintenance period on days 2 to 7, or

In a fifth aspect, the present disclosure is directed to a method of inhibiting cellular proliferation of cancer cells in a patient comprising contacting the cancer cells with a BET inhibitor, wherein

(a) a loading period on day 1 and a maintenance period on days 2 to 7, or

(b) a loading period on days 1 and 2 and a maintenance period on days 3 to 7; each individual daily amount of the BET inhibitor administered to the patient during the loading period is higher than each individual daily amount of the BET inhibitor administered to the patient during the maintenance period; and • optionally, a new 14 day cycle is started on day 1 after the end of the previous 14 day cycle.

Brief Description of the Drawings

Figure 1 shows the immunofluorescence staining of NUT carcinoma cells Ty-82. Ty-82 cells were grown in multichamber slides and treated without (Fig. 1a) or with 10 nM (Fig. 1b) or 30 nM (Fig. 1c) of BET inhibitor Compound 1 for 30 min. Cells are labeled with an antibody against NUT protein.

In Fig. 1 a the bright dots represent labeled megadomains where BRD4/NUT is bound to chromatin. Fig. 1b shows that treatment with 10 nM Compound 1 leads to (although not complete) detachment of BRD4/NUT from the chromatin.

Fig. 1c shows that treatment with 30 nM Compound 1 leads to complete detachment of BRD4/NUT from the chromatin.

Thus, it can be derived from Fig. 1 that the concentration to detach BRD4/NUT from the chromatin is approximately 30 nM.

Figure 2 shows the immunofluorescence staining of NUT carcinoma cells Ty-82. Ty-82 cells were grown in multichamber slides and treated without (Fig. 2a) or with 100 nM (Fig. 2b) or 300 nM (Fig. 2c) or 1000 nM (Fig. 2d) of BET inhibitor GSK 525762 for 30 min. Cells are labeled with an antibody against NUT protein.

In Fig. 2a the bright dots represent labeled megadomains where BRD4/NUT is bound to chromatin. Fig. 2b shows that treatment with 100 nM BET inhibitor GSK 525762 does not lead to detachment of BRD4/NUT from the chromatin.

Fig. 2c shows that treatment with 300 nM BET inhibitor GSK 525762 does not lead to detachment of BRD4/NUT from the chromatin.

Fig. 2d shows that treatment with 1000 nM BET inhibitor GSK 525762 partially leads to detachment of BRD4/NUT from the chromatin. Figure 3 shows the immunofluorescence staining of NUT carcinoma cells Ty-82. Ty-82 cells were grown in multichamber slides without treatment (Fig. 3a) or treated with 30 nM BET inhibitor Compound 1 (Fig. 3b to 3f) for 30 min, followed by washout of compound and subsequent treatment with 30 nM (Fig. 3b), 10 nM (Fig. 3c), 5 nM (Fig 3d), 2.5 nM (Fig 3e) and no (Fig 3f) BET inhibitor Compound 1 for 24 hours. Cells are labeled with an antibody against NUT protein. In Fig. 3a the bright dots represent labeled megadomains where BRD4/NUT is bound to chromatin. Fig. 3b shows that treatment with 30 nM BET inhibitor Compound 1 leads to complete detachment of BRD4/NUT from the chromatin.

Fig. 3c shows that treatment with 30 nM BET inhibitor Compound 1 followed by treatment with 10 nM BET inhibitor Compound 1 still maintains complete detachment of BRD4/NUT from the chromatin.

Fig. 3d shows that treatment with 30 nM BET inhibitor Compound 1 followed by treatment with 5 nM BET inhibitor Compound 1 still maintains detachment of BRD4/NUT from the chromatin.

Fig. 3e shows that treatment with 30 nM BET inhibitor Compound 1 followed by treatment with 2.5 nM BET inhibitor Compound 1 does not maintain detachment of BRD4/NUT from the chromatin.

Fig. 3f shows that treatment with 30 nM BET inhibitor Compound 1 followed by treatment without BET inhibitor Compound 1 does not maintain detachment of BRD4/NUT from the chromatin.

As shown, the initial concentration to detach BRD4/NUT from the chromatin is approximately 30 nM. The concentration to maintain BRD4/NUT off the chromatin is 5 nM. Thus, it can be concluded that it should be beneficial and desirable to reach an initiating concentration of 30 nM and a maintanance concentration of 5 nM.

Figure 4a shows the geometric mean plasma concentration-time profile of Compound 1 after single oral administration of 2.5 mg of Compound 1 on Day 1 of cancer patients in a clinical trial.

Figure 4b shows the geometric mean plasma concentration-time profile of Compound 1 after single oral administration of 6 mg of Compound 1 on Day 1 of cancer patients in a clinical trial.

Figure 5 shows boxplots stratified by Compound 1 Dose and Schedule B (white boxes - repeated intermittent dosing cycles two weeks on/one week off with constant amount of BET inhibitor Compound 1) or Schedule C (grey boxes - repeated intermittent dosing cycles one week on/one week off with loading amount of Compound 1 on day 1 and maintenance amount of Compound 1 on days 2 to 7). For each individual patient treated with either Schedule B or C platelets were measured at up to seven timepoints. Dots are observations (platelet nadir per patient up to day the median value. Initial Schedule C data demonstrates a reduction in severity/depth of mode of action related thrombocytopenia, in comparison to uninterrupted dosing or intermittent dosing (Schedule B), i.e. the patients have higher platelet counts. The platelet values are shown on the log scale.

Detailed description of the invention

It has been unexpectedly discovered that an advantageous dosing regimen for a BET inhibitor can be designed by understanding the biology of the drug target and how the BET inhibitor concentration can alter binding of bromodomains to chromatin, regulate transcription and affect anti-tumor efficacy and tolerability. Surprisingly, it was found that if a sufficiently potent BET inhibitor or, in alternative, a sufficiently high dose of a BET inhibitor is used, it can cause antineoplastic effect by triggering much stronger and longer lasting antiproliferative mechanism in cells. It was found that when a cancer cell is exposed in vitro to sufficiently high concentration of the BET inhibitor Compound 1 (see below) for as short as 30 minutes, bromodomain is detached from binding to chromatin and therefore can no longer exert its regulation of transcription (see Figures 1 and 2). To maintain detachment of bromodomain from the chromatin, lower concentrations, but beyond a certain threshold, are sufficient (see Figure 3). If the BET inhibitor concentration for the initiation process is below a certain threshold, bromodomain cannot be fully detached from the chromatin and does not lead to regulation of transcription and antiproliferative effect. This modality can help plan clinical trials in a way to achieve sufficiently high exposure on the target.

Daily, uninterrupted dosing of a BET inhibitor at a sufficiently high dose will have a strong antiproliferative effect on tumor cells, but will lead to severe adverse events of mode of action related thrombocytopenia (Schedule A, published data).

Intermittent dosing (Schedule B, see Figure 5 for Compound 1) at sufficiently high dose, described as two weeks on treatment and one week off treatment, still leads to adverse event of mode of action related thrombocytopenia.

It was observed that a strong and long-lasting effect of bromodomain detachment from chromatin can be achieved with a scheduling and a treatment as herein described. Interestingly, this treatment does not cause the adverse effect of mode of action related thrombocytopenia to the severity of uninterrupted dosing or intermittent dosing (Schedule B) but rather to a level that can be better clinically managed (Schedule C, see Figure 5 for Compound 1). During the breaks with no administration of the BET inhibitor an organism can recover from potential on-target effects or side effects; particularly the number of platelets can recover. Less frequent dosing can also lead to better patient friendliness and patient compliance. Due to better tolerability of the BET inhibitor when administered as herein described the problem of dose reduction and/or extended drug holidays which might lead to disease progression due to lack of efficacy, is bypassed. Additionally, the better tolerability provides for a better flexibility to use the BET inhibitor in combination with other antineoplastic agents increasing the overall efficacy of the combination therapy with a second antineoplastic agent.

Specifically, the present disclosure provides the following aspects, advantageous features and specific embodiments, respectively, as listed in the following items and concerning methods/treatments/methods-of-treatment for a patient suffering from cancer, alone or in combination:

In a first aspect [A1], the present disclosure is directed to a BET inhibitor for use in the treatment of a patient suffering from cancer, wherein the treatment comprises

(a) a loading period on day 1 and a maintenance period on days 2 to 7, or

In a second aspect [A2], the present disclosure is directed to a method for the treatment of a patient suffering from cancer, comprising administering to the patient a BET inhibitor, wherein

(a) a loading period on day 1 and a maintenance period on days 2 to 7, or

In a third aspect [A3], the present disclosure is directed to the use of a BET inhibitor for the preparation of medicament for the treatment of a patient suffering from cancer, wherein the treatment comprises

(a) a loading period on day 1 and a maintenance period on days 2 to 7, or

In a fourth aspect [A4], the present disclosure is directed to a method of reducing the size of a solid tumor in a patient comprising contacting the solid tumor with a BET inhibitor, wherein

(a) a loading period on day 1 and a maintenance period on days 2 to 7, or (b) a loading period on days 1 and 2 and a maintenance period on days 3 to 7; each individual daily amount of the BET inhibitor administered to the patient during the loading period is higher than each individual daily amount of the BET inhibitor administered to the patient during the maintenance period; and

In a fifth aspect [A5], the present disclosure is directed to a method of inhibiting cellular proliferation of cancer cells in a patient comprising contacting the cancer cells with a BET inhibitor, wherein

(a) a loading period on day 1 and a maintenance period on days 2 to 7, or

Unless otherwise defined herein, scientific and technical terms used herein have the meanings that are commonly understood by those of ordinary skill in the art. In the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Unless otherwise required by context, singular terms, e.g. “a”, “an”, and “the”, shall include pluralities and plural terms shall include the singular. The use of “and” and “or” means “and/or” unless stated otherwise. The use of the term “including”, as well as other forms, such as “includes” and “included”, is not limiting. Any range described here will be understood to include the endpoints and all values between the endpoints, i.e. the recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention. “BET”, “BET protein”, or “BET proteins” as used herein refers to the Bromodomain and Extra Terminal family of proteins. BET proteins function as transcription regulators and control many transcriptional programs that are required for cancer pathogenesis. There are 46 known bromodomain (BRD)-containing proteins in the human genome and four of them (BRD2, BRD3, BRD4, and BRDT) comprise the BET family. BRDT is exclusively expressed in testis and ovary, whereas BRD2, BRD3, and BRD4 are ubiquitously expressed. Each member of the BET family contains two bromodomains which recognize acetylated lysine residues on histone proteins. Once bound to the acetylated histone markers, BET family proteins often activate transcription through recruiting the positive transcription elongation factor complex (pTEFb) that is essential for ribonucleic acid (RNA) polymerase ll-dependent transcription elongation.

“Inhibitors of the bromodomain and extra terminal (BET) family of proteins” or “BET inhibitors” as used herein refers to any ligand binding to members of the bromodomain and extra terminal (BET) family of proteins, in particular ligands binding to BRD4, which, due to such binding, inhibit the interaction between the first (BRD4-BD1) and/or the second (BRD4-BD2) bromodomain of BRD4 and acetylated histones (in particular histone H3 and H4). Such inhibition of interaction can, e.g., be measured by an Alpha Screen assay such as disclosed in WO 2014/076237. Preferably, such inhibition of interaction occurs with an IC₅o in such assay of less than 5 mM, preferably less than 1 pM, preferably less than 100 nM. Preferably, the BET inhibitor is a small molecule chemical compound.

BET inhibitors are known in the art and are, e.g., disclosed in WO 2009/084693, WO 2011/054553, WO 2011/054841 , WO 2011/054843, WO 2011/054844, WO 2011/054845, WO 2011/054846,

WO 2011/054848, WO 2011/143669, WO 2011/161031 , WO 2012/075383, WO 2014/076146,

WO 2014/076237, WO 2014/154760, WO 2014/154762, WO 2015/013635, WO 2015/022332,

WO 2015/067770, WO 2015/169962, WO 2016/073903, WO 2017/044792, WO 2017/044849,

WO 2017/059319.

Whenever the disclosure herein refers to a BET inhibitor or a specific BET inhibitor is mentioned than it is to be understood that this is meant to include the chemical compound as such, i.e., e.g., a free base or a free acid, but is also meant to include any salts, in particular pharmaceutically acceptable salts, of any such chemical compound, and also all other solid forms of such chemical compound. If an absolute amount of BET inhibitor (in milligrams) is given and the BET inhibitor is, e.g., a salt form of a base or acid (base addition salt or acid addition salt) then it has to be understood that the amount of BET inhibitor refers to the absolute amount (in milligrams) of the pure form of the BET inhibitor (free base or free acid being the active ingredient) without the salt forming counterion.

Without wanting to be bound to any theory, it is believed that BET inhibitors most suitable to be used according to the methods and treatments as disclosed herein are BET inhibitors which can achieve Cmax plasma concentration in patients of a least ten times (preferably ten to 20 times) the GI_5O concentration in the proliferation assay of the NUT carcinoma cell line Ty-82 to cause significant detachment of bromodomain from chromatin. Cmax plasma concentration and Glso concentration in Ty-82 can be determined as disclosed herein.

Thus, in a sub-aspect [B1] of aspects [A1] to [A5] the BET inhibitor is a BET inhibitor which achieves Cmax plasma concentration in patients of a least ten times, preferably ten to 20 times, the GI_5O concentration in the proliferation assay of the NUT carcinoma cell line Ty-82.

In a sub-aspect [B2] of aspects [A1] to [A5] the BET inhibitor is selected from the group consisting of

All BET inhibitors listed in sub-aspect [B2] are well known in the art with structure, synthetic access and properties. Compound 1 , e.g., is disclosed as example 111-13 in WO 2014/076237.

Thus, in one sub-aspect [B3] the BET inhibitor is Compound 1. In another sub-aspect [B4] the BET inhibitor is GSK 525762.

In another sub-aspect [B5] the BET inhibitor is JQ1.

In another sub-aspect [B6] the BET inhibitor is OTX-015.

In another sub-aspect [B7] the BET inhibitor is TEN-010.

In another sub-aspect [B8] the BET inhibitor is CPI-0610. In another sub-aspect [B9] the BET inhibitor is PLX51107.

In another sub-aspect [B10] the BET inhibitor is ABBV-075.

In another sub-aspect [B11] the BET inhibitor is ABBV-744.

In another sub-aspect [B12] the BET inhibitor is BMS 986158.

In another sub-aspect [B13] the BET inhibitor is TG-1601.

In another sub-aspect [B14] the BET inhibitor is CC-90010.

In another sub-aspect [B15] the BET inhibitor is AZD5153.

In another sub-aspect [B16] the BET inhibitor is Compound 2.

In another sub-aspect [B17] the BET inhibitor is Compound 3.

In another sub-aspect [B18] the BET inhibitor is Compound 4.

The term "patient" as used herein includes animals which are capable of suffering from or afflicted with a cancer or any disorder involving, directly or indirectly, a cancer. Examples of patients include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats and transgenic non-human animals. In the preferred embodiment, the subject is a human being, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from cancer.

Thus, in a further sub-aspect [C1] of aspects [A1] to [A5] the patient is a human being.

“Treatment” .“treat”, or “treating” refer to a method of alleviating or abrogating a disease and/or its underlying symptoms. “Treating” or“treatment” does not require complete alleviation of signs or symptoms and does not require a cure. In the context of “treating” a patient suffering from cancer, “treating” can include reducing, slowing, or halting tumor progression in the patient. More specifically, as used herein, “treatment” can also include a stable disease (SD) response in addition to partial response (PR) and complete response (CR) as defined by RECIST 1.1 scoring criteria. Thus, “treatment” of cancer as used herein explicitly does not require complete remission or even partial remission.

“RECIST” or “RECIST 1.1” as used herein refers to “Responsive Evaluation Criteria in Solid Tumors” and is a set of published rules/criteria that define patient progression during treatment. As described herein, RECIST 1.1 scoring recognizes four distinct categories; “complete response” (CR), “partial response” (PR), “progressive disease” (PD), and “stable disease” (SD). “Complete response” as used herein requires disappearance of all target lesions, including any pathological lymph nodes having reduction in short axis to less than 10 mm.

“Partial response” as used herein requires at least a 30 % decrease in the sum of diameters of target lesions using baseline sum diameters of the lesions as the reference point.

“Stable disease” as used herein requires neither sufficient shrinking to qualify as a partial response nor sufficient increase to qualify as disease progression, using smallest sum diameters as a reference point.

“Progressive disease” as used herein requires at least a 20 % increase in the sum of diameters of target lesions using the smallest sum on study as the baseline reference. There must additionally be an absolute increase of at least 5.0 mm in lesion size. Finally, appearance of one or more new lesions is considered disease progression. Further RECIST 1.1 criteria is described in, for example, Eisenhauer et al. European Journal of Cancer 45 (2009) 228-247, hereby incorporated by reference in its entirety.

The amount of BET inhibitor to be daily administered to the patient during the treatment period may be administered divided into multiple doses, e.g. twice daily or three times daily, or, preferably, in a single daily dose (= once daily).

The “treatment period” as used herein is defined as the period of seven consecutive days during which the BET inhibitor is at least administered once daily. The treatment period of seven days is the first half of a 14 day cycle and is followed by the “rest period” which is the period of seven days following the treatment period in the second half of the 14 day cycle during which no BET inhibitor is administered.

Thus, in a further sub-aspect [D1] of aspects [A1] to [A5] the BET inhibitor is administered to the patient once daily during the treatment period.

“Administering”, “administer”, or “administration” as used herein explicitly includes self administration, i.e. by the subject in need thereof, or administration by another individual to the subject in need thereof. Preferably, “administering”, “administer”, or “administration” as used herein refers to oral administration, and, e.g. in case the patients are unable to swallow, administration via a feeding tube, including but not limited to a nasogastric feeding tube, a gastric feeding tube or a percutaneous endoscopic gastrostomy (= PEG) tube as known in the art.

Thus, in a further sub-aspect [E1] of aspects [A1] to [A5] the BET inhibitor is orally administered to the patient during the treatment period. In another sub-aspect [E2] the BET inhibitor is administered to the patient during the treatment period via a feeding tube.

In another sub-aspect [E3] the BET inhibitor is administered to the patient during the treatment period via a PEG tube.

The treatment period is divided in a first part called “loading period” on day 1 of the 14 day cycle and a second part called “maintenance period” on days 2 to 7 of the 14 day cycle, or, alternatively, a “loading period” on days 1 and 2 of the 14 day cycle and a “maintenance period” on days 3 to 7 of the 14 day cycle. Each individual daily amount of the BET inhibitor administered to the patient during the two day loading period may vary and each individual daily amount of the BET inhibitor administered to the patient during the six day or during the five day maintenance period may vary (/.e. the individual daily amounts are not necessarily equal) as long as each individual daily amount of the BET inhibitor administered to the patient during the loading period is higher than each individual daily amount of the BET inhibitor administered to the patient during the maintenance period. E.g. the individual daily amounts of the BET inhibitor during a two day loading period and a five day maintenance period of a 14 day cycle could be as follows: day 1 - 6 mg, day 2 - 5 mg, day 3 - 4 mg, days 4 to 7 - 3 mg.

Preferebly, however, each individual daily amount of the BET inhibitor administered to the patient during a two day loading period and each individual daily amount of the BET inhibitor administered to the patient during a five day or six day loading period is constant. E.g., the amounts of BET inhibitors to be administered during such preferred treatment periods could be as follows: day 1 - 6 mg, day 2 - 6 mg, days 3 to 7 - 3 mg, or day 1 - 6 mg, days 2 to 7 - 3 mg.

Thus, in a further sub-aspect [F1] of aspects [A1] to [A5] each individual daily amount of the BET inhibitor administered during the loading period is constant and each individual daily amount of the BET inhibitor administered during the maintenance period is constant.

Ideally and preferred, the individual amounts of the BET inhibitor daily administered to the patient should be administered equidistantly, /.e. the time between two individual administrations of an amount of BET inhibitor should be approximately the same throughout the treatment period.

Thus, in a further sub-aspect [G1] of aspects [A1] to [A5] each individual amount of the BET inhibitor is daily administered approximately at the same time of the day during the treatment period.

The 14 day cycle consisting of a treatment period and a rest period can be repeated as long as the cancer to be treated remains under control and/or is regressing and/or the treatment is clinically tolerated and/or as long as deemed necessary or beneficial according to the prescribing physician^'s assessment, i.e. dosing may be continued beyond the point at which the underlying cancer has begun to be treated and may be continued indefinitely.

A 14 day cycle which follows a previous 14 day cycle does not necessarily have to be identical with the previous 14 day cycle, i.e., different durations of the loading period and maintenance period may apply and/or different individual daily amounts of the BET inhibitor may be administered in the following 14 day cycle as long as each individual daily amount of the BET inhibitor administered to the patient during the loading period of said following 14 day cycle remains higher than each individual daily amount of the BET inhibitor administered to the patient during the maintenance period of said following 14 day cycle. Preferably, however, the treatment in a following 14 day cycle is the same as in the previous 14 day cycle, i.e. remains unchanged in terms of both duration of loading period/maintenance period and amounts of BET inhibitor to be daily administered during the treatment period.

Thus, in a further sub-aspect [H1] of aspects [A1] to [A5] the treatment in a following 14 day cycle is the same as in the previous 14 day cycle.

It is believed that the treatment as herein described can be broadly applied in cancer treatment and is not limited to specific cancers. Particularly preferred are cancers which are known to be amenable to treatment with BET inhibitors.

Thus, in a further sub-aspect [11] of aspects [A1] to [A5] the cancer to be treated is selected from the group consisting of prostate cancer (including but not limited to castration-resistant prostate cancer (CRPC)), bladder cancer, breast cancer (including but not limited to ductal breast cancer), cancers of the Gl tract (including but not limited to colon cancer, colorectal cancer, gastric cancer, pancreatic cancer (including but not limited to pseudopapillary pancreatic carcinoma and pancreatic adenocarcinoma), oesophageal cancer, cholangiocarcinoma, small bowel cancer, duodenal cancer), head and neck cancer (including but not limited to nasopharyngeal cancer), ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, liver cancer (including but not limited to hepatocellular carcinoma), neuroendocrine cancer, melanoma (including but not limited to uveal melanoma), lung cancer (including but not limitied to non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)), NUT carcinoma, lymphoma (including but not limited to diffuse large B-cell lymphoma (DLBCL), leukemias (including but not limited to acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL)), leiomyosarcoma, mesenchymal chondrosarcoma, salivary gland adenocarcinoma, osteosarcoma, adenoid cystic carcinoma, ependymoma, acinic cell carcinoma and merkel cell carcinoma.

In another sub-aspect [12] the cancer to be treated is selected from the group consisting of colon cancer, colorectal cancer, gastric cancer, pancreatic cancer (including but not limited to pseudopapillary pancreatic carcinoma and pancreatic adenocarcinoma), oesophageal cancer, cholangiocarcinoma, small bowel cancer, duodenal cancer, lung cancer (including but not limitied to non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)) and NUT carcinoma.

In another sub-aspect [13] the cancer to be treated is NUT carcinoma.

In another sub-aspect [14] the cancer to be treated harbours a NUT fusion (including but not limited to BRD4-NUT, BRD3-NUT and NSD3-NUT).

In another sub-aspect [15] the cancer to be treated is selected from the group consisting of

• a cancer harbouring a BET fusion;

• a cancer showing MYC overexpression;

• a cancer with amplification and/or high copy number gain of MYC;

• a cancer with amplification and/or high copy number gain of MYCN;

• a cancer with a translocation involving MYC;

• a cancer with a translocation involving MYCN;

• a cancer with a translocation involving BRD3; and

• a cancer with a translocation involving BRD4.

Specific for the treatments as herein described is the existence of a loading period and a maintenance period, wherein each individual daily amount of the BET inhibitor administered during the loading period is higher than each individual daily amount of the BET inhibitor administered during the maintenance period, i.e. the ratio of these daily amounts to be administered is > 1 (amount during loading period : amount during maintenance period > 1).

Consequently, in a further sub-aspect [J1] of aspects [A1] to [A5] each individual daily amount of the BET inhibitor administered to the patient during the loading period is up to about three times the individual daily amount of the BET inhibitor administered to the patient during the maintenance period.

In another sub-aspect [J2] each individual daily amount of the BET inhibitor administered to the patient during the loading period is between about 1.5 times to about three times the individual daily amount of the BET inhibitor administered to the patient during the maintenance period. In another sub-aspect [J3] each individual daily amount of the BET inhibitor administered to the patient during the loading period is between 1.5 times to three times the individual daily amount of the BET inhibitor administered to the patient during the maintenance period.

In another sub-aspect [J4] each individual daily amount of the BET inhibitor administered to the patient during the loading period is about two times the individual daily amount of the BET inhibitor administered to the patient during the maintenance period.

In another sub-aspect [J5] each individual daily amount of the BET inhibitor administered to the patient during the loading period is two times the individual daily amount of the BET inhibitor administered to the patient during the maintenance period.

In another sub-aspect [J6] each individual daily amount of the BET inhibitor administered to the patient during the loading period is up to three times the individual daily amount of the BET inhibitor administered to the patient during the maintenance period and the individual daily amount of the BET inhibitor administered to the patient during the maintenance period is about 2 mg to about 4 mg.

In another sub-aspect [J7] each individual daily amount of the BET inhibitor administered to the patient during the loading period is about 4 mg to about 8 mg and higher than each individual daily amount of the BET inhibitor administered to the patient during the maintenance period which is about 2 mg to about 4 mg.

In another sub-aspect [J8] each individual daily amount of the BET inhibitor administered to the patient during the loading period is about 4 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is about 2 mg.

In another sub-aspect [J9] each individual daily amount of the BET inhibitor administered to the patient during the loading period is 4 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is 2 mg.

In another sub-aspect [J10] each individual daily amount of the BET inhibitor administered to the patient during the loading period is about 5 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is about 2.5 mg.

In another sub-aspect [J11] each individual daily amount of the BET inhibitor administered to the patient during the loading period is 5 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is 2.5 mg. In another sub-aspect [J12] each individual daily amount of the BET inhibitor administered to the patient during the loading period is about 6 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is about 3 mg.

In another sub-aspect [J13] each individual daily amount of the BET inhibitor administered to the patient during the loading period is 6 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is 3 mg.

In another sub-aspect [J14] each individual daily amount of the BET inhibitor administered to the patient during the loading period is about 7 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is about 3.5 mg.

In another sub-aspect [J15] each individual daily amount of the BET inhibitor administered to the patient during the loading period is 7 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is 3.5 mg.

Sub-aspects [J6] to [J15] are particularly preferred and applicable if the BET inhibitor to be administered is Compound 1.

In another sub-aspect [J16] each individual daily amount of the BET inhibitor administered to the patient during the loading period is about 150 mg to about 200 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is about 75 mg to about 100 mg.

In another sub-aspect [J17] each individual daily amount of the BET inhibitor administered to the patient during the loading period is 150 mg to 200 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is 75 mg to 100 mg.

Sub-aspects [J16] and [J17] are particularly preferred and applicable if the BET inhibitor to be administered is GSK 525762.

“About” as used herein generally refers to amounts that are within ± 10 % from the reported value, e.g. ± 10 %, ± 9 %, ± 8 %, ± 7 %, ± 6 %, ± 5 %, ± 4 %, ± 3 %, ± 2 %, ± 1 %, < ± 1 %, and any intervening ranges therein. In the context of amounts of BET inhibitors to be administered, the term “about” includes values of ± 5 % from the reported value, e.g. ± 5 %, ± 4 %, ± 3 %, ± 2 %, ± 1 %, < ± 1 %, and any intervening ranges therein. For example, administering an amount of about 3 mg of the BET inhibitor would include administering 3.15 mg, 3.10 mg, 3.05 mg, 3.00 mg, 2.95 mg, 2.90 mg, 2.85 mg, and any intervening values therein.

The loading period within the treatment period is either a one day or two day loading period. Thus, in a further sub-aspect [K1] of aspects [A1] to [A5] the treatment period consists of a loading period on day 1 and a maintenance period on days 2 to 7.

In another sub-aspect [K2] the treatment period consists of a loading period on days 1 and 2 and a maintenance period on days 3 to 7.

Usually, it is intended to administer the BET inhibitor in formulated form, i.e. as part of a pharmaceutical composition.

Thus, in a further sub-aspect [L1] of aspects [A1] to [A5] the BET inhibitor is part of a pharmaceutical composition, the BET inhibitor optionally co-formulated with one or more pharmaceutically acceptable carriers, excipients and/or vehicles.

Oral dosage forms to be used are for example tablets (preferred), capsules, sachets, micropellets, granules or the like. The oral dosage forms can comprise in addition to the BET inhibitor further conventional carriers, excipients or vehicles used for pharmaceuticals. Examples of such carriers or excipients include, but are not limited to, disinteg rants, binders, lubricants, glidants, stabilizers, fillers, diluents, colorants, flavours and preservatives. One of ordinary skill in the art may select one or more of the aforementioned carriers with respect to the particular desired properties of the dosage form. The following references disclose techniques and excipients used to formulate oral dosage forms. See The Handbook of Pharmaceutical Excipients, 4^th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 20^th edition, Gennaro, Ed., Lippincott Williams & Wlkins (2003). The dosage forms are prepared for example by blending, granulating, compressing, compacting, filling, sieving, mixing and/or tableting.

Thus, in a further sub-aspect [L2] of aspect [L1] the pharmaceutical composition is a tablet.

The treatments and methods as herein described can be a monotherapy ora combination therapy.

Thus, in a further sub-aspect [M1] of aspects [A1] to [A5] the BET inhibitor is administered to the patient as a monotherapy.

In a further sub-aspect [M2] the treatment further comprises the administration of one or more additional active ingredient(s) which is/are to be administered to the patient.

Preferably, such additional active ingredient(s) to be administered to the patient is/are (a) antineoplastic agent(s). An “antineoplastic agent” is a pharmaceutical active ingredient that exhibits antiproliferative and/or anti-cancer activity. Many such antineoplastic agents are known in the art and may be successfully combined with the BET inhibitor treatment as herein disclosed. Thus, in a further sub-aspect [M3] the treatment further comprises the administration of one or more additional antineoplastic agent(s) which is/are to be administered to the patient.

“Solid tumor” or “solid tumors” as used herein refers to abnormal masses or growths of tissue that are generally free of cysts or liquid. Solid tumors may typically be benign or malignant, i.e. cancerous. Non-limiting examples of cancerous solid tumors include sarcomas and carcinomas. An “effective amount” of a BET inhibitor corresponds to an amount administered according to any aspect of the present disclosure, e.g. amounts corresponding to any of the dosing regimens or amounts described herein.

All sub-aspects [B] to [M] as disclosed and mentioned above are meant to further define preferred embodiments of aspects [A1] to [A5] and can be combined with each other and amongst each other, i.e. each such combination shall be deemed to be disclosed and to be part of the invention. Consequently, the invention comprises the following items 1 to 60:

1. A BET inhibitor for use in the treatment of a patient suffering from cancer, wherein the treatment comprises

(a) a loading period on day 1 and a maintenance period on days 2 to 7, or

2. A method for the treatment of a patient suffering from cancer, comprising administering to the patient a BET inhibitor, wherein

(a) a loading period on day 1 and a maintenance period on days 2 to 7, or

3. Use of a BET inhibitor for the preparation of medicament for the treatment of a patient suffering from cancer, wherein the treatment comprises

(a) a loading period on day 1 and a maintenance period on days 2 to 7, or

4. A method of reducing the size of a solid tumor in a patient comprising contacting the solid tumor with a BET inhibitor, wherein

(a) a loading period on day 1 and a maintenance period on days 2 to 7, or (b) a loading period on days 1 and 2 and a maintenance period on days 3 to 7; each individual daily amount of the BET inhibitor administered to the patient during the loading period is higher than each individual daily amount of the BET inhibitor administered to the patient during the maintenance period; and · optionally, a new 14 day cycle is started on day 1 after the end of the previous 14 day cycle. A method of inhibiting cellular proliferation of cancer cells in a patient comprising contacting the cancer cells with a BET inhibitor, wherein

• the BET inhibitor is not administered to the patient during a rest period on consecutive days 8 to 14 of the 14 day cycle; wherein the treatment period consists of (a) a loading period on day 1 and a maintenance period on days 2 to 7, or

(b) a loading period on days 1 and 2 and a maintenance period on days 3 to 7; each individual daily amount of the BET inhibitor administered to the patient during the loading period is higher than each individual daily amount of the BET inhibitor administered to the patient during the maintenance period; and · optionally, a new 14 day cycle is started on day 1 after the end of the previous 14 day cycle. The BET inhibitor for use according to item 1 , the method for the treatment according to item 2, the use of the BET inhibitor according to item 3, or the methods according to items 4 and 5, wherein the BET inhibitor is a BET inhibitor which achieves Cmax plasma concentration in patients of a least ten times, preferably ten to 20 times, the GI₅o concentration in the proliferation assay of the NUT carcinoma cell line Ty-82. The BET inhibitor for use according to item 1 , the method for the treatment according to item 2, the use of the BET inhibitor according to item 3, or the methods according to items 4 and 5, wherein the BET inhibitor is selected from the group consisting of

8. The BET inhibitor for use, the method for the treatment, the use of the BET inhibitor, or the methods according to item 7, wherein the BET inhibitor is Compound 1.

9. The BET inhibitor for use, the method for the treatment, the use of the BET inhibitor, or the methods according to item 7, wherein the BET inhibitor is GSK 525762. 10. The BET inhibitor for use, the method for the treatment, the use of the BET inhibitor, or the methods according to item 7, wherein the BET inhibitor is JQ1.

11. The BET inhibitor for use, the method for the treatment, the use of the BET inhibitor, or the methods according to item 7, wherein the BET inhibitor is OTX-015.

12. The BET inhibitor for use, the method for the treatment, the use of the BET inhibitor, or the methods according to item 7, wherein the BET inhibitor is TEN-010.

13. The BET inhibitor for use, the method for the treatment, the use of the BET inhibitor, or the methods according to item 7, wherein the BET inhibitor is CPI-0610.

14. The BET inhibitor for use, the method for the treatment, the use of the BET inhibitor, or the methods according to item 7, wherein the BET inhibitor is PLX51107. 15. The BET inhibitor for use, the method for the treatment, the use of the BET inhibitor, or the methods according to item 7, wherein the BET inhibitor is ABBV-075. 16. The BET inhibitor for use, the method for the treatment, the use of the BET inhibitor, or the methods according to item 7, wherein the BET inhibitor is ABBV-744.

17. The BET inhibitor for use, the method for the treatment, the use of the BET inhibitor, or the methods according to item 7, wherein the BET inhibitor is BMS 986158.

18. The BET inhibitor for use, the method for the treatment, the use of the BET inhibitor, or the methods according to item 7, wherein the BET inhibitor is TG-1601.

19. The BET inhibitor for use, the method for the treatment, the use of the BET inhibitor, or the methods according to item 7, wherein the BET inhibitor is CC-90010.

20. The BET inhibitor for use, the method for the treatment, the use of the BET inhibitor, or the methods according to item 7, wherein the BET inhibitor is AZD5153.

21. The BET inhibitor for use, the method for the treatment, the use of the BET inhibitor, or the methods according to item 7, wherein the BET inhibitor is Compound 2.

22. The BET inhibitor for use, the method for the treatment, the use of the BET inhibitor, or the methods according to item 7, wherein the BET inhibitor is Compound 3.

23. The BET inhibitor for use, the method for the treatment, the use of the BET inhibitor, or the methods according to item 7, wherein the BET inhibitor is Compound 4.

24. The BET inhibitor for use according to item 1 or 6 to 23, the method for the treatment according to item 2 or 6 to 23, the use of the BET inhibitor according to item 3 or 6 to 23, or the methods according to items 4 to 23, wherein the patient is a human being.

25. The BET inhibitor for use according to item 1 or 6 to 24, the method for the treatment according to item 2 or 6 to 24, the use of the BET inhibitor according to item 3 or 6 to 24, or the methods according to items 4 to 24, wherein the BET inhibitor is administered to the patient once daily during the treatment period.

26. The BET inhibitor for use according to item 1 or 6 to 25, the method for the treatment according to item 2 or 6 to 25, the use of the BET inhibitor according to item 3 or 6 to 25, or the methods according to items 4 to 25, wherein the BET inhibitor is orally administered to the patient during the treatment period.

27. The BET inhibitor for use according to item 1 or 6 to 25, the method for the treatment according to item 2 or 6 to 25, the use of the BET inhibitor according to item 3 or 6 to 25, or the methods according to items 4 to 25, wherein the BET inhibitor is administered to the patient during the treatment period via a feeding tube. 28. The BET inhibitor for use according to item 1 or 6 to 25, the method for the treatment according to item 2 or 6 to 25, the use of the BET inhibitor according to item 3 or 6 to 25, or the methods according to items 4 to 25, wherein the BET inhibitor is administered to the patient during the treatment period via a PEG tube.

29. The BET inhibitor for use according to item 1 or 6 to 28, the method for the treatment according to item 2 or 6 to 28, the use of the BET inhibitor according to item 3 or 6 to 28, or the methods according to items 4 to 28, wherein each individual daily amount of the BET inhibitor administered during the loading period is constant and each individual daily amount of the BET inhibitor administered during the maintenance period is constant.

30. The BET inhibitor for use according to item 1 or 6 to 29, the method for the treatment according to item 2 or 6 to 29, the use of the BET inhibitor according to item 3 or 6 to 29, or the methods according to items 4 to 29, wherein each individual amount of the BET inhibitor is daily administered approximately at the same time of the day during the treatment period.

31. The BET inhibitor for use according to item 1 or 6 to 30, the method for the treatment according to item 2 or 6 to 30, the use of the BET inhibitor according to item 3 or 6 to 30, or the methods according to items 4 to 30, wherein the treatment in a following 14 day cycle is the same as in the previous 14 day cycle.

32. The BET inhibitor for use according to item 1 or 6 to 31, the method for the treatment according to item 2 or 6 to 31 , the use of the BET inhibitor according to item 3 or 6 to 31 , or the methods according to items 4 to 31 , wherein the cancer to be treated is selected from the group consisting of prostate cancer (including but not limited to castration-resistant prostate cancer (CRPC)), bladder cancer, breast cancer (including but not limited to ductal breast cancer), cancers of the Gl tract (including but not limited to colon cancer, colorectal cancer, gastric cancer, pancreatic cancer (including but not limited to pseudopapillary pancreatic carcinoma and pancreatic adenocarcinoma), oesophageal cancer, cholangiocarcinoma, small bowel cancer, duodenal cancer), head and neck cancer (including but not limited to nasopharyngeal cancer), ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, liver cancer (including but not limited to hepatocellular carcinoma), neuroendocrine cancer, melanoma (including but not limited to uveal melanoma), lung cancer (including but not limitied to non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)), NUT carcinoma, lymphoma (including but not limited to diffuse large B-cell lymphoma (DLBCL), leukemias (including but not limited to acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL)), leiomyosarcoma, mesenchymal chondrosarcoma, salivary gland adenocarcinoma, osteosarcoma, adenoid cystic carcinoma, ependymoma, acinic cell carcinoma and merkel cell carcinoma.

33. The BET inhibitor for use according to item 1 or 6 to 32, the method for the treatment according to item 2 or 6 to 32, the use of the BET inhibitor according to item 3 or 6 to 32, or the methods according to items 4 to 32, wherein the cancer to be treated is selected from the group consisting of colon cancer, colorectal cancer, gastric cancer, pancreatic cancer (including but not limited to pseudopapillary pancreatic carcinoma and pancreatic adenocarcinoma), oesophageal cancer, cholangiocarcinoma, small bowel cancer, duodenal cancer), lung cancer (including but not limitied to non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)) and NUT carcinoma.

34. The BET inhibitor for use according to item 1 or 6 to 33, the method for the treatment according to item 2 or 6 to 33, the use of the BET inhibitor according to item 3 or 6 to 33, or the methods according to items 4 to 33, wherein the cancer to be treated is NUT carcinoma.

35. The BET inhibitor for use according to item 1 or 6 to 31, the method for the treatment according to item 2 or 6 to 31 , the use of the BET inhibitor according to item 3 or 6 to 31 , or the methods according to items 4 to 31 , wherein the cancer to be treated harbours a NUT fusion (including but not limited to BRD4-NUT, BRD3-NUT and NSD3-NUT).

36. The BET inhibitor for use according to item 1 or 6 to 31, the method for the treatment according to item 2 or 6 to 31 , the use of the BET inhibitor according to item 3 or 6 to 31 , or the methods according to items 4 to 31 , wherein the cancer to be treated is selected from the group consisting of

• a cancer harbouring a BET fusion;

• a cancer showing MYC overexpression;

• a cancer with amplification and/or high copy number gain of MYC;

• a cancer with amplification and/or high copy number gain of MYCN;

• a cancer with a translocation involving MYC;

• a cancer with a translocation involving MYCN;

• a cancer with a translocation involving BRD3; and

• a cancer with a translocation involving BRD4.

37. The BET inhibitor for use according to item 1 or 6 to 36, the method for the treatment according to item 2 or 6 to 36, the use of the BET inhibitor according to item 3 or 6 to 36, or the methods according to items 4 to 36, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is up to about three times the individual daily amount of the BET inhibitor administered to the patient during the maintenance period.

38. The BET inhibitor for use according to item 1 or 6 to 37, the method for the treatment according to item 2 or 6 to 37, the use of the BET inhibitor according to item 3 or 6 to 37, or the methods according to items 4 to 37, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is between about 1.5 times to about three times the individual daily amount of the BET inhibitor administered to the patient during the maintenance period.

39. The BET inhibitor for use according to item 1 or 6 to 38, the method for the treatment according to item 2 or 6 to 38, the use of the BET inhibitor according to item 3 or 6 to 38, or the methods according to items 4 to 38, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is between 1.5 times to three times the individual daily amount of the BET inhibitor administered to the patient during the maintenance period.

40. The BET inhibitor for use according to item 1 or 6 to 39, the method for the treatment according to item 2 or 6 to 39, the use of the BET inhibitor according to item 3 or 6 to 39, or the methods according to items 4 to 39, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is about two times the individual daily amount of the BET inhibitor administered to the patient during the maintenance period.

41. The BET inhibitor for use according to item 1 or 6 to 40, the method for the treatment according to item 2 or 6 to 40, the use of the BET inhibitor according to item 3 or 6 to 40, or the methods according to items 4 to 40, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is two times the individual daily amount of the BET inhibitor administered to the patient during the maintenance period.

42. The BET inhibitor for use according to item 1 or 6 to 36, the method for the treatment according to item 2 or 6 to 36, the use of the BET inhibitor according to item 3 or 6 to 36, or the methods according to items 4 to 36, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is up to three times the individual daily amount of the BET inhibitor administered to the patient during the maintenance period and the individual daily amount of the BET inhibitor administered to the patient during the maintenance period is about 2 mg to about 4 mg.

43. The BET inhibitor for use according to item 1 or 6 to 36, the method for the treatment according to item 2 or 6 to 36, the use of the BET inhibitor according to item 3 or 6 to 36, or the methods according to items 4 to 36, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is about 4 mg to about 8 mg and higher than each individual daily amount of the BET inhibitor administered to the patient during the maintenance period which is about 2 mg to about 4 mg.

44. The BET inhibitor for use according to item 1 or 6 to 36, the method for the treatment according to item 2 or 6 to 36, the use of the BET inhibitor according to item 3 or 6 to 36, or the methods according to items 4 to 36, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is about 4 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is about 2 mg.

45. The BET inhibitor for use according to item 1 or 6 to 36, the method for the treatment according to item 2 or 6 to 36, the use of the BET inhibitor according to item 3 or 6 to 36, or the methods according to items 4 to 36, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is 4 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is 2 mg.

46. The BET inhibitor for use according to item 1 or 6 to 36, the method for the treatment according to item 2 or 6 to 36, the use of the BET inhibitor according to item 3 or 6 to 36, or the methods according to items 4 to 36, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is about 5 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is about 2.5 mg.

47. The BET inhibitor for use according to item 1 or 6 to 36, the method for the treatment according to item 2 or 6 to 36, the use of the BET inhibitor according to item 3 or 6 to 36, or the methods according to items 4 to 36, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is 5 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is 2.5 mg. 48. The BET inhibitor for use according to item 1 or 6 to 36, the method for the treatment according to item 2 or 6 to 36, the use of the BET inhibitor according to item 3 or 6 to 36, or the methods according to items 4 to 36, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is about 6 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is about 3 mg.

49. The BET inhibitor for use according to item 1 or 6 to 36, the method for the treatment according to item 2 or 6 to 36, the use of the BET inhibitor according to item 3 or 6 to 36, or the methods according to items 4 to 36, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is 6 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is 3 mg.

50. The BET inhibitor for use according to item 1 or 6 to 36, the method for the treatment according to item 2 or 6 to 36, the use of the BET inhibitor according to item 3 or 6 to 36, or the methods according to items 4 to 36, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is about 7 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is about 3.5 mg.

51. The BET inhibitor for use according to item 1 or 6 to 36, the method for the treatment according to item 2 or 6 to 36, the use of the BET inhibitor according to item 3 or 6 to 36, or the methods according to items 4 to 36, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is 7 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is 3.5 mg.

52. The BET inhibitor for use according to item 1 or 6 to 36, the method for the treatment according to item 2 or 6 to 36, the use of the BET inhibitor according to item 3 or 6 to 36, or the methods according to items 4 to 36, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is about 150 mg to about 200 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is about 75 mg to about 100 mg.

53. The BET inhibitor for use according to item 1 or 6 to 36, the method for the treatment according to item 2 or 6 to 36, the use of the BET inhibitor according to item 3 or 6 to 36, or the methods according to items 4 to 36, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is 150 mg to 200 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is 75 mg to 100 mg.

54. The BET inhibitor for use according to item 1 or 6 to 53, the method for the treatment according to item 2 or 6 to 53, the use of the BET inhibitor according to item 3 or 6 to 53, or the methods according to items 4 to 53, wherein the treatment period consists of a loading period on day 1 and a maintenance period on days 2 to 7.

55. The BET inhibitor for use according to item 1 or 6 to 53, the method for the treatment according to item 2 or 6 to 53, the use of the BET inhibitor according to item 3 or 6 to 53, or the methods according to items 4 to 53, wherein the treatment period consists of a loading period on days 1 and 2 and a maintenance period on days 3 to 7.

56. The BET inhibitor for use according to item 1 or 6 to 55, the method for the treatment according to item 2 or 6 to 55, the use of the BET inhibitor according to item 3 or 6 to 55, or the methods according to items 4 to 55, wherein the BET inhibitor is part of a pharmaceutical composition, the BET inhibitor optionally co-formulated with one or more pharmaceutically acceptable carriers, excipients and/or vehicles.

57. The BET inhibitor for use, the method for the treatment, the use of the BET inhibitor, or the methods according to item 56, wherein the pharmaceutical composition is a tablet.

58. The BET inhibitor for use according to item 1 or 6 to 57, the method for the treatment according to item 2 or 6 to 57, the use of the BET inhibitor according to item 3 or 6 to 57, or the methods according to items 4 to 57, wherein the BET inhibitor is administered to the patient as a monotherapy.

59. The BET inhibitor for use according to item 1 or 6 to 57, the method for the treatment according to item 2 or 6 to 57, the use of the BET inhibitor according to item 3 or 6 to 57, or the methods according to items 4 to 57, wherein the treatment further comprises the administration of one or more additional active ingredient(s) which is/are to be administered to the patient.

60. The BET inhibitor for use according to item 1 or 6 to 57, the method for the treatment according to item 2 or 6 to 57, the use of the BET inhibitor according to item 3 or 6 to 57, or the methods according to items 4 to 57, wherein the treatment further comprises the administration of one or more additional antineoplastic agent(s) which is/are to be administered to the patient.

The most preferred embodiments of aspects [A1] to [A5] are characterized by the following combinations:

• the BET inhibitor is Compound 1 ;

• the BET inhibitor is administered to the patient once daily during the treatment period;

• the BET inhibitor is orally administered to the patient during the treatment period;

• each individual daily amount of the BET inhibitor administered to the patient during the loading period is 4 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is 2 mg; or

• each individual daily amount of the BET inhibitor administered to the patient during the loading period is 5 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is 2.5 mg; or

• each individual daily amount of the BET inhibitor administered to the patient during the loading period is 6 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is 3 mg; or

• each individual daily amount of the BET inhibitor administered to the patient during the loading period is 7 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is 3.5 mg; and

• the treatment period consists of a loading period on day 1 and a maintenance period on days 2 to 7.

Most preferred these preferred embodiments [A1] to [A5] are applied for the treatment of NUT carcinoma.

Examples

The following non-limiting Examples serve to further illustrate the present disclosure.

Immunofluorescence staining of NUT carcinoma cells Tv-82

Ty-82 cells (JCRB Japan No. 1330) are cultivated in RPMI-1640 with 10 % FCS.

For the assay, cells are seeded in Millipore Chamber slides with 4 wells (MerckMillipore, #PEZGS0416). Cells are then treated with BET inhibitor Compound 1 (diluted in culture medium) for 1 h. Then cells are carefully washed, supplemented with fresh medium (with or without BET inhibitor compound) and cultivated for additional 23 h. Cells are then washed with cold PBS and fixed for 5 min with 4 % PFA. Cells are then washed with PBS and kept at 4 °C until further use. Cells are permeabilized in 0.1 % TX-100, washed with PBS and treated with blocking buffer for 20 min (10 % normal goat serum in 2 % BSA/PBS).

Immunofluorescence staining was done as follows:

• 60 min 1^st antibody rabbit a-NUT 1 :1000 (Cell signaling #3625S) in blocking solution, wash 3 x with PBS.

• Incubate with 2^nd antibody goat anti-rabbit Alexa 488 1 :1000 (Mol. Probes, #A11008) in blocking solution in the dark. Wash 3 x in PBS and mount with ProLong gold with DAPI (life technologies, #P36931).

Pictures are taken on the Laser scanning microscope (LSM700).

Proliferation assay with NUT carcinoma cell line Tv-82

Cell culture:

Tumor cell line Ty-82 was obtained from JCRB (Japanese Cancer Research Resources Bank ),

• 1330). This cell line was cultured according to the manufacturer's instruction and authenticated by short tandem repeat (STR) analysis at Boehringer Ingelheim.

Proliferation assay:

Ty-82 cells are plated in 96-well flat-bottom microtiter plates and incubated overnight at 37 °C in a CO2 incubator. T est compound(s) are added at various concentrations for 96 hours. After 6-hour incubation with Alamar Blue solution (Invitrogen, Carlsbad, CA) at 37 °C, fluorescence is measured (Envision MultiModeReader; PerkinElmer) using an excitation wavelength of 531 nm and emission at 595 nm. Data were fitted by iterative calculation using a sigmoidal curve analysis program (Prism version 3.0; Graph Pad, La Jolla, CA) with variable hill slope. For calculation of GI50 values baseline values from a Tzero plate are fitted in the calculation (cells are plated in 96- well flat-bottom microtiter plates and incubated overnight at 37 °C in a C0₂ incubator. 24 h after plating the cells they are incubated with Alamar Blue solution for 6 h and fluorescence is measured using an excitation wavelength of 531 nm and emission at 595 nm).

PK analysis of BET inhibitor Compound 1 in patient blood

Compound 1 is currently undergoing clinical trials (see ClinicalTrials.gov Identifier NCT02516553 for more details).

For quantification of BET inhibitor plasma concentrations, blood is taken from a forearm vein in an EDTA-anticoagulant blood drawing tube at specific time points. The plasma samples are stored at about - 20 °C or below at the clinical site until shipment on dry ice to the bio-analytical laboratory. Cooling is continued at about - 20 °C or below until analysis.

Concentrations of Compound 1 in form of its free base in plasma (including Cmax) is determined by a validated assay based on liquid chromatography coupled to tandem mass spectrometry (LC- MSMS).

Determination of platelet counts of patients under treatment with BET inhibitor

Compound 1

The analysis of platelet count is performed as part of the safety lab by the investigative sites according to standard procedures. Platelets are measured in EDTA-anticoagulated whole blood. E.g., the test method is electrical impedance and the device is XE-5000 (Sysmex) or XS-1000i (Sysmex).

Platelets were measured pre-treatment and then during treatment on approximately day 1 , 2, 8, 14, 22 and at the end-of-treatment visit for patients in Schedule B, and on days 1 , 2, 8, 15, 21 , 29, and end-of-treatment for patients in Schedule C.

The normal number of platelets in the blood is about 150,000 to 400,000 platelets per microliter (pl_) or 150 to 400 ^c 10⁹/L. A lower-than-normal platelet count is called thrombocytopenia.

Patient profile of patients included in clinical trial

Inclusion criteria:

For all patients

Age 18 years or older at the time of signature of the informed consent;

Life expectancy of at least twelve weeks after the start of the treatment according to the investigator's judgement;

Male or female patients. Women of childbearing potential* must be ready and able to use highly effective methods of birth control per ICH M3(R2) that result in a low failure rate of less than 1 % per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. For women of childbearing potential using a contraceptive pill, an additional barrier method is necessary due to the potential CYP3A4 inducing effect of Compound 1. Male patients having a partner of childbearing potential must use condoms and ensure their partner is using a highly effective method of birth control as described above, during the trial and for at least three months after the end of the trial; *Any female who has experienced menarche and does not meet the criteria for "women not of childbearing potential" as described below.

Women not of childbearing potential are defined as: women who are postmenopausal (twelve months with no menses without an alternative medical cause) or who are permanently sterilized ( e.g ., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy).

- Written informed consent consistent with ICH-GCP and local legislation.

For patients with solid tumours

- Age 18 years or older at the time of signature of the informed consent. For NUT carcinoma (NC) patients, age 15 years or older at the time of signature of the informed consent (in Germany, if NC patients aged 15 to < 18 years are included, their imaging evaluation for the trial will only be with MRI and not with CT scan);

Patients with a histologically or cytologically confirmed diagnosis of an advanced unresectable and/or metastatic solid tumour, who have failed conventional treatment or for whom no therapy of proven efficacy exists, or who are not amenable to standard therapies;

Eastern Cooperative Oncology Group performance score 0 or 1 at the time of screening; Recovery of therapy-related toxicities from previous chemotherapy, tyrosine kinase inhibitors, hormone therapy, immunotherapy, antibodies, vaccine therapy, or radiotherapy to CTCAE < or = grade 1 (with the exception of alopecia, peripheral sensory neuropathy grade 2)

Written informed consent consistent with ICH-GCP and local legislation. For adolescent NC patients aged 15 to < 18 years written assent of the patient and written informed consent of the parents (both or one according to national regulation) or legal guardian of the adolescent o optional for those patients until extension of the MTD cohort, o or the patients in the extension of MTD cohort at the same time points as described below for the expansion phase. For these patients in the extension of the MTD cohort, if they have an accessible lesion for biopsy, they will be offered optional consent for tumour biopsies

In addition, all patients included in the expansion phase (part lb) must: have been diagnosed with one of the fourtypes of tumours selected: small cell lung cancer (SCLC), metastatic castrate resistant prostate cancer (mCRPC), colorectal cancer (CRC) or NUT carcinoma (NC) (for which the "midline" origin is not a prerequisite)

Have a measurable disease (radiated lesions and lesions used for biopsy do not qualify as target lesions), according to RECIST 1.1 (R09-0262) (for NC patients only non- measurable disease is acceptable); or according to PCWG3 (R17-3377) for the mCRPC cohort have progressive disease within the last 6 months, according to RECIST 1.1 according to PCWG3 for the mCRPC cohort

Have a tumour lesion accessible for biopsies (pre- and at steady state under treatment in Cycle 1 , ideally from the same anatomic lesion) (except for mCRPC patients having only bone metastases or for patients with therapeutic INR because of treatment with a vitamin K antagonist or a novel oral anticoagulant. Biopsies are optional for NC patients)

Give written informed consent for two tumour biopsies, one at screening and one after start of treatment, between Day 8 and Day 11 of Cycle 1 (or between day 3 and day 8 if the day of biopsy in Cycle 1 needs to be moved (when applicable)

In patients with DLBCL

Patients with histologically confirmed DLBCL who have failed 2 or more lines of systemic therapy including an anti-CD-20 therapy and an anthracycline or who are not amenable to standard therapies but have an indication for therapy as per investigator's judgement. Standard therapies may also include but are not limited to CAR-T cells therapy, depending on approved therapies in the country where the patient is treated ECOG Performance Status 0, 1 or 2 at the time of screening

Measurable disease (radiated lesions do not qualify as target lesions) according to according to RECIL 2017 on the CT scan part of the FDG/PET-CT scan Recovery of therapy-related toxicities from previous anti-lymphoma therapy to CTCAE <= grade 1 (with the exception of alopecia, peripheral sensory neuropathy grade 2)

- written informed consent for tumour biopsies (optional)

Further inclusion criteria apply

Exclusion criteria:

For all patients

Inability to swallow tablets Second malignancy currently requiring another anti-cancer therapy Serum creatinine greater than 1.5 mg/dL (>132 pmol/L, SI unit equivalent)

Women who are pregnant, nursing, or who plan to become pregnant while in the trial Treatment with other investigational drugs or participation in another clinical interventional trial within the past four weeks or within five times the half-life of the previous investigational drug, whichever is shorter, before start of therapy or concomitant with this trial

Patients unable to comply with the protocol

Patients who are actively abusing alcohol or drugs. Since no alcohol or drug testing is required per protocol, it is at the investigator's discretion to determine abuse.

For patients with solid tumours

- Additional other serious illness, concomitant non-oncological disease (e.g. active infectious disease or known chronic Hepatitis B/Hepatitis C infection and HIV), or ongoing toxicity from prior therapies considered by the investigator to potentially compromise patient's safety in this trial

History or presence of cardiovascular abnormalities deemed clinically relevant by the investigator such as uncontrolled hypertension, congestive heart failure NYHA classification of 3, unstable angina or poorly controlled arrhythmia. Myocardial infarction within 6 months prior to study entry. Left Ventricular Ejection Fraction (LVEF) less than 50 % at baseline

Clinical evidence of symptomatic progressive brain or leptomeningeal disease during the last 28 days before the start of treatment with Compound 1

- Absolute neutrophil count less than 1500/mm^A3 Platelet count less than 100 000/mm^A3

Bilirubin greater than 1.5 mg/dL (>26 pmol/L, SI unit equivalent) (except known Gilbert's syndrome, accepted up to 2 mg/dL or up to 34.2 pmol/L in this case)

- Aspartate amino transferase (AST) and/or alanine amino transferase (ALT) greater than 2.5 times the upper limit of normal (if related to liver metastases, greater than five times the upper limit of normal)

Treatment with other investigational drugs or participation in another clinical interventional trial within the past four weeks (past two weeks for NC patients) or within five times the half-life of the previous investigational drug, whichever is the shorter, before start of therapy or concomitant with this trial Systemic anti-cancer therapy within four weeks (past two weeks for NC patients) or five times the half-life of the drug, whichever is shorter. Radiotherapy given for curative intent or other than palliative radiotherapy within the past four weeks before start of therapy or concomitantly with this trial. This These restrictions does not apply to LHRH agonists or antagonists, steroids (given at a stable dose in the last four weeks) used for palliative intent, bisphosphonates, and denosumab and to palliative radiotherapy (no wash out required)

For patients with DLBCL

Patient is eligible for curative salvage high dose therapy followed by stem cell transplant - Primary central nervous system (CNS) lymphoma or known CNS involvement

Prior allogeneic bone marrow or stem cell transplant High-dose therapy with stem cell support <3 months prior to visit 1 - AST or ALT >2.5 x upper limit of normal (CTCAE grade 2 or higher)

Total bilirubin >1.5 x upper limit of normal (CTCAE grade 2 or higher) - Absolute neutrophil count <1.0 x 10^A9/L(without growth factor support)

Platelets <100 x 10^A9/L (without transfusions)

Significant concurrent medical disease or condition which according to the investigator's judgement would either compromise patient safety or interfere with the evaluation of the safety of the test drug, e.g. symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within 6 months prior to study entry, cardiac arrhythmia requiring therapy with the exception of extra systoles or minor conduction abnormalities Chronic or ongoing infection requiring treatment at the time of enrolment or within the previous two weeks, e.g. active infectious disease or known Hepatitis B/Hepatitis C infection, HIV - Systemic anti-DLBCL therapy within the past two weeks or five times the half-life of the drug, whichever is shorter (palliative radiotherapy and agents used for palliative reasons for example steroids and bisphosphonates, are allowed)

Further exclusion criteria apply

Claims

(a) a loading period on day 1 and a maintenance period on days 2 to 7, or

• optionally, start of a new 14 day cycle on day 1 after the end of the previous 14 day

2. The BET inhibitor for use according to claim 1 , wherein the BET inhibitor is selected from the group consisting of

3. The BET inhibitor for use according to claim 2, wherein the BET inhibitor is Compound 1.

4. The BET inhibitor for use according to any one of claim 1 to 3, wherein the BET inhibitor is administered to the patient once daily during the treatment period.

5. The BET inhibitor for use according to any one of claim 1 to 4, wherein the BET inhibitor is orally administered to the patient during the treatment period.

6. The BET inhibitor for use according to any one of claim 1 to 5, wherein the cancer to be treated is selected from the group consisting of prostate cancer (including but not limited to castration-resistant prostate cancer (CRPC)), bladder cancer, breast cancer (including but not limited to ductal breast cancer), cancers of the Gl tract (including but not limited to colon cancer, colorectal cancer, gastric cancer, pancreatic cancer (including but not limited to pseudopapillary pancreatic carcinoma and pancreatic adenocarcinoma), oesophageal cancer, cholangiocarcinoma, small bowel cancer, duodenal cancer), head and neck cancer (including but not limited to nasopharyngeal cancer), ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, liver cancer (including but not limited to hepatocellular carcinoma), neuroendocrine cancer, melanoma (including but not limited to uveal melanoma), lung cancer (including but not limitied to non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)), NUT carcinoma, lymphoma (including but not limited to diffuse large B- cell lymphoma (DLBCL), leukemias (including but not limited to acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL)), leiomyosarcoma, mesenchymal chondrosarcoma, salivary gland adenocarcinoma, osteosarcoma, adenoid cystic carcinoma, ependymoma, acinic cell carcinoma and merkel cell carcinoma.

7. The BET inhibitor for use according to any one of claim 1 to 6, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is up to about three times the individual daily amount of the BET inhibitor administered to the patient during the maintenance period.

8. The BET inhibitor for use according to any one of claim 1 to 7, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is between about 1.5 times to about three times the individual daily amount of the BET inhibitor administered to the patient during the maintenance period.

9. The BET inhibitor for use according to any one of claim 1 to 6, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is about 4 mg to about 8 mg and higher than each individual daily amount of the BET inhibitor administered to the patient during the maintenance period which is about 2 mg to about 4 mg.

10. The BET inhibitor for use according to any one of claim 1 to 6, wherein each individual daily amount of the BET inhibitor administered to the patient during the loading period is about 4 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is about 2 mg; or each individual daily amount of the BET inhibitor administered to the patient during the loading period is about 5 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is about 2.5 mg; or each individual daily amount of the BET inhibitor administered to the patient during the loading period is about 6 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is about 3 mg; or - each individual daily amount of the BET inhibitor administered to the patient during the loading period is about 7 mg and each individual daily amount of the BET inhibitor administered to the patient during the maintenance period is about 3.5 mg.

11. The BET inhibitor for use according to any one of claim 1 to 10, wherein the BET inhibitor is part of a pharmaceutical composition, the BET inhibitor optionally co-formulated with one or more pharmaceutically acceptable carriers, excipients and/or vehicles.

12. The BET inhibitor for use according to any one of claim 1 to 11 , wherein the treatment further comprises the administration of one or more additional antineoplastic agent(s) which is/are to be administered to the patient.