Improved Anti-cancer treatment regimen

Abstract

The present invention relates to treatment regimens for increasing efficacy and potentecy of anti-cancer agents in the treatment of cancers, in particular to treatment and dosing regimens with improved treatment outcome.

Description

cImproved anti-cancer treatment regimenField of the Invention

[0001] The present invention relates to treatment regimens for increasing efficacy and potentecy of anti-cancer agents in the treatment of cancers, in particular to treatment and dosing regimens with improved treatment outcome.Background of the invention

[0002] Cancer is an overwhelming burden to our society with approximately 14 million new cases of cancer diagnosed in 2014. Despite the introduction of many new treatment modalities / options, de novo or acquired resistance to the applied treatments still represents the major cause of death from cancer.

[0003] For example, colorectal cancer (CRC) is one of the most common cancers in Europe and worldwide over 1.8 million new cases and 881,000 deaths are estimated to occur in 2018. Unfortunately, a large proportion of these patients will develop metastatic disease (mCRC) despite prior adjuvant treatment and approximately 20% of newly diagnosed CRC patients did present with metastatic disease before the introduction of screening.

[0004] The standard of care to patients with local recurrence or mCRC is either surgery and / or chemotherapy and targeted therapy with monoclonal antibodies. For incurable patients, standard drugs are 5-flourouracil and derivatives, oxaliplatin, irinotecan, bevacizumab and panitumumab or cetuximab. When patients progress after exposure to these drugs, the standard is best supportive care, off label use of checkpoint inhibitors if indicated by histomorphological findings (MSS / MSI) or preferably enrollment in early clinical trials. Several other drugs are approved for metastatic colorectal cancer. These drugs are regorafenib, aflibercept, ramucirumab, lonsurf / TAS-102, but because of low efficacy, significant toxicity and lack of predictive markers for patient selection, they are not widely used and are not accepted for use in several countries, including Denmark. In this context, it is important to note that other drugs may have a sound biological rationale for potential effect in colorectal cancer patients and some of these have shown some effect in colorectal cancer in early phase trials but without clinical impact in unselected patients.

[0005] Objective response rate to first line treatment of mCRC is 40 - 50% independent of whether FOLFOX or FOLFIRI treatment is applied. In second line treatment of this disease, the objective response rates drop to below 20% suggesting some degree of cross-resistance between these drugs.

[0006] Thus, one major problem in the treatment of mCRC is the frequent development of drug resistance. In practical terms, this means the cancer continues to either grow during anti-cancer treatment (de novo resistance) or re-grow after an initial response to anti-cancer treatment (acquired resistance).

[0007] Acquired resistance is often accompanied by cross-resistance to other anti-cancer drugs.

[0008] Irinotecan containing treatment is often used in the treatment of mCRC. However, most of the patients rapidly develop resistance to this drug. Upregulation of the ATP-binding cassette super- family G member 2 (ABCG2) drug efflux pump is often observed in irinotecan resistant disease and since the active metabolite of irinotecan, SN38, is a substrate for this efflux pump, ABCG2 upregulation is considered a major resistance mechanism for irinotecan treatment.

[0009] Neutropenia and diarrhea are frequent dose-limiting side effects of irinotecan and may be severe. Irinotecan has also been associated with steatosis, steatohepatitis, and hepatic vascular damage. There is a marked interpatient variability in pharmacodynamics and pharmacokinetics that correlates poorly with body surface area-based dosing. Pharmacokinetic variability has been related to biliary excretion of unconjugated bilirubin. Even modest elevations in serum bilirubin increase the risk for severe neutropenia and diarrhea associated with increased concentrations of SN38.

[0010] The compound SCO-101, also known as NS3728 was first described in WO 2000 / 24707. SCO- 101 has later been shown to be an effective potentiator of a range of anti-cancer agents and is currently being developed for cancer combination therapies, in particular for treatment of resistant cancers. WO 2017 / 198700 describes SCO-101 and its use in combination therapies for treatment of cancers.Summary of the Invention

[0011] Based on clinical evidence from a Phase 2 study, the present inventors have found that a combination drug comprising a regulator compound, such as SCO-101, and one or more anti-cancer agents display promising effects in the treatment of cancer, and in particular for cancers which have previously shown resistance against one or more anti-cancer agents when administered without the regulator compound.

[0012] Accordingly, in a first aspect the present invention provides a combination drug comprising, separately or together, a) one or more anti-cancer agents; and b) a regulator compound which is an UGT1A1 and / or ABCG2 inhibitor, for use in the treatment of cancer in a patient, wherein the one or more anti-cancer agents and the regulator compound are administered during a treatment cycle comprising a plurality of days.

[0013] In a further aspect, the present disclosure provides a method of increasing the plasma drug exposure (AUC) of an anti-cancer agent comprising administering to a patient, receiving the anticancer agent for treatment of a cancer, a regulator compound effectively inhibiting the degradation, clearance, and / or binding of the anti-cancer agent and / or a therapeutically active metabolite thereof, and thereby increasing the plasma drug exposure of an anti-cancer agent.

[0014] In a further aspect, the present disclosure provides a combination drug comprising, separately or together, a) one or more anti-cancer agents, and b) a regulator compound, for use in the treatment of cancer in a patient. In some aspects the present disclosure refers to a combination drug comprising a) one or more anti-cancer agents, and b) a regulator compound for the treatment of cancer in a patient, and in other aspects the present disclosure refers to a regulator compound for the treatment of cancer in a patient, wherein the treatment further comprises administering one or more anti-cancer agents to the patient. The present disclosure thus concerns the effects associated with combined use, where separately or simultaneously administered, of the a) one or more anti-cancer agents and b) the regulator compound in a patient. Hence, the embodiments provided in the present disclosure for the combination drug for use in cancer treatment also apply for the regulator compound for use in the treatment of cancer, wherein the treatment further involves administering one or more anti-cancer agents to the patient.

[0015] In one aspect, a regulator compound is provided for use in the treatment of gastric cancer in a patient in combination with one or more anti-cancer agents.

[0016] In one aspect, a regulator compound is provided for use in increasing the plasma drug exposure (AUC) of an anti-cancer agent in a patient receiving the one or more anti-cancer agents for treatment of a cancer, wherein the regulator compound is an inhibitor of the degradation, clearance, and / or binding of the anti-cancer agent and / or a therapeutically active metabolite thereof, and thereby increasing the plasma drug exposure of the one or more anti-cancer agents.

[0017] In one aspect, a regulator compound is provided for use in the treatment of a cancer, wherein the treatment comprises combination with one or more anti-cancer agents.

[0018] In one aspect, a method of treating cancer in a patient is provided, comprising administering a regulator compound and one or more anti-cancer agents to the patient.Incorporation by reference

[0019] All publications, patents, and patent applications referred to herein are incorporated by reference to the same extent as if each individual publication, patent, or patent application wasc specifically and individually indicated to be incorporated by reference. In the event of a conflict between a term herein and a term in an incorporated reference, the term herein prevails.Description of drawings

[0020] The figures included herein are illustrative and simplified for clarity, and they merely show details which are essential to the understanding of the invention, while other details may have been left out. When using reference numerals in drawings, throughout the specification, claims and drawings the same reference numerals are used for identical or corresponding parts. The figures and drawing include:Figure 1 shows the cell viability (% of untreated control) in response to SN-38 in the ABCG2 high expression cell line SCH and the low expression cell line MKN45, respectively.Figure 2 shows the cell viability (% of untreated control) in response to 20 pM SCO-101, SN-38 and the combination, respectively (96h drug exposure and cell viability assay measured by CellTiter-Glo).Figure 3 shows the Kaplan-Meier curve for the Progression Free Survival (PFS) for the 21 patients in CORIST Part 3 that were evaluable for PFS. The median PFS (mPFS) was 4.6 months. Censoring is displayed with circles.Figure 4 shows the Kaplan-Meier curve for the Progression Free Survival (PFS) for the 15 patients in CORIST Part 3 that were evaluable for PFS separated on the Bilirubin Index (Bl) on Dayl2 / Day5, with a cut point of 0.3. The median PFS (mPFS) is 5.2 months for patients with BI<0.3 and the mPFS for patients with a BI>0.3 is 3.5 months. Censoring is displayed with circles. Patients with no bilirubin index value are excluded from the analysis. Bl < 0.3: "Transient Increase". Median PFS (mPFS) 4.9 months. Bl > 0.3: "Persistent Increase". Median PFS (mPFS) 3.7 months. P=0.48 (The Log-rank test).Figure 5 shows the Kaplan-Meier curve for the Progression Free Survival (PFS) for the 19 patients in CORIST Part 3 that were evaluable for PFS separated on the UGT1A1 genotype. The UGT1A1 genotype analyzed is the "UGT1A1*28", which contains seven TA repeats in the promoter, and these extra TA repeats result in decreased UGT1A1 transcription efficiency leading to reduced UGT1A1 expression. The genotypes are classified into wild type (WT), i.e. no mutations; UGT1A1*28 heterozygote (one allele mutated) or UGT1A1 homozygote (both alleles mutated). The median PFS (mPFS) is 7.0 months for patients with WT UGT1A1, 3.5 months for patients with heterozygote genotype and 2.8 months for patients with homozygote genotype. Patients with no data on UGT1A1 genotype are excluded from the analysis. Censoring is displayed with circles.Detailed Description of the Invention

[0021] The features and advantages of the present disclosure are readily apparent to a person skilledin the art by the below detailed description of embodiments and examples of the invention with reference to the figures and drawings included herein.Definitions

[0022] The term "irinotecan" as used herein refers to a topoisomerase inhibitor of the general formula.Irinotecan is also known under the trade name Camptosar

[0023] The term "SN-38" as used herein refers to a topoisomerase I inhibitor of the general formulaSN-38 is the active metabolite of irinotecan.

[0024] The term "SCO-101" or "NS3728" refers to a compound of the general formula:or a pharmaceutically acceptable salt thereof.

[0025] The term "cancer progression" as used herein to describe that a cancer has progressed despite receiving prior treatment means that hat the cancer has continued to grow, spread, or worsen, even after being treated with specified therapy intended to control or eradicate it.

[0026] The term "anti-cancer agent" as used herein refers to a chemotherapeutic agent, that has activity against a susceptible cancer cell.

[0027] The term "UGT1A1 inhibitor" as used herein refers to a molecule which is capable of binding to human uridine diphosphate (UDP)-glycuronosyl transferase (UGT1A1), particularly in humans or animals and decrease the enzymatic activity of the UGT1A1. UGT1A1, for example found in the liver of humans, gluronidation a range of different molecules hereinunder several anti-cancer agents, bilirubin, and other molecules usually converting them to less active and more water-soluble forms. Whether or not a particular molecule is an UGT1A1 inhibitor can be determined by examining the molecule's IC50 in vitro in a UGT1A1 inhibition assays known in the art.

[0028] The term "ABCG2 inhibitor" as used herein refers to a molecule which is capable of binding to the ABCG2 efflux pump in human or animal cells and thereby reduce it pumping capacity. Efflux pumps are proteinaceous transporters localized in the cytoplasmic membrane of all kinds of cells. They are active transporters, meaning that they require a source of chemical energy to perform their function.

[0029] The term "UGT1A1 substrate" as used herein refers to a molecule which is capable of being chemically transformed by enzymatic aid of uridine diphosphate (UDP)-glycuronosyl transferase (UGT1A1). Typically, a UGT1A1 substrate is capable of being glucuronidated by UGT1A1.

[0030] The term "recommended dose" as used herein refers to the recommended dosage or dose of an anti-cancer agent as approved by a medicines agency, such as the EMA, the FDA or the Danish Medicines Agency. The doses of the anti-cancer agent irinotecan (CAMPTOSAR) recommended by the FDA are:Colorectal cancer combination regimen 1: Irinotecan 125 mg / m2; intravenous infusion over 90 minutes on days 1, 8,15, 22 with Leucovorin 20 mg / m2 intravenous bolus infusion on days 1, 8, 15, 22 followed by 5-Fluorouracil intravenous bolus infusion on days 1, 8, 15, 22 every 6 weeks.Colorectal cancer combination regimen 2: Irinotecan 180 mg / m2 intravenous infusion over 90 minutes on days 1, 15, 29 with LV, 200 mg / m2 intravenous infusion over 2 hours on days 1, 2, 15, 16, 29, 30 followed by 5-FU 400 mg / m2 intravenous bolus infusion on days 1, 2, 15, 16, 29, 30 and 5-FU 600 mg / m2 intravenous infusion over 22 hours on days 1, 2, 15, 16, 29, 30.Colorectal cancer single agent regimen 1: Irinotecan 125 mg / m2 intravenous infusion over 90 minutes on days 1, 8, 15, 22 then 2-week rest. (2.2).cColorectal cancer single agent regimen 2: Irinotecan 350 mg / m2 intravenous infusion over 90 minutes on day 1 every 3 weeks. (2.2)Based on medicines agencies' recommendations as described above, it is known to the skilled person, which dose of an anti-cancer agent is the recommended dose.

[0031] Body surface area (BSA) is commonly used in the calculation of drug dosages and the amounts of fluids to be administered IV in the medical setting. The body surface area is expressed in m2, and a dose in milligram (mg) can thus be normalized according to body surface area, i.e. expressed as mg / m2. For many clinical purposes, BSA is a better indicator of metabolic mass than body weight because it is less affected by abnormal adipose mass. Doses of chemotherapeutic agents are often provided in mg / m2. The typical body surface area is generally taken to be 1.7 m2, but the body surface area depends on more than just height and weight. Other influential factors include the age and gender of the individual. There was an average BSA of 1.73 m2for 3,000 cancer patients from 1990 to 1998 in a European Organisation for Research and Treatment of Cancer (EORTC) database.

[0032] During 2005 there was an average BSA of 1.79 m2 for 3,613 adult cancer patients in the UK. Among them the average BSA for men was 1.91 m2and for women was 1.71 m2. BSA is a long-time term / unit generally practiced and recognized by doctors / oncologists worldwide.

[0033] The term "pharmaceutically acceptable salt" as used herein refers, without limitation, to inorganic and organic acid addition salts such as the hydrochloride derived from hydrochloric acid, the hydrobromide derived from hydrobromic acid, the nitrate derived from nitric acid, the perchlorate derived from perchloric acid, the phosphate derived from phosphoric acid, the sulphate derived from sulphuric acid, the formate derived from formic acid, the acetate derived from acetic acid, the aconate derived from aconitic acid, the ascorbate derived from ascorbic acid, the benzenesulphonate derived from benzensulphonic acid, the benzoate derived from benzoic acid, the cinnamate derived from cinnamic acid, the citrate derived from citric acid, the embonate derived from embonic acid, the enantate derived from enanthic acid, the fumarate derived from fumaric acid, the glutamate derived from glutamic acid, the glycolate derived from glycolic acid, the lactate derived from lactic acid, the maleate derived from maleic acid, the malonate derived from malonic acid, the mandelate derived from mandelic acid, the methanesulphonate derived from methane sulphonic acid, the naphthalene- 2-sulphonate derived from naphtalene-2-sulphonic acid, the phthalate derived from phthalic acid, the salicylate derived from salicylic acid, the sorbate derived from sorbic acid, the stearate derived from stearic acid, the succinate derived from succinic acid, the tartrate derived from tartaric acid, the toluene-p-sulphonate derived from p-toluene sulphonic acid, and the like. Such salts may be formed by procedures well known and described in the art.

[0034] The term "FOLFIRI" used herein refers to a chemotherapy regimen for treatment of cancer,such as colorectal cancer. It is made up of the following drugs FOL-folinic acid (leucovorin), a vitamin B derivative used as a "rescue" drug for high doses of the drug methotrexate but increases the cytotoxicity of 5-fluorouracil; F - fluorouracil (5-FU), a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis; and IRI - irinotecan (Camptosar), a topoisomerase inhibitor, which prevents DNA from uncoiling and duplicating. One recommended dosage regimen consists of: irinotecan (180 mg / m2IV over 90 minutes) concurrently with folinic acid (400 mg / m2[or 2 x 250 mg / m2] IV over 120 minutes) followed by 5-fluorouracil (400-500 mg / m2IV bolus) then 5-fluorouracil (2400-3000 mg / m2intravenous infusion over 46 hours).

[0035] The term "treatment regimen" used herein refers to a method for treating cancer cells and / or tumours comprising cancer cells in a patient that includes administering simultaneously or sequentially therapeutically effective amounts of the regulator compound and the anti-cancer agent(s) of the invention.

[0036] The phrase "therapeutically effective amount" as used herein refers to that amount of a molecule, composition, kit or treatment regimen as a whole that produces some desired local or systemic effect, typically at a reasonable benefit / risk ratio in the context of a treatment regimen or method. The therapeutically effective amount of such substance will vary depending upon the patient and disease condition being treated, the weight and age of the patient, the severity of the disease condition, the manner of administration and the like. For example, certain compositions described herein may be administered in a sufficient amount to produce a desired effect at a reasonable benefit / risk ratio applicable to such treatment.

[0037] The terms "substantially" or "approximately" or "about", as used herein refers to a reasonable deviation around a value or parameter such that the value or parameter is not significantly changed. These terms of deviation from a value should be construed as including a deviation of the value where the deviation would not negate the meaning of the value deviated from. For example, in relation to a reference numerical value the terms of degree can include a range of values plus or minus 10% from that value. For example, deviation from a value can include a specified value plus or minus a certain percentage from that value, such as plus or minus 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from the specified value.

[0038] The term "and / or" as used herein is intended to represent an inclusive "or". The wording X and / or Y is meant to mean both X or Y and X and Y. Further the wording X, Y and / or Z is intended to mean X, Y and Z alone or any combination of X, Y, and Z.

[0039] The terms "comprise" and "include" as used throughout the specification and the accompanying items as well as variations such as "comprises", "comprising", "includes" and "including" are to be interpreted inclusively. These words are intended to convey the possiblec inclusion of other elements or integers not specifically recited, where the context allows.

[0040] The articles "a" and "an" are used herein refers to one or to more than one (i.e., to one or at least one) of the grammatical object of the article. By way of example, "an element" may mean one element or more than one element.

[0041] Terms like "preferably", "commonly", "particularly", and "typically" are not utilized herein to limit the scope of the invention or, unless specifically described otherwise, to imply that certain features are critical, essential, or even important to the structure or function of the invention. Rather, unless specifically described otherwise, these terms are merely intended to highlight alternative or additional features that can or cannot be utilized in a particular embodiment of the present invention.

[0042] The term "de novo resistance" as used herein about cancer cells refers to cancer cells not sensitive to chemotherapy, without any prior exposure to the chemotherapy.

[0043] The term "acquired resistance" as used herein about cancer cells refers to cancer cells that have shown prior sensitivity to a chemotherapy and that have developed reduced sensitivity to the chemotherapy by after treating it with the chemotherapy.

[0044] The term "re-sensitizing" as used herein about cancer cells refers to cancer cells that have shown resistance to chemotherapy - either de novo resistance or acquired resistance, and which cells after an intervention - for example treatment with a drug that reverses sensitivity - regain or develop sensitivity to the chemotherapy drug.

[0045] The term "prior treatment" as used herein: the present disclosure describes patients having received a prior treatment with irinotecan or its active metabolite SN-38, where the cancer has progressed despite the prior treatment. In this situation, the present disclosure may refer to "administering irinotecan in amounts from X% to Y% of the total daily irinotecan dosage of the prior treatment", where X is for instance 50 and y is for instance 100. In the present context, the term "the total daily irinotecan dosage of the prior treatment" is the maximum irinotecan dosage deemed tolerable by the clinician for the particular patient. This dosage will be described in the patient's medical records. In is thus an aspect of the present disclosure to provide a dosage sometimes adjusted according to this particular "total daily irinotecan dosage of the prior treatment" which may vary for example depending on the type of patient and the cancer characteristics.

[0046] The term "bilirubin index" as used herein refers to a patient's rate of bilirubin normalization subsequent to administration of an UGT1A1 inhibitor to the patient. Herein, the bilirubin index is determined subsequent to administration of an UGT1A1 inhibitor to the patient for a number of consecutive days, such as 1, 2, 3, 4, 5, or 6, preferably 6 days. In some embodiments, based on 6 consecutive days of administration with an UGT1A1 inhibitor, the bilirubin index can be determined as the bilirubin serum concentration (unconjugated or total bilirubin) on day 12 divided with thebilirubin serum concentration on day 7 and thus is an indicator of how much the patients' UGT1A1 activity has normalized following cessation of treatment with the UGT1A1 inhibitor, such as SCO-101, and can be determined using bilirubin as a surrogate marker. Based on 6 consecutive days of administration with an UGT1A1 inhibitor, the bilirubin index is determined as the bilirubin serum concentration (unconjugated or total bilirubin) on day 12 divided with the bilirubin serum concentration on day 7 and thus is an indicator of how much the patients' UGT1A1 activity has normalized following cessation of SCO-101 treatment, and can be determined using bilirubin as a surrogate marker. In some embodiments, the bilirubin index is determined by comparison on bilirubin serum concentrations obtained from other days than day 7 and day 12. The bilirubin index is also referred to herein as the CT2 / CTiratio, wherein CTiis the plasma concentration of unconjugated bilirubin in the patient at a time point Tl, whereas CT2 is the plasma concentration of unconjugated bilirubin in the patient at a time point T2 which is after discontinuing administration of the UGT1A1 inhibitor.

[0047] The invention provides for a method of increasing the plasma drug exposure (AUC) of anticancer agent(s) comprising administering to a patient, receiving the anti-cancer agent(s) for treatment of a cancer, a regulator compound effectively inhibiting the degradation, clearance, and / or binding of the anti-cancer agent and / or a therapeutically active metabolite thereof, and thereby increasing the plasma drug exposure of an anti-cancer agent.

[0048] In some embodiments of the invention the administration of the regulator compound also increases the plasma half-life (ty2) of the anti-cancer agent, due to the regulator compounds degradation, clearance, and / or binding of the anti-cancer agent. The body may degrade the anticancer agent through metabolic processes into an inactive or less active metabolite or it may clear the anti-cancer agent modified or unmodified through renal clearance, or the anti-cancer agent may be bound by another compound, thereby masking the anti-cancer agent from being active against a cancer, or a combination of the foregoing. For example, irinotecan undergoes in the body metabolic first conversion into its active metabolite SN-38 by carboxylesterases and subsequently conversion by UGT1A1 glucuronidation into the inactive and more water-soluble SN-38-glucoronide, which is excreted from hepatic cells, e.g. via the ABCG2 efflux pump, and eliminated from the body via biliary excretion to the feces.

[0049] In particular embodiments the method of the invention the plasma drug exposure (AUC) and / or the plasma half-life (ty2) is increased by more that 10%, such as more than 25%, , such as more than 30%, such as more than 40%, such as more than 50%, such as more than 60%, such as more than 70%, such as more than 75%, such as more than 80%, such as more than 90%, such as more than 100%, such more than 120%, such as more than 140%, such as more than 160%, such as more than180%, such as more than 200%, such as more than 220%, such as more than 240%, such as more than 260%, such as more than 280%, such as more than 300%, as compared to if the anti-cancer agent was administered without also administering the regulator compound.

[0050] The administration of the anti-cancer agent provides for a maximum plasma concentration (Cmax) of the anti-cancer agent. In some embodiments of the invention the administration of the regulator compound provides for an increased Cmax of the anti-cancer agent compared to the Cmax when administering the anti-cancer agent without the regulator compound, optionally even compared to the Cmax when using a higher dose of the anti-cancer agent.

[0051] In some embodiments of the invention the plasma drug exposure (AUC) of the administered anti-cancer agent when also administering the regulator compound is increased, even compared to the AUC of the anti-cancer agent being administered at a higher dose without the regulator compound.Regulator Compounds

[0052] The regulator compound is preferably a UGT1A1 and / or ABCG2 inhibitor. The UGT1A1 and / or ABCG2 inhibitor of the present disclosure preferably has an IC50 of 20 pM or less, such as 15 pM or less, such as 10 pM or less, such as 5 pM or less against ABCG2. In one embodiment, the IC50 is 5 pM or less, such as 4 pM or less, such as 3 pM or less, such as 2 pM or less, for example between 0.1 pM and 2.0 pM. In some embodiments, the UGTIAland / or ABCG2 inhibitor is non-competitive, while in other embodiments the UGT1A1 and / or ABCG2 inhibitor is competitive. The regulator compound may also be a SRPK1 inhibitor.

[0053] The regulator compound is in some embodiments SCO-101 of the formula:or a pharmaceutically acceptable salt thereof. SCO-101 has an IC50 towards UGT1A1 of approximately0.1 pM.Patients and selection criteria

[0054] In some embodiments, the patient treated with the combination drug of the presentdisclosure has received prior anti-cancer treatments. In some embodiments, the patient has received a prior treatment with irinotecan or its active metabolite SN-38, and the cancer has progressed despite the prior treatment. In some embodiments, the present disclosure concerns adjusting the dosage of the combination drug based on the patient's prior tolerated dosage, namely the dosage of the prior treatment.

[0055] In some embodiments, the patient has further received a prior treatment with an antimetabolite anti-cancer agent, such as 5-flurouracil or an analog therof, such as capecitabine, and optionally folinic acid, and wherein the cancer has progressed despite the prior treatment.

[0056] In some embodiments, the patient has received a prior treatment with irinotecan, 5- fluorouracil, and folinic acid (FOLFIRI) and wherein the dosage of irinotecan has been reduced at most 33% from the recommended dosage according to the SmPC (corresponding to reduction to a dosage of 67% of the recommended dosage according to the SmPC).

[0057] The patient treated by the present combination drug is in some embodiments selected based on one or more of the following criteria. In some embodiments, these criteria define patients that will benefit significantly from treatment.

[0058] In some embodiments, the patient has received a prior treatment with an oxaliplatincontaining treatment regimen and no indication for re-challenge with oxaliplatin.

[0059] In some embodiments, the patient has not received surgery less than two weeks prior to the treatment.In some embodiments, the patient has one or more or all of the clinical laboratory values selected from the group consisting of: a) absolute neutrophils count (ANC) > 1.5 x 109 / L; b) haemoglobin > 6,0 mmol / L; c) platelets > 100 x 109 / L; d) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN; e) total serum bilirubin < 1.0 ULN; f) alkaline phosphatase < 2.5 x ULN; g) normal kidney function defined by either creatinine (< 1.5 ULN) or calculated creatinine clearance or eGFR within normal limits determined according to local standards; and h) adequate blood clotting function as defined by the International Normalized Ratio (INR) < 1.5.

[0060] In some embodiments, the patient is 18 years of age or older.

[0061] In some embodiments, the patient has colorectal adenocarcinoma, optionally wherein the colorectal adenocarcinoma has been histologically verified.

[0062] In some embodiments, the patient has non-resectable metastatic colorectal cancer. Inaddition to the foregoing patient characteristics, the patient can also be characterized by exclusion criteria, i.e. by not having one or more conditions as outlined in the following:In some embodiments, the patient is characterized by not having one or more of criteria selected from the group consisting of: a) malabsorption syndrome or previous surgeries with resection of the stomach or small intestine, such as ileostomy; b) difficulty in swallowing tablets; c) clinical symptoms of CNS metastases requiring steroid treatment; d) an active infection requiring parenteral or oral antibiotic treatment; e) HIV; f) hepatitis B or C; g) stroke within < 6 months prior to the treatment; h) transient ischemic attach (TIA) within < 6 months prior to the treatment; i) myocardial infarction within < 6 months prior to the treatment; j) unstable angina; k) New York Heart Association (NYHA) Grade II or greater congestive heart failure (CHF); and l) Serious cardiac arrhythmia requiring medication.UGT1A1 genotype

[0063] In some embodiments, the present disclosure concerns treatment of a patient characterized by having a UGT1A1 genotype which is non-mutated on UGT1A1*28, i.e. UGT1A1 wildtype. As demonstrated in Figure 5, there is a significant increase in probability of survival for patients having UGT1A1 wildtype, and consequently, the combination drug of the present disclosure, in particular using the Stage 3 treatment regimen as described herein, is surprisingly effective for this patient population. In some embodiments, the gb PHARM UGT1A1 in vitro diagnostic kit is used for DNA genotyping in terms of the presence of 5TA (UGT1A1*36), 6TA (UGT1A1*1), 7TA (UGT1A1*28) and 8TA (UGT1A1*37) polymorphisms in the UGT1A1 gene. The detection is based on the Q-FRET probe and uses the analysis of melting curves for genotyping.

[0064] In some embodiments, the present disclosure concerns treatment of a patient characterized by having a UGT1A1 genotype which is non-mutated (wildtype) on a gene selected from the group consisting of: 5TA (UGT1A1*36), 6TA (UGT1A1*1), 7TA (UGT1A1*28) and 8TA (UGT1A1*37).

[0065] In some embodiments, the present disclosure concerns treatment of a patient characterized by having a UGT1A1 genotype which is mutated on a gene selected from the group consisting of: 5TA (UGT1A1*36), 6TA (UGT1A1*!), 7TA (UGT1A1*28) and 8TA (UGT1A1*37).cBilirubin index

[0066] In some embodiments, the present disclosure concerns treatment of a patient characterized by a bilirubin index of a threshold value or below, such as 0.3 or below. As shown in Figure 4, treatment of the patient group having a bilirubin index of 0.3 or below display a measureable higher probability of survival than patients with a bilirubin index of more than 0.3.

[0067] Thus, in some embodiments, the present disclosure concerns treatment of a patient characterized by having a bilirubin index of a threshold value or below, such as 0.3 or below, wherein the bilirubin index is determined by a method comprising the consecutive steps of: a) administering a first predefined dosage of the regulator compound, such as SCO-101 to the patient one or more times; b) determining the plasma concentration of unconjugated bilirubin in the patient at a time point Tl; c) discontinuing administration of the regulator compound; d) determining the plasma concentration of unconjugated bilirubin at a time point T2 after discontinuing administration of the regulator compound; e) determining a ratio CTZ / CTI between the T2 and the Tl plasma concentrations of unconjugated bilirubin, wherein the ratio equals the bilirubin index.

[0068] In some embodiments, T2 is 6 days subsequent to Tl, such as wherein T2 is on day 12 of a treatment cycle and Tl is on day 5 of the treatment cycle.

[0069] In some embodiments, bilirubin is used as a biomarker for identifying patients most likely to benefit from a treatment of the present disclosure, i.e. a combination drug. In some embodiments, the bilirubin index determined as described herein is used to identify such patients.

[0070] According to the present disclosure, the threshold value should be understood by the skilled person as a bilirubin index that separates patients having normalized UGT1A1 activity from patients who do not have normalized UGT1A1 activity. The bilirubin index can be determined as described herein, for example as described under "bilirubin index" of the definitions' section.

[0071] In one embodiment, the threshold value is defined such that: a. all values below the threshold value indicates that the patient's UGT1A1 activity has normalized following cessation of treatment with the UGT1A1 inhibitor; and b. all values above the threshold value indicates that the patient's UGT1A1 activity has not normalized following cessation of treatment with the UGT1A1 inhibitor.

[0072] In one embodiment, the threshold value is defined such that: a. CTZ / CTI values below the threshold value indicates a higher UGT1A1 function in the patient andc b. CTZ / CTI values above the threshold value indicates a lower abnormal UGT1A1 function in the patient.

[0073] In one embodiment, the threshold value is defined such that: a. all values below the threshold value indicates that the patient's bilirubin serum concentration has normalized following cessation of treatment with the UGT1A1 inhibitor; and b. all values above the threshold value indicates that the patient's bilirubin serum concentration has not normalized following cessation of treatment with the UGT1A1 inhibitor.

[0074] In one embodiment, the threshold value is defined such that: a. CTZ / CTI values below the threshold value indicates a faster bilirubin serum concentration normalization in the patient and b. CTZ / CTI values above the threshold value indicates a slower bilirubin serum concentration normalization in the patient.

[0075] In one embodiment, the threshold value is a range. In some embodiments, the threshold value is a range from 0.20 to 0.50, such as from 0.20 to 0.25, such as from 0.25 to 0.30, such as from 0.30 to 0.35, such as from 0.35 to 0.40, such as from 0.40 to 0.45, such as from 0.45 to 0.50.

[0076] In some embodiments, the threshold value is from 0.20 to 0.50, such as from 0.20 to 0.25, such as from 0.25 to 0.30, such as from 0.30 to 0.35, such as from 0.35 to 0.40, such as from 0.40 to 0.45, such as from 0.45 to 0.50.

[0077] In some embodiments, the threshold value is from 0.20 to 0.35, such as from 0.20 to 0.21, such as from 0.21 to 0.22, such as from 0.22 to 0.23, such as from 0.23 to 0.24, such as from 0.24 to 0.25, such as from 0.25 to 0.26, such as from 0.26 to 0.27, such as from 0.27 to 0.28, such as from 0.28 to 0.29, such as from 0.29 to 0.30, such as from 0.30 to 0.31, such as from 0.31 to 0.32, such as from 0.32 to 0.33, such as from 0.33 to 0.34, such as from 0.34 to 0.35.

[0078] In one embodiment, the threshold value is from 0.3 to 0.5, such as from 0.3 to 0.4, such as from 0.4 to 0.5, for example 0.4. In one embodiment, the threshold value is 0.3. In one embodiment, the threshold value is 0.5.

[0079] In one embodiment, the threshold value is equivalent to from 0.20 to 0.35 if the second time point is 5 days subsequent to the first time point. In one embodiment, the threshold value is defined such that if the second time point is 5 days subsequent to the first time point, the threshold value is from 0.20 to 0.35.

[0122] In one embodiment, the time point T1 is 48 hours or less from the point in time (Tmax) subsequent to step 1) of the present disclosure, where the plasma concentration of unconjugated bilirubin in the patient is about the maximal plasma concentration of unconjugated bilirubin (Cmax) resulting from administering the first predefined dosage of a regulator compound which is a UGT1A1c inhibitor to the patient one or more times. In the present context, the first predefined dosage of an UGT1A1 inhibitor is administered to the patient one or more times, and the plasma concentration of unconjugated bilirubin is highest approximately directly after the last first predefined dosage of UGT1A1 inhibitor has been administered to the patient. In some embodiments, T1 is the point in time (Tmax) where the plasma concentration of unconjugated bilirubin in the patient is about the maximal plasma concentration of unconjugated bilirubin (Cmax) resulting from administering the first predefined dosage of an UGT1A1 inhibitor to the patient one or more times, or is 48 hours or less from the Tmax of unconjugated bilirubin, such as 36 hours or less, such as 24 hours or less, such as 12 hours or less, such as 6 hours or less, such as 3 hours or less.

[0123] In some embodiments, T1 is the point in time where the plasma concentration of unconjugated bilirubin is about the Cmax of the plasma concentration of unconjugated bilirubin or the point in time where the plasma concentration of unconjugated is within 50% from the Cmax, such as within 45% from the Cmax, such as within 40% from the Cmax, such as within 35% from the Cmax, such as within 30% from the Cmax, such as within 25% from the Cmax, such as within 20% from the Cmax, such as within 15% from the Cmax, such as within 10% from the Cmax, such as within 5% from the Cmax.

[0124] In some embodiments, the T2 is the point in time subsequent to step 3 of the present disclosure where the plasma concentration of unconjugated bilirubin has normalized. In some embodiments, the T2 is from 1 to 10 days subsequent to the Tl, such as from 2 to 9 days, such as from 3 to 8 days, such as from 4 to 7 days, such as from 5 to 6 days subsequent to Tl.

[0125] In some embodiments, the ratio CT2 / CT1 is determined by administering a first predefined dosage of an UGT1A1 inhibitor to the patient one or more times; determining the plasma concentration of unconjugated bilirubin in the patient at a time point Tl; determining the plasma concentration of unconjugated bilirubin at a time point T2 after discontinuing administration of the UGT1A1 inhibitor; and determining a ratio CT2 / CT1 between the T2 and the Tl plasma concentrations of unconjugated bilirubin, wherein no UGT1A1 inhibitor is administered to the patient between the two time points Tl and T2.Anti-cancer agents

[0080] In some embodiments, the regulator compound is provided for use in the treatment of a cancer, wherein the treatment comprises combination with one or more anti-cancer agents.

[0081] The one or more anti-cancer agents of the present disclosure suitably comprise an UGT1A1 and / or an ABCG2 substrate. In some embodiments the one or more anti-cancer agents are selected from the group consisting of topoisomerase inhibitors, antihormone agents, alkylating agents, mitoticc inhibitors, antimetabolites, anti-tumor antibiotics, corticosteroids, targeted anti-cancer therapy agents, differentiating agents, and / or immunotherapy agents, alone or any combination thereof. In particular embodiments the anti-cancer agent(s) is a topoisomerase inhibitor, more particularly a topoisomerase I or topoisomerase II inhibitor. Preferred topoisomerase I inhibitors are those selected from the group consisting of irinotecan, its active metabolite SN-38, and topotecan. In special embodiments the anti-cancer agent is irinotecan and / or its active metabolite SN-38.

[0082] A selected (first) anti-cancer agent can further be administered in combination with one or more further anti-cancer agents. Such further anti-cancer agents include 5-fluorouracil, optionally in combination with folinic acid. In a preferred embodiment the anti-cancer agent includes a combination of irinotecan, 5-fluorouracil, and folinic acid (FOLFIRI).

[0083] In some embodiments, the one or more anti-cancer agents comprise: a) Irinotecan or its active metabolite SN-38. In some embodiments, the one or more anti-cancer agents comprise: a) Irinotecan or its active metabolite SN-38; b) 5-fluorouracil; and c) Folinic acid.

[0084] In some embodiments, the one or more anti-cancer agents further comprise 5-fluorouracil and optionally folinic acid.

[0085] In some embodiments, the treatment further comprises administration of a further anticancer agent.

[0086] In some embodiments, the further anti-cancer agent is a Vascular Endothelial Growth Factor (VEGF) inhibitor or an Epidermal Growth Factor Receptor (EGFR) inhibitor.

[0087] In some embodiments, the EGFR inhibitor is selected from the group consisting of: cetuximab, erlotinib, gefitinib, afatinib, osimertinib, panitumumab, and necitumumab.

[0088] In some embodiments, the VEGF inhibitor is selected from the group consisting of: bevacizumab, ramucirumab, aflibercept, sunitinib, sorafenib, pazopanib, axitinib, cabozantinib, and lenvatinib.

[0089] In some embodiments, the combination drug is provided, wherein: a) the regulator compound is SCO-101; b) the one or more anti-cancer agents comprise Irinotecan or its active metabolite, SN-38, for example as part of FOLFIRI; and wherein the treatment further comprises administration of: c) a VEGF inhibitor, such as bevacizumab.

[0090] In some embodiments, the above combination drug of

[0089] is well suited for treatment of metastatic colorectal cancer, for example as second line treatment.

[0091] In some embodiments, the combination drug is provided, wherein: a) the regulator compound is SCO-101; b) the one or more anti-cancer agents comprise Irinotecan or its active metabolite, SN-38, for examplec as part of FOLFIRI; and wherein the treatment further comprises administration of: c) an EGFR inhibitor, such as cetuximab.

[0092] In some embodiments, the combination drug of

[0091] is well suited for treatment of metastatic colorectal cancer, in particular for treatment of KRAS wild type cancer.

[0093] In some embodiments, the cancer is characterized as a KRAS wild-type cancer.

[0094] In some embodiments, the cancer is metastatic colorectal cancer.

[0095] In some embodiments, the cancer is metastatic colorectal cancer and the treatment is provided to the patient as first line treatment, second line treatment, or third line treatment.Treatment and dosage regimens

[0096] Specific treatment and / or dosage regimes depends on the regulator compound, the nature of the one or more anti-cancer agents and the cancer to be treated. In some embodiments, the regulator compound and / or the one or more anti-cancer agents are administered to the patient daily. Daily administration may be administration once a day or more than once a day, such as twice a day. Daily administration is to be understood as within a 24-hour period of time. The treatment and / or dosage regime may also include treatment cycles comprising periods of treatment interrupted by pauses. Acordingly, a treatment can be repeated a number of times, such as 2 times or more, such as 3 times or more, such as 4 times or more, such as 5 times or more, such as 6 times or more, such as 7 times or more, such as 8 times or more, such as 9 times or more, such as 10 times or more, such as 11 times or more, such as 12 times or more, such as 13 times or more, such as 14 times or more, such as 15 times or more, such as 16 times or more, such as 17 times or more, such as 18 times or more, such as 19 times or more, such as 20 times or more, such as 21 times or more, such as 22 times or more, such as 23 times or more, such as 24 times or more, such as 25 times or more, such as 26 times or more, such as 27 times or more, such as 28 times or more, such as 29 times or more, such as 30 times or more, 31 times or more, such as 32 times or more, such as 33 times or more, such as 34 times or more, such as 35 times or more, such as 36 times or more, such as 37 times or more, such as 38 times or more, such as 39 times or more, such as 40 times or more, such as 41 times or more, such as 42 times or more, such as 43 times or more, such as 44 times or more, such as 45 times or more, such as 46 times or more, such as 47 times or more, such as 48 times or more, such as 49 times or more, such as 50 times or more, such as 51 times or more.

[0097] In one embodiment, the treatment regime further comprises administering to the patient a Granulocyte colony-stimulating factor (G-CSF). The administration of the Granulocyte colonystimulating factor (G-CSF) may be done prior to, simultaneously with, or subsequently to the administration of the anti-cancer agent(s) within a treatment cycle. In some embodiments, the G-CSFc is administered prior to, simultaneously with, or subsequently to the administration of the one or more anti-cancer agents.

[0098] As shown in Example 1, using treatment cycles of SCO-101 and FOLFIRI in selected dosing regimen is surprisingly effective. In particular when SCO-101 is administered on day 2 to 5 and FOLFIRI is administered on day 2 to 4 of a treatment cycle as done in Stage 3 of the study in Example 1. Further, treatment regimens comprising SCO-101 in doses of 150 mg, 200 mg or 250 and FOLFIRI with 50% irinotecan is surprisingly effective. Good effects were observed for the maximum tolerated dose (MTD) of 150 mg SCO-101.Dosing specifics

[0099] Due to the of increase in plasma drug exposure (AUC) and / or the Cmax and / or the ty2of the anti-cancer agent(s) in some embodiments the anti-cancer agent can be administered below the recommended dose according to the Summary of Product Characteristics, while still provide effective treatment at a tolerable toxicity level. In particular the anti-cancer agent(s) dosage can be from 40% to 80% of the Summary of Product Characteristics, such as from 40% to 60% such as from 40 to 41%, such as from 41% to 42%, such as from 42% to 43%, such as from 43% to 44%, such as from 44% to 45%, such as from 45% to 46%, such as from 46% to 47%, such as from 47% to 48%, such as from 48% to 49%, such as from 49% to 50%, such as from 50% to 51%, such as from 51% to 52%, such as from 52% to 53%, such as from 53% to 54%, such as from 54% to 55%, such as from 55% to 56%, such as from 56% to 57%, such as from 57% to 58%, such as from 58% to 59%, such as from 59% to 60%.

[0100] In the embodiment where the regulator compound is SCO-101 or a pharmaceutically acceptable salt thereof and the anti-cancer agent comprise irinotecan and / or its active metabolite SN- 38, the SCO-101 is advantageously administered in amounts / doses which are toxicologically acceptable, yet sufficient for maintaining a plasma concentration of SCO-101 of at least 10 pg / mL for a period of time of at least 24 hours after administration of the irinotecan or the SN-38. In the embodiment where the regulator compound is SCO-101 or a pharmaceutically acceptable salt thereof and the anti-cancer agent comprises irinotecan and / or its active metabolite SN-38, the SCO-101 is advantageously administered in amounts / doses which are toxicologically acceptable, yet sufficient for maintaining a plasma concentration of SCO-101 of at least 5 pg / mL for a period of time of at least 24 hours after administration of the irinotecan or the SN-38.

[0101] In the embodiment where the regulator compound is SCO-101 or a pharmaceutically acceptable salt thereof and the anti-cancer agent comprises irinotecan and / or its active metabolite SN-38, the SCO-101 is advantageously administered in amounts / doses providing an area under the curve (AUC) of SN-38 of more than 385 h*ng / ml from single dose administration of irinotecan or SN-38, such as at least 400 h*ng / ml, such as at least 450 h*ng / ml, such as at least 500 h*ng / ml, such as at least 550 h*ng / ml, such as at least 600 h*ng / ml, such as at least 650 h*ng / ml, such as at least 700 h*ng / ml, such as at least 750 h*ng / ml, such as at least 800 h*ng / ml, such as at least 850 h*ng / ml, such as at least 900 h*ng / ml, such as at least 950 h*ng / ml, such as at least 1000 h*ng / ml, such as at least 1050 h*ng / ml, such as at least 1100 h*ng / ml, such as at least 1150 h*ng / ml, such as at least 1200 h*ng / ml, such as at least 1250 h*ng / ml, such as at least 1300 h*ng / ml, such as at least 1350 h*ng / ml, such as at least 1400 h*ng / ml, such as at least 1450 h*ng / ml, such as at least 1500 h*ng / ml, such as at least 1550 h*ng / ml, such as at least 1600 h*ng / ml, such as at least 1650 h*ng / ml, such as at least 1700 h*ng / ml, such as at least 1750 h*ng / ml, such as at least 1800 h*ng / ml, such as at least 1850 h*ng / ml, such as at least 1900 h*ng / ml, such as at least 1950 h*ng / ml, such as at least 2000 h*ng / ml.

[0102] In one embodiment, the regulator compound is SCO-101 or a pharmaceutically acceptable salt thereof, the administered anti-cancer agent comprises irinotecan and SCO-101 is administered in amounts / doses providing an area under the curve (AUC) of SN-38 of from 390 to 3500 h*ng / ml from single dose administration of irinotecan or SN-38, such as from 400 to 3300 h*ng / ml, such as from 450 to 3100 h*ng / ml, such as from 500 to 2900 h*ng / ml, such as from 550 to 2700 550 h*ng / ml, such as from 600 to 2500 h*ng / ml. In some embodiments, SCO-101 or a pharmaceutically acceptable salt thereof is administered in amounts / doses providing an AUC of SN-38 of 6000 h*ng / m or less.

[0103] In the embodiment where the regulator compound is SCO-101 or a pharmaceutically acceptable salt thereof and the anti-cancer agent comprises from 25 mg / m2 to 180 mg / m2, such as from 25 mg / m2 to 170 mg / m2 irinotecan and / or its active metabolite SN-38, the SCO-101 is advantageously administered in amounts / doses providing an area under the curve (AUC) of SN-38 of more than 385 h*ng / ml from single dose administration of irinotecan or SN-38, such as at least 400 h*ng / ml, such as at least 450 h*ng / ml, such as at least 500 h*ng / ml, such as at least 550 h*ng / ml, such as at least 600 h*ng / ml, such as at least 650 h*ng / ml, such as at least 700 h*ng / ml, such as at least 750 h*ng / ml, such as at least 800 h*ng / ml, such as at least 850 h*ng / ml, such as at least 900 h*ng / ml, such as at least 950 h*ng / ml, such as at least 1000 h*ng / ml, such as at least 1050 h*ng / ml, such as at least 1100 h*ng / ml, such as at least 1150 h*ng / ml, such as at least 1200 h*ng / ml, such as at least 1250 h*ng / ml, such as at least 1300 h*ng / ml, such as at least 1350 h*ng / ml, such as at least 1400 h*ng / ml, such as at least 1450 h*ng / ml, such as at least 1500 h*ng / ml, such as at least 1550 h*ng / ml, such as at least 1600 h*ng / ml, such as at least 1650 h*ng / ml, such as at least 1700 h*ng / ml, such as at least 1750 h*ng / ml, such as at least 1800 h*ng / ml, such as at least 1850 h*ng / ml, such as at least 1900 h*ng / ml, such as at least 1950 h*ng / ml, such as at least 2000 h*ng / ml.

[0104] In the embodiment where the regulator compound is SCO-101 or a pharmaceutically acceptable salt thereof and the anti-cancer agent comprises irinotecan and / or its active metabolite SN-38, the SCO-101 is advantageously administered in amounts / doses maintaining a plasma concentration of SCO-101 of at least 5 pg / mL for a period of time of at least 24 hours after administration of the irinotecan or the SN-38. In other embodiments SCO-101 is administered in amounts / doses which are toxicologically acceptable, yet sufficient for maintaining a plasma concentration of SCO-101 of at least 15 pg / mL, such as at least 20 pg / mL, such as at least 25 pg / mL, such as at least 30 pg / mL, such as 35 pg / mL, such as 40 pg / mL, such as at least 45 pg / mL, such as at least 50 pg / mL, such as at least 60 pg / mL, such as at least 65 pg / mL, such as at least 70 pg / mL, such as at least 75 pg / mL, such as at least 80 pg / mL, such as at least 85 pg / mL, such as at least 90 pg / mL, such as at least 95 pg / mL, such as at least 100 pg / mL for a period of time of at least 24 hours after administration of the irinotecan or the SN-38. Generally, the plasma concentration of SCO-101 should be kept below 200 pg / mL, such as between 30 to 70 pg / mL. In one embodiment, the plasma concentration of SCO-101 should be kept below 200 pg / mL, such as between 10 to 40 pg / mL. In more particular embodiments the SCO-101 or the pharmaceutically acceptable salt thereof is administered in a total daily dose of at least 20 mg, such as at least 30 mg, such as at least 40 mg, such as at least 50 mg, such as at least 60 mg, such as at least 70 mg, such as at least 80 mg, such as at least 90 mg, such as at least 100 mg, such as at least 120 mg, such as at least 140 mg, such as at least 160 mg, such as at least 180 mg, such as at least 200 mg, such as at least 250 mg, such as at least 300 mg, such as at least 350 mg. Generally, the daily dose of SCO-101 should be kept below 400 mg. Preferably, the total daily dose of SCO-101 is 150 mg. The total daily dose of SCO-101 can be administered as a once- daily dose or more preferable in twice-daily doses or even divided into further doses during a 24-hour period to minimize fluctuations on SCO-101 plasma levels.

[0105] In the embodiment where the regulator compound is SCO-101 or a pharmaceutically acceptable salt thereof and the anti-cancer agent comprise irinotecan and / or its active metabolite SN- 38, the irinotecan and / or SN-38 is advantageously administered in amounts / doses which are toxicologically acceptable, yet sufficient for maintaining a plasma concentration of SN-38 of at least 2 ng / ml for at least 48 hours. In some embodiments where the regulator compound is SCO-101 or a pharmaceutically acceptable salt thereof and the anti-cancer agent comprises irinotecan and / or its active metabolite SN-38, the irinotecan and / or SN-38 is advantageously administered in amounts / doses which are toxicologically acceptable, yet sufficient for maintaining a plasma concentration of SN-38 of at least 1 ng / ml for at least 48 hours. In particular such dose(s) provides for a maximum plasma concentration (Cmax) of irinotecan and / or SN-38 of at least 5 ng / ml, such as at least 10 ng / ml, such as at least 15 ng / ml, such as at least 20 ng / ml, such as at least 25 ng / ml, such as atleast 30 ng / ml, such as at least 35 ng / ml, such as at least 40 ng / ml, such as at least 45 ng / ml, such as at least 50 ng / ml, such as at least 55 ng / ml, such as at least 60 ng / ml, such as at least 65 ng / ml, such as at least 70 ng / ml, such as at least 75 ng / ml, such as at least 80 ng / ml, such as at least 85 ng / ml, such as at least 90 ng / ml, such as at least 95 ng / ml, such as at least 100 ng / ml.

[0106] In one embodiment, SCO-101 or a pharmaceutically acceptable salt thereof is administered in amounts / doses providing a plasma concentration of SN-38 of from 1 ng / ml to 40 ng / ml for at least 48 hours, such as from 1 ng / ml to 10 ng / ml, such as from 10 ng / ml to 15 ng / ml, such as from 15 ng / ml to 20 ng / ml, such as from 20 ng / ml to 25 ng / ml, such as from 25 ng / ml to 30 ng / ml, such as from 30 ng / ml to 35 ng / ml, such as from 35 ng / ml to 40 ng / ml.

[0107] In one embodiment, SCO-101 or a pharmaceutically acceptable salt thereof is administered in amounts / doses providing a maximum plasma concentration (Cmax) of SN-38 of from 5 ng / ml to 140 ng / ml, such as from 5 ng / ml to 10 ng / ml, such as from 10 ng / ml to 15 ng / ml, such as from 15 ng / ml to 20 ng / ml, such as from 20 ng / ml to 25 ng / ml, such as from 25 ng / ml to 30 ng / ml, such as from 30 ng / ml to 35 ng / ml, such as from 35 ng / ml to 40 ng / ml, such as from 40 ng / ml to 45 ng / ml, such as from 45 ng / ml to 50 ng / ml, such as from 50 ng / ml to 55 ng / ml, such as from 55 ng / ml to 60 ng / ml, such as from 60 ng / ml to 65 ng / ml, such as from 65 ng / ml to 70 ng / ml, such as from 70 ng / ml to 75 ng / ml, such as from 75 ng / ml to 80 ng / ml, such as from 80 ng / ml to 85 ng / ml, such as from 85 ng / ml to 90 ng / ml, such as from 90 ng / ml to 95 ng / ml, such as from 95 ng / ml to 100 ng / ml, such as from 100 ng / ml to 105 ng / ml, such as from 105 ng / ml to 110 ng / ml, such as from 110 ng / ml to 115 ng / ml, such as from 115 ng / ml to 120 ng / ml, such as from 120 ng / ml to 125 ng / ml, such as from 125 ng / ml to 130 ng / ml, such as from 130 ng / ml to 135 ng / ml, such as from 135 ng / ml to 140 ng / ml.

[0108] In some embodiments, the plasma concentration of SN-38 should be kept below 150 ng / mL. In some embodiments, irinotecan is administered in amounts from 20% to 95% of the recommended dose according to the Summary of Product Characteristics, such as from 20% to 25%, such as from 25% to 30%, such as from 30% to 35%, such as from 35% to 40%, such as from 40% to 45%, such as from 45% to 50%, such as from 50% to 55%, such as from 55% to 60%, such as from 60% to 65%, such as from 65% to 70%, such as from 70% to 75%, such as from 75% to 80%, such as from 80% to 85%, such as from 85% to 90%, such as from 90% to 95%. In further embodiments the irinotecan and / or SN-38 is administered in a total daily dose which is at most 40% to 80% of the recommended dose according to the Summary of Product Characteristics, such as at most 40% to 60% such as from 40 to 41%, such as from 41% to 42%, such as from 42% to 43%, such as from 43% to 44%, such as from 44% to 45%, such as from 45% to 46%, such as from 46% to 47%, such as from 47% to 48%, such as from 48% to 49%, such as from 49% to 50%, such as from 50% to 51%, such as from 51% to 52%, such as from 52% to 53%, such as from 53% to 54%, such as from 54% to 55%, such as from 55% to 56%, suchas from 56% to 57%, such as from 57% to 58%, such as from 58% to 59%, such as from 59% to 60%, such as from 60% to 61%, such as from 61% to 62%, such as from 62% to 63%, such as from 63% to 64%, such as from 64% to 65%, such as from 65% to 66%, such as from 66% to 67%, such as from 67% to 68%, such as from 68% to 69%, such as from 69% to 70%, such as from 70% to 71%, such as from 71% to 72%, such as from 72% to 73%, such as from 73% to 74%, such as from 74% to 75%, such as from 75% to 76%, such as from 76% to 77%, such as from 77% to 78%, such as from 78% to 79%, such as from 79% to 80% of 180 mg / m2. More particularly, the irinotecan and / or SN-38 is administered in a total daily dose of less than 110 mg / m2. More particularly, the irinotecan and / or SN-38 is administered in a total daily dose of 110 mg / m2 or less. In some embodiments, the irinotecan and / or SN-38 is administered in a total daily dose of 120 mg / m2 or less. In some embodiments, the irinotecan and / or SN-38 is administered in a total daily dose of 130 mg / m2 or less. In some embodiments, the irinotecan and / or SN-38 is administered in a total daily dose of 140 mg / m2 or less. In some embodiments, the irinotecan and / or SN-38 is administered in a total daily dose of 150 mg / m2 or less. In some embodiments, the irinotecan and / or SN-38 is administered in a total daily dose of 160 mg / m2 or less. In some embodiments, the irinotecan and / or SN-38 is administered in a total daily dose of 170 mg / m2 or less. In some embodiments, the irinotecan and / or SN-38 is administered in a total daily dose of 180 mg / m2 or less. Similar to dosing SCO-101, the total daily dose of irinotecan and / or SN-38 can be administered as a once-daily dose or as twice-daily doses of a lesser amount or even divided into further doses during a 24-hour period to minimize fluctuations in irinotecan and / or SN-38 plasma levels.

[0109] In some embodiments, SCO-101 or a pharmaceutically acceptable salt thereof is administered in a total daily dose of from 20 mg to 400 mg, such as from 50 mg to 350 mg, such as from 100 mg to 300 mg; and the anti-cancer agent, such as irinotecan, is administered in a total daily dose of 110 mg / m2 or less, such as 100 mg / m2 or less, such as 90 mg / m2 or less, such as 80 mg / m2 or less, such as 70 mg / m2 or less, such as 60 mg / m2 or less.

[0110] Amounts with respect to the regulator compound, such as SCO-101 are based on the non-salt form of the compound, for example the free acid of SCO-101.

[0111] In some embodiments, the regulator compound is SCO-101 or a pharmaceutically acceptable salt thereof, the administered anti-cancer agent comprises from 25 mg / m2 to 180 mg / m2, such as from 25 mg / m2 to 170 mg / m2 irinotecan and wherein the SCO-101 is administered in amounts / doses providing an area under the curve (AUC) of SN-38 of more than 385 h*ng / ml from single dose administration of irinotecan or SN-38, such as at least 400 h*ng / ml, such as at least 450 h*ng / ml, such as at least 500 h*ng / ml, such as at least 550 h*ng / ml, such as at least 600 h*ng / ml, such as at least 650 h*ng / ml, such as at least 700 h*ng / ml, such as at least 750 h*ng / ml, such as at least 800 h*ng / ml,such as at least 850 h*ng / ml, such as at least 900 h*ng / ml, such as at least 950 h*ng / ml, such as at least 1000 h*ng / ml, such as at least 1050 h*ng / ml, such as at least 1100 h*ng / ml, such as at least 1150 h*ng / ml, such as at least 1200 h*ng / ml, such as at least 1250 h*ng / ml, such as at least 1300 h*ng / ml, such as at least 1350 h*ng / ml, such as at least 1400 h*ng / ml, such as at least 1450 h*ng / ml, such as at least 1500 h*ng / ml, such as at least 1550 h*ng / ml, such as at least 1600 h*ng / ml, such as at least 1650 h*ng / ml, such as at least 1700 h*ng / ml, such as at least 1750 h*ng / ml, such as at least 1800 h*ng / ml, such as at least 1850 h*ng / ml, such as at least 1900 h*ng / ml, such as at least 1950 h*ng / ml, such as at least 2000 h*ng / ml.

[0112] In some embodiments, the regulator compound is SCO-101 or a pharmaceutically acceptable salt thereof administered in a total daily dose of at least 20 mg, such as at least 30 mg, such as at least 40 mg, such as at least 50 mg, such as at least 60 mg, such as at least 70 mg, such as at least 80 mg, such as at least 90 mg, such as at least 100 mg, such as at least 120 mg, such as at least 140 mg, such as at least 160 mg, such as at least 180 mg, such as at least 200 mg, such as at least 250 mg, such as at least 300 mg, such as at least 350 mg.

[0113] In some embodiments, the regulator compound is SCO-101 or a pharmaceutically acceptable salt thereof administered in a total daily dose of from 20 mg to 400 mg, such as from 50 mg to 350 mg, such as from 100 mg to 300 mg. In some embodiments, the regulator compound is SCO-101 or a pharmaceutically acceptable salt thereof administered in a total daily dose of 100 mg, 150 mg, 200 mg, or 250 mg. In some embodiments, the regulator compound is SCO-101 administered in a total daily dose of 250 mg.

[0114] In some embodiments, irinotecan is administered in amounts from 20% to 100% of the recommended dose according to the Summary of Product Characteristics, such as from 20% to 25%, such as from 25% to 30%, such as from 30% to 35%, such as from 35% to 40%, such as from 40% to 45%, such as from 45% to 50%, such as from 50% to 55%, such as from 55% to 60%, such as from 60% to 65%, such as from 65% to 70%, such as from 70% to 75%, such as from 75% to 80%, such as from 80% to 85%, such as from 85% to 90%, such as from 90% to 95%, such as from 95% to 100%.

[0115] In some embodiments, irinotecan is administered in amounts from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, such as from 40 to 41%, such as from 41% to 42%, such as from 42% to 43%, such as from 43% to 44%, such as from 44% to 45%, such as from 45% to 46%, such as from 46% to 47%, such as from 47% to 48%, such as from 48% to 49%, such as from 49% to 50%, such as from 50% to 51%, such as from 51% to 52%, such as from 52% to 53%, such as from 53% to 54%, such as from 54% to 55%, such as from 55% to 56%, such as from 56% to 57%, such as from 57% to 58%, such as from 58% to 59%, such as from 59% to 60%.

[0116] In some embodiments, irinotecan is administered in amounts from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, such as from 40 to 41%, such as from 41% to 42%, such as from 42% to 43%, such as from 43% to 44%, such as from 44% to 45%, such as from 45% to 46%, such as from 46% to 47%, such as from 47% to 48%, such as from 48% to 49%, such as from 49% to 50%, such as from 50% to 51%, such as from 51% to 52%, such as from 52% to 53%, such as from 53% to 54%, such as from 54% to 55%, such as from 55% to 56%, such as from 56% to 57%, such as from 57% to 58%, such as from 58% to 59%, such as from 59% to 60%.

[0117] In some embodiments, the irinotecan is administered in a total daily dose of of 170 mg / m2 or less, such as a total daily dose of 160 mg / m2 or less, such as a total daily dose of 150 mg / m2 or less, such as a total daily dose of 140 mg / m2 or less, such as a total daily dose of 130 mg / m2 or less, such as a total daily dose of 120 mg / m2 or less, such as a total daily dose of 110 mg / m2 or less.

[0118] In some embodiments, the irinotecan is administered in one daily dose of less than 110 mg / m2. In some embodiments, irinotecan is administered in amounts from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, and 5-fluorouracil and folinic acid each administered in amounts from 80% to 100% of the recommended dose according to the Summary of Product Characteristics. In some embodiments, the one or more anti-cancer agents comprise irinotecan administered in a total daily dose of 50% of the recommended dose according to the Summary of Product Characteristics on a first day, and then subsequently escalated to 65% of the recommended dose according to the Summary of Product Characteristics followed by 80% of the recommended dose according to the Summary of Product Characteristics.

[0119] In some embodiments, the regulator compound is SCO-101 and administered in a total daily dose of 150 mg, 200 mg, or 250 mg.

[0120] In preferred embodiments, the regulator compound is SCO-101 and administered in a total daily dose of 250 mg in a treatment cycle where SCO-101 is administered daily for four consecutive days and the anti-cancer agent comprises FOLFIRI administered daily on the same days as SCO-101 except for the fourt day. In this case, SCO-101 is administered e.g. on day 2, 3, 4, and 5, and FOLFIRI is administered e.g. on day 2, 3, and 4. In some embodiments of this particular treatment regimen, the Irinotecan dose of FOLFIRI is from 40 to 60% of 180 mg / m2, such as 50%.Dosing based on prior treatment

[0121] In some embodiments, the one or more anti-cancer agents comprise irinotecan and the treatment comprises administering irinotecan in amounts from 50% to 100% of the total daily irinotecan dosage of the prior treatment, such as from 50% to 55%, such as from 55% to 60%, such asfrom 60% to 65%, such as from 65% to 70%, such as from 70% to 75%, such as from 75% to 80%, such as from 80% to 85%, such as from 85% to 90%, such as from 90% to 95%, such as from 95% to 100%.

[0122] In some embodiments, the one or more anti-cancer agents comprise irinotecan and the treatment comprises administering irinotecan in an amount from 50% to 100% of the total daily irinotecan dosage of the prior treatment, such as from 50% to 51%, such as from 51% to 52%, such as from 52% to 53%, such as from 53% to 54%, such as from 54% to 55%, such as from 55% to 56%, such as from 56% to 57%, such as from 57% to 58%, such as from 58% to 59%, such as from 59% to 60%, such as from 60% to 61%, such as from 61% to 62%, such as from 62% to 63%, such as from 63% to 64%, such as from 64% to 65%, such as from 65% to 66%, such as from 66% to 67%, such as from 67% to 68%, such as from 68% to 69%, such as from 69% to 70%, such as from 70% to 71%, such as from 71% to 72%, such as from 72% to 73%, such as from 73% to 74%, such as from 74% to 75%, such as from 75% to 76%, such as from 76% to 77%, such as from 77% to 78%, such as from 78% to 79%, such as from 79% to 80%, such as from 80% to 81%, such as from 81% to 82%, such as from 82% to 83%, such as from 83% to 84%, such as from 84% to 85%, such as from 85% to 86%, such as from 86% to 87%, such as from 87% to 88%, such as from 88% to 89%, such as from 89% to 90%, such as from 90% to 91%, such as from 91% to 92%, such as from 92% to 93%, such as from 93% to 94%, such as from 94% to 95%, such as from 95% to 96%, such as from 96% to 97%, such as from 97% to 98%, such as from 98% to 99%, such as from 99% to 100%.

[0123] In some embodiments, the treatment further comprises 5-fluorouracil and optionally folinic acid. In some embodiments the treatment is FOLFIRI.

[0124] The following section on treatment cycles include further treatments where the dosing is based on a prior treatment.Treatment cycles

[0125] In some embodiments, the one or more anti-cancer agents and the regulator compound are administered during a treatment cycle comprising a plurality of days.

[0126] In some embodiments, the treatment cycle comprises administering the regulator compound on day X of the treatment cycle, and then administering the regulator compound each following day for a number of consecutive days, wherein X is 1 or 2.

[0127] In some embodiments, the number with respect to regulator compound is from 3 to 6, such as from 3 to 4, such as from 4 to 5, or such as from 5 to 6.

[0128] In some embodiments, the treatment cycle comprises administering the one or more anticancer agents on day Y of the treatment cycle, and then administering the one or more anti-cancer agents each following day for a number of consecutive days, wherein Y is any number from 1 to 7,c such as from 1 to 2, such as from 2 to 3, such as from 3 to 4, such as from 4 to 5, such as from 5 to 6, such as from 6 to 7.

[0129] In some embodiments, the number with respect to one or more anti-cancer agents is from 2 to 5, such as from 2 to 3, such as from 3 to 4, or such as from 4 to 5.Specific treatment regimens

[0130] In some embodiments, the treatment cycle comprises: a) a total daily dose of 150 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose irinotecan of from 50% to 100% of the total daily dosage of irinotecan of the prior treatment, for example from 50% to 99% of the total daily dosage of irinotecan of the prior treatment, such as from 50% to 90%, for example 65% or 80%, administered each day from day 5 to and including day 7.

[0131] In some embodiments, the treatment cycle comprises: a) a total daily dose of 100 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose irinotecan of 50% to 100% of the total daily dosage of irinotecan of the prior treatment, for example from 50% to 99% of the total daily dosage of irinotecan of the prior treatment, such as from 50% to 90%, for example 65% or 80%, administered each day from day 5 to and including day 7.

[0132] In some embodiments, the treatment cycle comprises: a) a total daily dose of 150 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose of irinotecan of from 40% to 95% of the total daily dosage of irinotecan of the prior treatment, for example from 50% to 90%, such as from 50 to 80%, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the total daily dosage of 5- fluorouracil and folinic acid of the prior treatment, administered each day from day 2 to and including day 4.

[0133] In some embodiments, the treatment cycle comprises: a) a total daily dose of 200 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose of irinotecan of from 40% to 95% of the total daily dosage of irinotecan of the prior treatment, for example from 50% to 90%, such as from 50 to 80%, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the total daily dosage of 5- fluorouracil and folinic acid of the prior treatment, administered each day from day 2 to and including day 4.

[0134] In some embodiments, the treatment cycle comprises: a) a total daily dose of 200 mg SCO-101 on each day from day 2 to and including day 5;- 1 -b) a total daily dose of irinotecan of from 40% to 95% of the total daily dosage of irinotecan of the prior treatment, for example from 50% to 90%, such as from 50 to 80%, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the total daily dosage of 5- fluorouracil and folinic acid of the prior treatment, administered each day from day 2 to and including day 4.

[0135] In some embodiments, the treatment cycle comprises: a) a total daily dose of 250 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose of irinotecan of from 40% to 95% of the total daily dosage of irinotecan of the prior treatment, for example from 50% to 90%, such as from 50 to 80%, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the total daily dosage of 5- fluorouracil and folinic acid of the prior treatment, administered each day from day 2 to and including day 4.

[0136] In some embodiments, the treatment cycle comprises: a) a total daily dose of 150 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose irinotecan, 5-fluorouracil and folinic acid (FOLFIRI) of from 60% to 90% of the recommended dose according to the Summary of Product Characteristics, for example 65% or 80%, administered each day from day 5 to and including day 7.

[0137] In some embodiments, the treatment cycle comprises: a) a total daily dose of 100 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose irinotecan, 5-fluorouracil and folinic acid (FOLFIRI) of 50% to 90% of the recommended dose according to the Summary of Product Characteristics, for example 50%, administered each day from day 5 to and including day 7.

[0138] In some embodiments, the treatment cycle comprises: a) a total daily dose of 150 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose of irinotecan of from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the recommended dose according to the Summary of Product Characteristics, administered each day from day 2 to and including day 4.

[0139] In some embodiments, the treatment cycle comprises: a) a total daily dose of 200 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose of irinotecan of from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the recommended dose according to the Summary of Product Characteristics, administered each day from day 2 to and including day 4.

[0140] In some embodiments, the treatment cycle comprises: a) a total daily dose of 200 mg SCO-101 on each day from day 2 to and including day 5; b) a total daily dose of irinotecan of from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the recommended dose according to the Summary of Product Characteristics, administered each day from day 2 to and including day 4.

[0141] In some embodiments, the treatment cycle comprises: a) a total daily dose of 250 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose of irinotecan of from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the recommended dose according to the Summary of Product Characteristics, administered each day from day 2 to and including day 4.

[0142] In some embodiments, the use comprises from 1 to 30 treatment cycles, such as from 1 to 2, such as from 2 to 3, such as from 3 to 4, such as from 4 to 5, such as from 5 to 6, such as from 6 to 7, such as from 7 to 8, such as from 8 to 9, such as from 9 to 10, such as from 10 to 11, such as from 11 to 12, such as from 12 to 13, such as from 13 to 14, such as from 14 to 15, such as from 15 to 16, such as from 16 to 17, such as from 17 to 18, such as from 18 to 19, such as from 19 to 20, such as from 20 to 21, such as from 21 to 22, such as from 22 to 23, such as from 23 to 24, such as from 24 to 25, such as from 25 to 26, such as from 26 to 27, such as from 27 to 28, such as from 28 to 29, such as from 29 to 30 treatment cycles.

[0143] In some embodiments, the treatment cycle comprises: a) a total daily dose of 250 mg SCO-101 on each day from day 2 to and including day 5; b) a total daily dose of irinotecan of from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, for example 50%, and a total daily dose of 5- fluorouracil and folinic acid of from 90% to 100% of the recommended dose according to the Summary of Product Characteristics, administered each day from day 2 to and including day 4.

[0144] In some embodiments, the treatment cycle comprises: a) a total daily dose of 250 mg SCO-101 on each day from day 1 to and including day 4; b) a total daily dose of irinotecan of from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, for example 50%, and a total daily dose of 5- fluorouracil and folinic acid of from 90% to 100% of the recommended dose according to the Summary of Product Characteristics, administered each day from day 1 to and including day 3.cCancers

[0145] Cancers, which can advantageously be treated by the method of the invention, include but is not limited to, cancers which forms solid tumors, such as sarcomas, carcinomas and lymphomas. In some embodiments the cancer is or know to become a metastatic cancer. In some embodiments, the cancer is a solid tumor, optionally sarcoma, carcinoma and / or lymphoma.

[0146] In some embodiments the cancer is selected from the group consisting of colorectal cancer, breast cancer, lung cancer (including non small cell lung cancer and small cell lung cancer), glioblastomas, head and neck cancers, malignant melanomas, basal cell skin cancer, squamous cell skin cancer, liver cancer, pancreatic cancer, prostate cancer, anal cancer, cervix uteri cancer, bladder cancer, corpus uteri cancer, ovarian cancer, gall bladder cancer, leukemia's (including myeloid and lymphatic leukemia), and / or myelomatosis. In further embodiments the cancer includes metastatic colorectal cancer; metastatic pancreatic cancer and / or metastatic breast cancer.

[0147] In some embodiments, the cancer is selected from the group consisting of colorectal cancer, breast cancer, gastric cancer, lung cancer (including non small cell lung cancer and small cell lung cancer), glioblastomas, head and neck cancers, malignant melanomas, basal cell skin cancer, squamous cell skin cancer, liver cancer, pancreatic cancer, prostate cancer, anal cancer, cervix uteri cancer, bladder cancer, corpus uteri cancer, ovarian cancer, gall bladder cancer, leukemia's (including myeloid and lymphatic leukemia), and / or myelomatosis.

[0148] In some embodiments the regulator compound re-sensitises the cancer, especially resistant cancer to the anti-cancer agent.

[0149] In some embodiments, the cancer is colorectal cancer, such as metastatic colorectal cancer.In some embodiments, the cancer is gastric cancer, such as metastatic gastric cancer. In some embodiments, the cancer is gastric cancer and the one or more anti-cancer agents comprise irinotecan. In some embodiments, the cancer is gastric cancer and the one or more anti-cancer agents does not comprise leucovorin and / or 5-fluorouracil. In some embodiments, the cancer is gastric cancer and the one or more anti-cancer agents comprise irinotecan and does not comprise leucovorin and / or 5-fluorouracil.

[0150] In some embodiments, the cancer is pancreatic cancer, such as metastatic pancreatic cancer. In some embodiments, the cancer is breast cancer, such as metastatic breast cancer.

[0151] In some embodiments, the cancer is a resistant cancer which is resistant to the anti-cancer agent when administered alone. In particlar embodiments the cancer to be treated is or becomes resistant to the anti-cancer agent when administered without the regulator compound of the invention. Such resistance may be de novo resistance and / or it may be an acquired resistance.

[0152] In some embodiments, the cancer expresses ABCG2. In some embodiments, the cancer is gastric cancer expressing ABCG2. In some embodiments, the cancer is over-expressing ABCG2, for example gastric cancer over-expressing ABCG2. In some embodiments, the cancer expressing ABCG2 has an expression level of at least 5%, such as at least 6%, such as at least 7%, such as at least 8%, such as at least 9%, such as at least 10%.Combination drugs

[0153] In a further aspect the invention provides a combination drug comprising, separately or together, a) one or more anti-cancer agents, and b) a regulator compound, for use in the treatment of cancer. In some embodiments, the combination drug is provided wherein the amount of the regulator compound effectively increases the plasma drug exposure (AUC) of the one or more anti-cancer agents when administering the combination drug to a patient.

[0154] In some embodiments, the treatment comprises sequential or simultaneous administration of the one or more anti-cancer agents and the regulator compound.

[0155] In some embodiments, a regulator compound is provided for use in the treatment of cancer. In some embodiments, the regulator is provided for use in the treatment of gastric cancer. In some embodiments, the regulator compound is SCO-101 and the cancer is gastric cancer. In further embodiments, the regulator compound is SCO-101 and the cancer is gastric cancer, and the one or more anti-cancer agents comprise irinotecan or its active metabolite SN-38, and optionally 5- fluorouracil and folinic acid.

[0156] In preferred embodiments, a combination drug is provided comprising, separately or together, a) irinotecan; and b) a regulator compound, wherein the regulator compound is SCO-101 or a pharmaceutically acceptable salt thereof, for use in the treatment of metastatic colorectal cancer in a patient, wherein irinotecan and the regulator compound are administered during a treatment cycle comprising a plurality of days, for example wherein the regulator compound is administered for from 3 to 5 consecutive days, such as 4 consecutive days. In some particular embodiments, the daily dose of SCO-101 is 250 mg.Selected embodiments1. A combination drug comprising, separately or together, a) one or more anti-cancer agents; and b) a regulator compound; for use in the treatment of cancer in a patient.2. The combination drug for use of embodiment 1, wherein the regulator compound is an UGT1A1 and / or ABCG2 inhibitor.3. The combination drug for use of any preceding embodiment, wherein the regulator compound is SCO-101 of the formula:or a pharmaceutically acceptable salt thereof.4. The combination drug for use of any preceding embodiment, wherein the patient has received a prior treatment with irinotecan or its active metabolite SN-38, and the cancer has progressed despite the prior treatment.5. The combination drug for use of any preceding embodiment, wherein the patient has further received a prior treatment with an antimetabolite anti-cancer agent, such as 5-flurouracil or an analog therof, such as capecitabine, and optionally folinic acid, and wherein the cancer has progressed despite the prior treatment.6. The combination drug for use of any preceding embodiments, wherein the patient has received a prior treatment with irinotecan, 5-fluorouracil, and folinic acid (FOLFIRI) and wherein the dosage of irinotecan has been reduced at most 33% from the recommended dosage according to the SmPC (corresponding to reduction to a dosage of 67% of the recommended dosage according to the SmPC).7. The combination drug for use of any preceding embodiments, wherein the patient has received a prior treatment with an oxaliplatin-containing treatment regimen and has no indication for re-challenge with oxaliplatin.8. The combination drug for use of any preceding embodiment, wherein the patient has not received surgery less than two weeks prior to the treatment.9. The combination drug for use of any preceding embodiment, wherein the patient has one or more or all of the clinical laboratory values selected from the group consisting of: a) absolute neutrophils count (ANC) > 1.5 x 109 / L; b) haemoglobin > 6,0 mmol / L; c) platelets > 100 x 109 / L; d) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN; e) total serum bilirubin < 1.0 ULN; f) alkaline phosphatase < 2.5 x ULN; g) normal kidney function defined by either creatinine (< 1.5 ULN) or calculated creatinine clearance or eGFR within normal limits determined according to local standards; and h) adequate blood clotting function as defined by the International Normalized Ratio (INR) < 1.5.10. The combination drug for use of any preceding embodiment, wherein the patient is 18 years of age or older.11. The combination drug for use of any preceding embodiment, wherein the patient has colorectal adenocarcinoma, optionally wherein the colorectal adenocarcinoma has been histologically verified.12. The combination drug for use of any preceding embodiment, wherein the patient has non- resectable metastatic colorectal cancer.13. The combination drug for use of any preceding embodiment, wherein the patient is characterized by having a UGT1A1 genotype which is non-mutated (wildtype) on a gene selected from the group consisting of: 5TA (UGT1A1*36), 6TA (UGT1A1*1), 7TA (UGT1A1*28) and 8TA (UGT1A1*37).14. The combination drug for use of any preceding embodiment, wherein the patient ischaracterized by having a UGT1A1 genotype which is mutated on a gene selected from the group consisting of: 5TA (UGT1A1*36), 6TA (UGT1A1*1), 7TA (UGT1A1*28) and 8TA (UGT1A1*37).15. The combination drug for use of any preceding embodiment, wherein the patient is characterized by having a bilirubin index of a threshold value or below, wherein the bilirubin index is determined by a method comprising the consecutive steps of: a) administering a first predefined dosage of the regulator compound, such as SCO-101 to the patient one or more times; b) determining the plasma concentration of unconjugated bilirubin in the patient at a time point Tl; c) discontinuing administration of the regulator compound; d) determining the plasma concentration of unconjugated bilirubin at a time point T2 after discontinuing administration of the regulator compound; e) determining a ratio CTZ / CTI between the T2 and the Tl plasma concentrations of unconjugated bilirubin, wherein the ratio equals the bilirubin index.16. The combination drug for use according to embodiment 15, wherein the threshold value is a range.17. The combination drug for use according to any one of embodiments 15-16, wherein the threshold value is a range from 0.20 to 0.50, such as from 0.20 to 0.25, such as from 0.25 to 0.30, such as from 0.30 to 0.35, such as from 0.35 to 0.40, such as from 0.40 to 0.45, such as from 0.45 to 0.50.18. The combination drug for use according to embodiment 15, wherein the threshold value is from 0.20 to 0.35, such as from 0.20 to 0.21, such as from 0.21 to 0.22, such as from 0.22 to 0.23, such as from 0.23 to 0.24, such as from 0.24 to 0.25, such as from 0.25 to 0.26, such as from 0.26 to 0.27, such as from 0.27 to 0.28, such as from 0.28 to 0.29, such as from 0.29 to 0.30, such as from 0.30 to 0.31, such as from 0.31 to 0.32, such as from 0.32 to 0.33, such as from 0.33 to 0.34, such as from 0.34 to 0.35.19. The combination drug for use according to embodiment 15, wherein the threshold value is 0.3.20. The combination drug for use according to any one of embodiments 15-19, wherein T2 is 6days subsequent to Tl, such as wherein T2 is on day 12 of a treatment cycle and T1 is on day 5 of the treatment cycle.21. The combination drug for use of any preceding embodiment, wherein the patient is characterized by not having one or more of criteria selected from the group consisting of: a) malabsorption syndrome or previous surgeries with resection of the stomach or small intestine, such as ileostomy; b) difficulty in swallowing tablets; c) clinical symptoms of CNS metastases requiring steroid treatment; d) an active infection requiring parenteral or oral antibiotic treatment; e) HIV; f) hepatitis B or C; g) stroke within < 6 months prior to the treatment; h) transient ischemic attach (TIA) within < 6 months prior to the treatment; i) myocardial infarction within < 6 months prior to the treatment; j) unstable angina; k) New York Heart Association (NYHA) Grade II or greater congestive heart failure (CHF); and l) Serious cardiac arrhythmia requiring medication.22. The combination drug for use of any preceding embodiment, wherein, the one or more anticancer agents comprise an UGT1A1 and / or an ABCG2 substrate.23. The combination drug for use of any preceding embodiment, wherein the one or more anticancer agents comprise: a) Irinotecan or its active metabolite SN-38.24. The combination drug for use of any preceding embodiment, wherein the anti-cancer agents comprise: a) Irinotecan or its active metabolite SN-38; b) 5-fluorouracil; and c) Folinic acid.25. The combination drug for use of any preceding embodiment, wherein the regulator compound is SCO-101 or a pharmaceutically acceptable salt thereof, the administered anti-canceragent comprises from 25 mg / m2 to 180 mg / m2, such as from 25 mg / m2 to 170 mg / m2 irinotecan and wherein the SCO-101 is administered in amounts / doses providing an area under the curve (AUC) of SN-38 of more than 385 h*ng / ml from single dose administration of irinotecan or SN-38, such as at least 400 h*ng / ml, such as at least 450 h*ng / ml, such as at least 500 h*ng / ml, such as at least 550 h*ng / ml, such as at least 600 h*ng / ml, such as at least 650 h*ng / ml, such as at least 700 h*ng / ml, such as at least 750 h*ng / ml, such as at least 800 h*ng / ml, such as at least 850 h*ng / ml, such as at least 900 h*ng / ml, such as at least 950 h*ng / ml, such as at least 1000 h*ng / ml, such as at least 1050 h*ng / ml, such as at least 1100 h*ng / ml, such as at least 1150 h*ng / ml, such as at least 1200 h*ng / ml, such as at least 1250 h*ng / ml, such as at least 1300 h*ng / ml, such as at least 1350 h*ng / ml, such as at least 1400 h*ng / ml, such as at least 1450 h*ng / ml, such as at least 1500 h*ng / ml, such as at least 1550 h*ng / ml, such as at least 1600 h*ng / ml, such as at least 1650 h*ng / ml, such as at least 1700 h*ng / ml, such as at least 1750 h*ng / ml, such as at least 1800 h*ng / ml, such as at least 1850 h*ng / ml, such as at least 1900 h*ng / ml, such as at least 1950 h*ng / ml, such as at least 2000 h*ng / ml.26. The combination drug for use of any preceding embodiment, wherein the regulator compound is SCO-101 or a pharmaceutically acceptable salt thereof administered in a total daily dose of at least 20 mg, such as at least 30 mg, such as at least 40 mg, such as at least 50 mg, such as at least 60 mg, such as at least 70 mg, such as at least 80 mg, such as at least 90 mg, such as at least 100 mg, such as at least 120 mg, such as at least 140 mg, such as at least 160 mg, such as at least 180 mg, such as at least 200 mg, such as at least 250 mg, such as at least 300 mg, such as at least 350 mg.27. The combination drug for use of any preceding embodiment, wherein the regulator compound is SCO-101 or a pharmaceutically acceptable salt thereof administered in a total daily dose of from 20 mg to 400 mg, such as from 50 mg to 350 mg, such as from 100 mg to 300 mg.28. The combination drug for use of any preceding embodiment, wherein the regulator compound is SCO-101 or a pharmaceutically acceptable salt thereof administered in a total daily dose of 100 mg, 150 mg, 200 mg, or 250 mg.29. The combination drug for use of embodiments 23-28, wherein irinotecan is administered in amounts from 20% to 100% of the recommended dose according to the Summary of Product Characteristics, such as from 20% to 25%, such as from 25% to 30%, such as from 30% to 35%, such as from 35% to 40%, such as from 40% to 45%, such as from 45% to 50%, such as from 50% to 55%, such as from 55% to 60%, such as from 60% to 65%, such as from 65% to 70%, such as from 70% to 75%,such as from 75% to 80%, such as from 80% to 85%, such as from 85% to 90%, such as from 90% to 95%, such as from 95% to 100%.30. The combination drug for use of embodiments 23-29, wherein irinotecan is administered in amounts from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, such as from 40 to 41%, such as from 41% to 42%, such as from 42% to 43%, such as from 43% to 44%, such as from 44% to 45%, such as from 45% to 46%, such as from 46% to 47%, such as from 47% to 48%, such as from 48% to 49%, such as from 49% to 50%, such as from 50% to 51%, such as from 51% to 52%, such as from 52% to 53%, such as from 53% to 54%, such as from 54% to 55%, such as from 55% to 56%, such as from 56% to 57%, such as from 57% to 58%, such as from 58% to 59%, such as from 59% to 60%.31. The combination drug for use of embodiments 4-30, wherein the one or more anti-cancer agents comprise irinotecan and the treatment comprises administering irinotecan in amounts from 50% to 100% of the total daily irinotecan dosage of the prior treatment, such as from 50% to 55%, such as from 55% to 60%, such as from 60% to 65%, such as from 65% to 70%, such as from 70% to 75%, such as from 75% to 80%, such as from 80% to 85%, such as from 85% to 90%, such as from 90% to 95%, such as from 95% to 100%.32. The combination drug for use of embodiment 31, wherein the treatment further comprises 5- fluorouracil and optionally folinic acid.33. The combination drug for use of embodiments 23-29, wherein irinotecan is administered in amounts from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, such as from 40 to 41%, such as from 41% to 42%, such as from 42% to 43%, such as from 43% to 44%, such as from 44% to 45%, such as from 45% to 46%, such as from 46% to 47%, such as from 47% to 48%, such as from 48% to 49%, such as from 49% to 50%, such as from 50% to 51%, such as from 51% to 52%, such as from 52% to 53%, such as from 53% to 54%, such as from 54% to 55%, such as from 55% to 56%, such as from 56% to 57%, such as from 57% to 58%, such as from 58% to 59%, such as from 59% to 60%.34. The combination drug for use of any one of embodiments 23-30, wherein the irinotecan is administered in a total daily dose of of 170 mg / m2 or less, such as a total daily dose of 160 mg / m2 or less, such as a total daily dose of 150 mg / m2 or less, such as a total daily dose of 140 mg / m2 or less,such as a total daily dose of 130 mg / m2 or less, such as a total daily dose of 120 mg / m2 or less, such as a total daily dose of 110 mg / m2 or less.35. The combination drug for use of any one of embodiments 23-34, wherein the irinotecan is administered in one daily dose of less than 110 mg / m2.36. The combination drug for use according to any one of the preceding embodiments, wherein irinotecan is administered in amounts from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, and 5-fluorouracil and folinic acid each administered in amounts from 80% to 100% of the recommended dose according to the Summary of Product Characteristics.37. The combination drug for use according to any of the preceding embodiments, wherein the regulator compound is SCO-101 and administered in a total daily dose of 150 mg, 200 mg, or 250 mg.38. The combination drug for use according to any of the preceding embodiments, wherein the one or more anti-cancer agents and the regulator compound are administered during a treatment cycle comprising a plurality of days.39. The combination drug for use according to embodiment 38, wherein the treatment cycle comprises administering the regulator compound on day X of the treatment cycle, and then administering the regulator compound each following day for a number of consecutive days, wherein X is l or 2.40. The combination drug for use according to embodiment 39, wherein the number with respect to regulator compound is from 3 to 6, such as from 3 to 4, such as from 4 to 5, or such as from 5 to 6.41. The combination drug for use according to any one of embodiments 38-40, wherein the treatment cycle comprises administering the one or more anti-cancer agents on day Y of the treatment cycle, and then administering the one or more anti-cancer agents each following day for a number of consecutive days, wherein Y is any number from 1 to 7, such as from 1 to 2, such as from 2 to 3, such as from 3 to 4, such as from 4 to 5, such as from 5 to 6, such as from 6 to 7.42. The combination drug for use according to embodiment 41, wherein the number with respect to one or more anti-cancer agents is from 2 to 5, such as from 2 to 3, such as from 3 to 4, or such asfrom 4 to 5.43. The combination drug for use according to any one of embodiments 38-42, wherein the treatment cycle comprises: a) a total daily dose of 150 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose irinotecan of from 50% to 100% of the total daily dosage of irinotecan of the prior treatment, for example from 50% to 99% of the total daily dosage of irinotecan of the prior treatment, such as from 50% to 90%, for example 65% or 80%, administered each day from day 5 to and including day 7.44. The combination drug for use according to any one of embodiments 38-42, wherein the treatment cycle comprises: a) a total daily dose of 100 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose irinotecan of 50% to 100% of the total daily dosage of irinotecan of the prior treatment, for example from 50% to 99% of the total daily dosage of irinotecan of the prior treatment, such as from 50% to 90%, for example 65% or 80%, administered each day from day 5 to and including day 7.45. The combination drug for use according to any one of embodiments 38-42, wherein the treatment cycle comprises: a) a total daily dose of 150 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose of irinotecan of from 40% to 95% of the total daily dosage of irinotecan of the prior treatment, for example from 50% to 90%, such as from 50 to 80%, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the total daily dosage of 5- fluorouracil and folinic acid of the prior treatment, administered each day from day 2 to and including day 4.46. The combination drug for use according to any one of embodiments 38-42, wherein the treatment cycle comprises: a) a total daily dose of 200 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose of irinotecan of from 40% to 95% of the total daily dosage of irinotecan of the prior treatment, for example from 50% to 90%, such as from 50 to 80%, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the total daily dosage of 5- fluorouracil and folinic acid of the prior treatment, administered each day from day 2 to and includingday 4.47. The combination drug for use according to any one of embodiments 38-42, wherein the treatment cycle comprises: a) a total daily dose of 200 mg SCO-101 on each day from day 2 to and including day 5; b) a total daily dose of irinotecan of from 40% to 95% of the total daily dosage of irinotecan of the prior treatment, for example from 50% to 90%, such as from 50 to 80%, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the total daily dosage of 5- fluorouracil and folinic acid of the prior treatment, administered each day from day 2 to and including day 4.48. The combination drug for use according to any one of embodiments 38-42, wherein the treatment cycle comprises: a) a total daily dose of 250 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose of irinotecan of from 40% to 95% of the total daily dosage of irinotecan of the prior treatment, for example from 50% to 90%, such as from 50 to 80%, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the total daily dosage of 5- fluorouracil and folinic acid of the prior treatment, administered each day from day 2 to and including day 4.49. The combination drug for use according to any one of embodiments 38-42, wherein the treatment cycle comprises: a) a total daily dose of 150 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose irinotecan, 5-fluorouracil and folinic acid (FOLFIRI) of from 60% to 90% of the recommended dose according to the Summary of Product Characteristics, for example 65% or 80%, administered each day from day 5 to and including day 7.50. The combination drug for use according to any one of embodiments 38-42, wherein the treatment cycle comprises: a) a total daily dose of 100 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose irinotecan, 5-fluorouracil and folinic acid (FOLFIRI) of 50% to 90% of the recommended dose according to the Summary of Product Characteristics, for example 50%, administered each day from day 5 to and including day 7.c51. The combination drug for use according to any one of embodiments 38-42, wherein the treatment cycle comprises: a) a total daily dose of 150 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose of irinotecan of from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the recommended dose according to the Summary of Product Characteristics, administered each day from day 2 to and including day 4.52. The combination drug for use according to any one of embodiments 38-42, wherein the treatment cycle comprises: a) a total daily dose of 200 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose of irinotecan of from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the recommended dose according to the Summary of Product Characteristics, administered each day from day 2 to and including day 4.53. The combination drug for use according to any one of embodiments 38-42, wherein the treatment cycle comprises: a) a total daily dose of 200 mg SCO-101 on each day from day 2 to and including day 5; b) a total daily dose of irinotecan of from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the recommended dose according to the Summary of Product Characteristics, administered each day from day 2 to and including day 4.54. The combination drug for use according to any one of embodiments 38-42, wherein the treatment cycle comprises: a) a total daily dose of 250 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose of irinotecan of from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the recommended dose according to the Summary of Product Characteristics, administered each day from day 2 to and including day 4.55. The combination drug for use according to any one of the preceding embodiments, wherein the use comprises from 1 to 30 treatment cycles, such as from 1 to 2, such as from 2 to 3, such as from3 to 4, such as from 4 to 5, such as from 5 to 6, such as from 6 to 7 , such as from 7 to 8, such as from 8 to 9, such as from 9 to 10, such as from 10 to 11, such as from 11 to 12, such as from 12 to 13, such as from 13 to 14, such as from 14 to 15, such as from 15 to 16, such as from 16 to 17, such as from 17 to 18, such as from 18 to 19, such as from 19 to 20, such as from 20 to 21, such as from 21 to 22, such as from 22 to 23, such as from 23 to 24, such as from 24 to 25, such as from 25 to 26, such as from 26 to 27, such as from 27 to 28, such as from 28 to 29, such as from 29 to 30 treatment cycles.56. The combination drug for use according to any one of the preceding embodiments, wherein the one or more anti-cancer agents is irinotecan administered in a total daily dose of 50% of the recommended dose according to the Summary of Product Characteristics on a first day, and then subsequently escalated to 65% of the recommended dose according to the Summary of Product Characteristics followed by 80% of the recommended dose according to the Summary of Product Characteristics.57. The combination drug for use according to any one of the preceding embodiments, wherein the treatment comprises administering to the patient a Granulocyte colony-stimulating factor (G-CSF).58. The combination drug for use according to embodiment 57, wherein the G-CSF is administered prior to, simultaneously with, or subsequently to the administration of the one or more anti-cancer agents.59. The combination drug for use of any preceding embodiment, wherein the cancer is a solid tumor, optionally sarcoma, carcinoma and / or lymphoma.60. The combination drug for use of any preceding embodiment, wherein the cancer is metastatic cancer.61. The combination drug for use of any preceding embodiment, wherein the cancer is selected from the group consisting of colorectal cancer, breast cancer, gastric cancer, lung cancer (including non small cell lung cancer and small cell lung cancer), glioblastomas, head and neck cancers, malignant melanomas, basal cell skin cancer, squamous cell skin cancer, liver cancer, pancreatic cancer, prostate cancer, anal cancer, cervix uteri cancer, bladder cancer, corpus uteri cancer, ovarian cancer, gall bladder cancer, leukemia's (including myeloid and lymphatic leukemia), and / or myelomatosis.62. The combination drug for use of embodiment 61, wherein the cancer is colorectal cancer, such as metastatic colorectal cancer.63. The combination drug for use of embodiment 61, wherein the cancer is gastric cancer, such as metastatic gastric cancer.64. The combination drug for use of embodiment 61, wherein the cancer is pancreatic cancer, such as metastatic pancreatic cancer.65. The combination drug for use of embodiment 61, wherein the cancer is breast cancer, such as metastatic breast cancer.66. The combination drug for use of any preceding embodiment, wherein the cancer is a resistant cancer which is resistant to the anti-cancer agent when administered alone.67. The combination drug for use of embodiment 66, wherein the resistance is de novo resistance.68. The combination drug for use of embodiment 66, wherein resistance is acquired resistance.69. The combination drug for use of any of embodiments 66 to 68, wherein treatment with the regulator compound re-sensitises the cancer to the anti-cancer agent.70. The combination drug for use of any one of the preceding embodiments, wherein the treatment comprises sequential or simultaneous administration of the one or more anti-cancer agents and the regulator compound.71. The combination drug for use of any one of the preceding embodiments, wherein the cancer over-expresses ABCG2.72. The combination drug for use of any one of the preceding embodiments, wherein the cancer is gastric cancer over-expressing ABCG2.73. A regulator compound for use in the treatment of gastric cancer in combination with one or more anti-cancer agents.74. The regulator compound for use of embodiment 73, wherein the regulator compound is SCO- 101 of the formula:or a pharmaceutically acceptable salt thereof.75. The regulator compound for use of any one of embodiments 73-74, wherein the one or more anti-cancer agents comprise irinotecan or its active metabolite, SN-38.76. The regulator compound for use of embodiment 75, wherein the one or more anti-cancer agents further comprise 5-fluorouracil and optionally folinic acid.77. A regulator compound for use in increasing the plasma drug exposure (AUC) of an anti-cancer agent in a patient receiving the anti-cancer agent for treatment of a cancer, wherein the regulator compound is an inhibitor of the degradation, clearance, and / or binding of the anti-cancer agent and / or a therapeutically active metabolite thereof, and thereby increasing the plasma drug exposure of an anti-cancer agent.78. A regulator compound for use in the treatment of a cancer, wherein the treatment comprises combination with one or more anti-cancer agents.79. A combination drug comprising, separately or together, a) an anti-cancer agent, and b) a regulator compound, wherein an amount of the regulator compound effectively increases the plasma drug exposure (AUC) of the anti-cancer agent when administering the combination drug to a patient.80. The combination drug of embodiment 79, wherein the anti-cancer agent is irinotecan and / or its active metabolite SN-38 and the regulator compound is SCO-101 of the formula:or a pharmaceutically acceptable salt thereof.ExamplesExample 1: A Phase 2 Trial of SCO-101 in combination with FOLFIRI for Patients with Metastatic Colorectal Cancer (mCRC) with acquired Resistance to FOLFIRIMaterials and methods

[0157] Chemicals used in the examples herein e.g. for buffers and substrates were of pharmaceutically acceptable grade.Dosing schedules

[0158] In this trial, SCO-101 was administered in combination with FOLFIRI. The enrolled patients are last line metastatic colorectal cancer patients that have previously relapsed on FOLFIRI and are therefore expected to be resistant to FOLFIRI. Two different dosing schedules (Schedule 1 and Schedule 2) were tested in this study. In both Schedule 1 and Schedule 1, SCO-101 was administered once daily from day 1 up to day 6, followed by a drug holiday of 8 days (until day 14) to constitute one treatment cycle. FOLFIRI treatment administration followed local standard procedures and was dosed on different days in Schedule 1 and Schedule 2.

[0159] Schedule 1: FOLFIRI administration on day 5 to day 7 of each treatment cycle,

[0160] Schedule 2: FOLFIRI administration on day 2 to day 4 of each treatment cycle.

[0161] In both schedule 1 and schedule 2, SCO-101 was administered once daily on day 1 to day 6. In case of relevant toxicity (according to DLT definitions), a shortened schedule over 4 days was tested. Dosing schedule 1 and schedule 2 (including the 4-day schedule) is illustrated in Table 1.cTable 1: Dosing Schedules of SCO-101 and FOLFIRI tested.1Dosage and administration of FOLFIRI is repeated every 2ndweek and will follow local standard procedures.2Dosing of SCO-101 may be reduced to a 4-day schedule where SCO-101 is only administered on day 2 to day 5 in case of relevant toxicity with the 6-day schedule using Schedule 2.

[0162] Treatment schedules will be repeated every 2 weeks for up to 12 months or until disease progression (PD), unacceptable toxicity or patients or doctor's decision to terminate the treatment.

[0163] Schedule 1 (completed): In stage 1, the dosage of SCO-101 will be initiated at 150 mg and may be escalated by increments of 50 mg to a maximum of 350 mg. Stage 2 will be performed with the dose established as the recommended phase II dose (RP2D) in stage 1 for Schedule 1.

[0164] Schedule 2: In stage 3, the dosage of SCO-101 and irinotecan will be determined. Initially, the dose of SCO-101 will be increased in cohorts of 3 + 3 patients starting at 150 mg, while the dose of irinotecan and 5-FU and leucovorin is maintained at the same dose levels. 5-FU and leucovorin will be administrated according to standard local clinical practice and irinotecan will be administered at 50% of the recommended SmPC dose (90 mg / m2).

[0165] If 2 DLTs occur in any dose level between cohort 1 to 4 with the Schedule 2 6-day regimen, the previous dose level will be expanded but also in parallel, the same dose level with 2 DLTs will be tested using a reduced (shortened) SCO-101 treatment course of only 4 days (day 2 to day 5), while FOLFIRI administration remains unchanged on days 2 to 4. The DSMB together with the sponsor will assess the data of the two de-escalated SCO-101 dose schedules and allow in case the shortened course is safe to resume dose escalation.

[0166] After the SCO-101 MTD has been established with these dose levels of irinotecan and 5-FU, the MTD of the irinotecan (in combination with SCO-101 MTD) will be determined. In this irinotecan dose escalation step, the dose of irinotecan will be increased in cohorts of 3 + 3 patients with increments of 15% to a maximum of 80% of the recommend dose. Based on the evidence of the prior cohorts, the sponsor and DSMB may choose to skip one or both additional cohorts.Study design

[0167] This is a multi-center, open label, dose escalation, Phase 2 study of SCO-101 in combination with FOLFIRI. The study is divided into 4 stages as described further below. Two different dosing schedules (Schedule 1 and Schedule 2) will be tested in this study. The study design is similar for Schedule 1 and Schedule 2 and consist of an initial dose escalation stage where the MTDs for eachSchedule 1 and Schedule 2 are determined, followed by an expansion stage, where the MTD dose levels are further evaluated in a larger patient group. Schedule 1 is tested in Stage 1 and Stage 2. Schedule 2 is tested in Stage 3 and Stage 4.

[0168] Common for all stages is that enrolled mCRC patients will be treated in treatment cycles of 14 days, with SCO-101 dosed orally, once daily for up to 6 days (Day 1 and up to Day 6 of the treatment cycle). In Schedule 1, FOLFIRI treatment is initiated on Day 5 of the treatment cycle. In Schedule 2, FOLFIRI treatment is initiated on day 2. After 4 chemotherapy cycles (i.e., 8 treatment weeks) have been completed a CT- / MRI-scan will be performed for tumor assessment as per RECIST version 1.1.

[0169] Patients will complete up to 12 months treatment during the treatment period and attend the end of trial visit after the last cycle is completed.Selection of patientsStudy Population

[0170] The target population for this study is metastatic CRC patients who have progressed on treatment with FOLFIRI, and who have now expended all other on-label treatment alternatives.As of June 2021, 18 patients (i.e., the maximum number planned) have been enrolled in stage 1. Stage 2 enrolled 25 patients. Stage 3 will enroll patients in cohorts of 3 + 3 patients, up to 36 patients in total. Stage 4 will include up to 24 patients with RAS wild-type and RAS mutation. In total, up to 103 mCRC patients are planned to be included in the study.Inclusion Criteria:Subjects are required to meet all the following criteria for enrollment into the applicable part (stage 1, stage 2, stage 3 or stage 4) of the study:■ Ability to understand and willingness to provide written informed consent before any trial- related activities.■ Age 18 years or older.■ Histologically verified colorectal adenocarcinoma.■ Non-resectable mCRC in patients:A. Stage 1: with or without BRAF, RAS or repair enzyme mutations***.B. Stage 2: without BRAF, RAS or known repair enzyme mutations***C. Stage 3 and stage 4: with or without BRAF, RAS or repair enzyme mutations, actual status to be confirmed prior to enrollment****■ Previous treatment and documented progressive disease with irinotecan and 5-FU (including 5-FU based analogs, e.g. capecitabine) based chemotherapy regimens (with or without antiangiogenetic and EGFR inhibitory biological treatment)*.■ Maximum reduction of 33% in prior dose of FOLFIRI■ Previous treatment with an oxaliplatin-containing treatment regimen and no indication for rechallenge with oxaliplatin. The patient can have received oxaliplatin treatment before and / or after treatment with FOLFIRI.■ A. Stage 1 and 3 only: Evaluable disease by CT scan or MRIB. Stage 2 and stage 4 only: Measurable disease by CT scan or MRI, according to RECIST 1.1.■ Performance status of ECOG < 1.■ Recovered to Grade 1 or less from prior surgery or acute toxicities of prior radiotherapy or treatment with cytotoxic or biologic agents*****.■ > 2 weeks must have elapsed since any prior surgery■ Adequate conditions as evidenced by the following clinical laboratory values:• Absolute neutrophils count (ANC) > 1.5 x 109 / L• Haemoglobin > 6,0 mmol / L• Platelets > 100 x 109 / L• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN*• Total serum bilirubin < 1.0 ULN**• Alkaline phosphatase < 2.5 x ULN*• Normal kidney function defined by the centers with the method usually employed locally, i.e. either creatinine (< 1.5 ULN) or calculated creatinine clearance or eGFR within normal limits determined according to local standards.• Adequate blood clotting function as defined by the International Normalized Ratio (INR) < 1.5.■ Life expectancy equal to or longer than 3 months.■ Sexually active males and females of child-producing potential must use adequate highly effective contraception during the trial and for at least 6 months after the last dose of study drug. Moreover, monthly pregnancy testing will be done during the treatment phase of the trial. (Highly effective contraceptive measures are methods that can achieve a failure rate of less than 1% per year. These include: intrauterine devices, hormonal contraceptives associated with inhibition of ovulation (oral, implants, transdermal patches, hormonal vaginal devices or injections with prolonged release). A vasectomised partner or sexual abstinence may be regarded as highly effective methods, if this is the usual and preferred lifestyle of the subject. Sterilised or infertile subjects are exempt from the requirement to use contraception. In orderto be considered sterile or infertile, subjects must generally have undergone surgical sterilisation (vasectomy / bilateral salpingectomy, hysterectomy and bilateral oophorectomy) or be postmenopausal defined as 12 months or more with no menses prior to enrolment. Doublebarrier methods (condom+cervical cap with spermicide) are not considered highly effective)■ Signed informed consent.■ Patients are only eligible for inclusion if no further on label treatment alternatives are available, i.e: a. They have progressed on all available standard treatments, and / or b. are intolerant of all remaining standard treatments, and / or c. decline treatment with all other standard therapy, and / or d. if the patient from the treating doctors medical view cannot be offered further standard treatments for their cancer disease.*AST is not mandatory. In case of known liver metastases with ALT and AST < 5 x ULN and / or alkaline phosphatase < 5 x ULN: Patients who do not conform to the transaminase and / or alkaline phosphatase inclusion criteria, but who by the PI are considered in good PS and otherwise eligible for inclusion, and where the transaminase and / or alkaline phosphatase levels are considered elevated due to other reasons than deteriorated lever capacity, may be considered for inclusion based on conferred agreement between PI and sponsor.** Unconjugated bilirubin may be measured as the difference between total bilirubin and conjugated bilirubin.*** BRAF- and RAS mutation status and repair enzyme status in the category MSI, dMSS and pMSS can be collected from the patient's journal.**** status must be confirmed prior to enrollment using local standard procedures, unless a recent test less than 90 days old from planned treatment date is available. An exception is possible only for patients with previously confirmed RAS mutation, who can also be enrolled based on historical confirmation of RAS mutation available up to 24 months prior to study enrollment. Patients with unknown RAS status are not eligible for inclusion.***** A minimum of 3 weeks must have elapsed since the last administration of previous anti-cancer treatment before planned first administration of SCO-101. f Evidence of progression within 8 weeks of last anti-cancer treatment.Exclusion CriteriaSubjects meeting any of the following criteria will be excluded from enrollment:■ Concurrent chemotherapy, radiotherapy, or other investigational drugs during study period.■ Malabsorption syndrome or previous surgeries with resection of the stomach or small intestine, whereby absorption of SCO-101 may be affected. This includes patients with ileostomy.■ Difficulty in swallowing tablets.■ Clinical symptoms of CNS metastases requiring steroids.■ Any active infection requiring parenteral or oral antibiotic treatment.■ Known HIV positivity.■ Known active hepatitis B or C.■ Clinically significant (i.e. active) cardiovascular disease:• Stroke within < 6 months prior to day 1• Transient ischemic attach (TIA) within < 6 months prior to day 1• Myocardial infarction within < 6 months prior to day 1• Unstable angina• New York Hart Association (NYHA) Grade II or greater congestive hearth failure (CHF)• Serious cardiac arrhythmia requiring medication■ Mental status is not fit for clinical study or CNS disease including symptomatic epilepsy.■ Other medications or conditions that in the Investigator's opinion would contraindicate study participation of safety reasons or interfere with the interpretation of study results. Other severe medical conditions, including serious heart disease, unstable diabetes, uncontrolled hypercalcemia, clinically active infections or previous organ transplants. Participation in another clinical trial with experimental medication within 30 days prior to registration.■ Known hypersensitivity to SCO-101, irinotecan, 5FU or structurally similar drugs, e.g. capecitabine, leucovorin and G-CSF.■ Pregnant women or women who are breastfeeding.■ Patients with known Dihydropyrimidine dehydrogenase (DPD) deficiencyClinical benefit rate (CBR)

[0171] The Clinical Benefit Rate (CBR) is a measure used in clinical trials, particularly in oncology, to assess the efficacy of a treatment. It is one of several metrics used to evaluate how well a cancer treatment works in patients. The clinical benefit rate (CBR) is defined as the % of patients that have either complete response, partial response or stable disease according to the following categories: Complete Response (CR): This refers to where no new lesions are detected and the cancer disappears completely following treatment.Partial Response (PR): This refers to where no new lesions are detected and a reduction of the tumorc size of more than 30% compared to the baseline.Stable Disease (SD): In this category, no new lesions are detected and the tumor size has not decreased more than 30% or increased more than 20% compared to baseline. This indicates that the disease is being controlled by the treatment.Calculation: CBR is calculated as the percentage of patients who have achieved either CR, PR, or SD, typically for a specified minimum period of time. The CBR is used to provide a more comprehensive assessment of the treatment's benefit. While measures like overall survival (OS) and progression-free survival (PFS) or median progression-free survival (mPFS) are crucial, CBR offers additional information, especially in situations where a treatment may not significantly shrink the tumor but can prevent it from growing.Results

[0172] In addition to determination of maximum tolerated dose (MTD), several parameters for signs of efficacy were also observed. These include clinical benefit rate (CBR), median progression free survival (mPFS), and tumor reduction (in %) as shown in tables 3 and 4.

[0173] In the dose escalation study CORIST Part 1 the 8 week CBR was 27.8% for the 18 evaluable patients. In part 2, which was an efficacy study, the 8 week CBR was 42% for the 21 evaluable patients. In the dose escalation study CORIST Part 3 the 8 week CBR was 76% for the 21 evaluable patients.

[0174] For a single cohort in Part 3 (with the modified 6 Days schedule and 150 mg SCO-101) the 8 week CBR was 100% for the 6 evaluable patients.

[0175] For the 16 week CBR in the three parts, the CBR is 11.1% in Part 1, 21% in Part 2 and 48% in Part 3.

[0176] The CBR data clearly indicates that the dosing regiments applied in Part 3 are more efficient when evaluated for early signs of efficacy.

[0177] In the dose escalation study, namely CORIST Part 1, the 8 week CBR was 27.8% for the 18 evaluable patients.

[0178] In the CORIST part 2 study, which was an efficacy study, the 8 week CBR was 42% for the 21 evaluable patients.

[0179] In the dose escalation study CORIST Part 3, the 8 week CBR was 76% for the 21 evaluable patients. For a single cohort in Part 3 (with the modified 6 Days schedule and 150 mg SCO-101) the 8 week CBR was 100% for the 6 evaluable patients.

[0180] For the 16 week CBR in the three parts, the CBR was 11.1% in Part 1, 21% in Part 2 and 48% in Part 3.

[0181] The CBR data clearly indicates that the dosing regiments applied in Part 3 are more efficientc when evaluated for early signs of efficacy. For the Progression Free survival (PFS) the same trend was observed. The median PFS (mPFS) was 3.8 months, which is longer than the 2.0 months observed in Part 2. For the MTD cohort of 150 mg SCO-101, the mPFS was 5.0 months.

[0182] Tumor shrinkage was observed in several patients and in one cohort (4Days, 250 mg SCO-101) there was at least one patient with an objective response according to international guidelines (RECIST 1.1), meaning that the tumor had shrinked more than 30% in response to the treatment with SCO-101 and FOLFIRI. This was in a cohort of 6 patients meaning that the objective response rate is 17%. This objective response rate is significantly higher than objective response rates determined for third line mCRC patients in Phase III clinical studies of selected approved anti-cancer agents (Clinical Colorectal Cancer, Vol. 19, No. 3, 165-77, 2020).

[0183] Further, generally, stronger tumor reduction was observed in Part 3 compared to Part 1 and2. This indicates that the dosing regiments applied in part 3 have a stronger anti-tumor effect.cTable 2: CBR at week 8 & 16 and PFS in CORIST Part 1, 2 & 3.Table 3: Tumor reduction in CORIST Part 1, 2 & 3Conclusions

[0184] The present example demonstrates the treatment of cancer, in particular colorectal cancer using treatment cycles of SCO-101 and FOLFIRI in different dosing regimen. The present example further demonstrates surprisingly effective treatment regimens comprising SCO-101 and FOLFIRI, in particular when SCO-101 is administered on day 2 to 5 and FOLFIRI is administered on day 2 to 4 of a treatment cycle as done in Stage 3 of the present study. Further, the present example demonstrates that treatment regimens comprising SCO-101 in doses of 150 mg, 200 mg or 250 and FOLFIRI with 50% irinotecan is surprisingly effective. In particular, the combination of 250 mg SCO-101 and FOLFIRI with50% irinotecan appears clinically very relevant.Example 2: Combination treatment of gastric cancer

[0185] The effect of ABCG2 inhibition by SCO-101 or the positive control Kol43 has been investigated on the viability of gastric cancer cells in the presence or absence of SN-38 (the active metabolite of irinotecan).

[0186] Four different gastric cancer cell lines have been investigated and the levels of ABCG2 protein characterized by flow cytometry (Table 4).

[0187] For each drug in each cell line dose-response curves were established to determine the IC50 values for the effect on cell viability.

[0188] In Figure 1, the response to SN-38 in the ABCG2 high expression cell line SCH and the low expression cell line MKN45 is shown. The ABCG2 high expressing cell line SCH is clearly more resistant to SN-38 than the ABCG2 low expressing MKN45 cell line.

[0189] None of the four cell lines were sensitive to SCO-101 or Kol43. IC50 values for SN-38, SCO- 101 and Kol43 are shown in Table 4. As presented in Table 4, the cell lines with the highest ABCG2 levels are the most resistant to SN-38 as demonstrated by the higher IC50 values.Table 4: The table describes the number of ABCG2 positive cells in each of the four gastric cancer cell lines, and the IC50 (pM) values for SN-38, SCO-101 or Kol34

[0190] The two ABCG2 positive cell lines were tested with 6x6 different combinations of either SN- 38 / SCO-101 or SN-38 / Kol43. The cell viability was determined after 96h of exposure. In Figure 2 an example is shown demonstrating combination effects of SCO-101 and SN-38 in ABCG2 positive SCH cells.

[0191] Based on the total cell viability read-out of the 6x6 comnination experiments the Bliss median synergy index was calculated (Table 5). A score higher than 5 indicates synergy, and a score less than -5 indicates antagonismcTable 5: The Bliss median synergy index is shown for the combination of either SN-38 / Kol43 or for SN-38 / SCO- 101 tested in a 6x6 matrix set-up. The input data for the Bliss median synergy index is the percentage of inhibition (cell viability) for either compound alone and the inhibition observed for each combination.Conclusion

[0192] Based on the present example, these combination studies demonstrated strong synergy between SCO-101 and SN-38 in gastric cancer, in particular ABCG2 high expressing gastric cancer cells.

[0193] The Ko 143 positive control for ABCG2 inhibition further supports that ABCG2 inhibition results in synergistic effects on cell viability in ABCG2 expressing gastric cancer cells.

[0194] These initial pre-clinical cell line data support the hypothesis that SCO-101 targets and inhibits ABCG2 in gastric cancer cells and the combination with SN-38 causes synergistic effects on cell viability.

Claims

Claims1. A combination drug comprising, separately or together, a) one or more anti-cancer agents; and b) a regulator compound which is an UGT1A1 and / or ABCG2 inhibitor, for use in the treatment of cancer in a patient, wherein the one or more anti-cancer agents and the regulator compound are administered during a treatment cycle comprising a plurality of days.

2. The combination drug for use of claim 1, wherein the regulator compound is SCO-101 of the formula:or a pharmaceutically acceptable salt thereof.

3. The combination drug for use of any preceding claim, wherein the patient has received a prior treatment with irinotecan or its active metabolite SN-38, and the cancer has progressed despite the prior treatment.

4. The combination drug for use of any preceding claim, wherein the patient has further received a prior treatment with an antimetabolite anti-cancer agent, such as 5-flurouracil or an analog therof, such as capecitabine, and optionally folinic acid, and wherein the cancer has progressed despite the prior treatment.

5. The combination drug for use of any preceding claims, wherein the patient has received a prior treatment with irinotecan, 5-fluorouracil, and folinic acid (FOLFIRI) and wherein the dosage of irinotecan has been reduced at most 33% from the recommended dosage according to the SmPC (corresponding to reduction to a dosage of 67% of the recommended dosage according to the SmPC).

6. The combination drug for use of any preceding claims, wherein the patient has received a prior treatment with an oxaliplatin-containing treatment regimen and has no indication for re-c challenge with oxaliplatin.

7. The combination drug for use of any preceding claim, wherein the patient has not received surgery less than two weeks prior to the treatment.

8. The combination drug for use of any preceding claim, wherein the patient has one or more or all of the clinical laboratory values selected from the group consisting of: a) absolute neutrophils count (ANC) > 1.5 x 109 / L; b) haemoglobin > 6,0 mmol / L; c) platelets > 100 x 109 / L; d) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN; e) total serum bilirubin < 1.0 ULN; f) alkaline phosphatase < 2.5 x ULN; g) normal kidney function defined by either creatinine (< 1.5 ULN) or calculated creatinine clearance or eGFR within normal limits determined according to local standards; and h) adequate blood clotting function as defined by the International Normalized Ratio (INR) < 1.5.

9. The combination drug for use of any preceding claim, wherein the patient is 18 years of age or older.

10. The combination drug for use of any preceding claim, wherein the patient has colorectal adenocarcinoma, optionally wherein the colorectal adenocarcinoma has been histologically verified.

11. The combination drug for use of any preceding claim, wherein the patient has non-resectable metastatic colorectal cancer.

12. The combination drug for use of any preceding claim, wherein the patient is characterized by having a UGT1A1 genotype which is non-mutated (wildtype) on a gene selected from the group consisting of: 5TA (UGT1A1*36), 6TA (UGT1A1*1), 7TA (UGT1A1*28) and 8TA (UGT1A1*37).

13. The combination drug for use of any preceding claim, wherein the patient is characterized by having a UGT1A1 genotype which is mutated on a gene selected from the group consisting of: 5TA (UGT1A1*36), 6TA (UGT1A1*1), 7TA (UGT1A1*28) and 8TA (UGT1A1*37).c14. The combination drug for use of any preceding claim, wherein the patient is characterized by having a bilirubin index of a threshold value or below, wherein the bilirubin index is determined by a method comprising the consecutive steps of: a) administering a first predefined dosage of the regulator compound, such as SCO-101 to the patient one or more times; b) determining the plasma concentration of unconjugated bilirubin in the patient at a time point Tl; c) discontinuing administration of the regulator compound; d) determining the plasma concentration of unconjugated bilirubin at a time point T2 after discontinuing administration of the regulator compound; e) determining a ratio CTZ / CTI between the T2 and the Tl plasma concentrations of unconjugated bilirubin, wherein the ratio equals the bilirubin index.

15. The combination drug for use according to claim 14, wherein the threshold value is a range.

16. The combination drug for use according to any one of claims 14-15, wherein the threshold value is a range from 0.20 to 0.50, such as from 0.20 to 0.25, such as from 0.25 to 0.30, such as from 0.30 to 0.35, such as from 0.35 to 0.40, such as from 0.40 to 0.45, such as from 0.45 to 0.50.

17. The combination drug for use according to claim 14, wherein the threshold value is from 0.20 to 0.35, such as from 0.20 to 0.21, such as from 0.21 to 0.22, such as from 0.22 to 0.23, such as from 0.23 to 0.24, such as from 0.24 to 0.25, such as from 0.25 to 0.26, such as from 0.26 to 0.27, such as from 0.27 to 0.28, such as from 0.28 to 0.29, such as from 0.29 to 0.30, such as from 0.30 to 0.31, such as from 0.31 to 0.32, such as from 0.32 to 0.33, such as from 0.33 to 0.34, such as from 0.34 to 0.35.

18. The combination drug for use according to claim 14, wherein the threshold value is 0.3.

19. The combination drug for use according to any one of claims 14-18, wherein T2 is 6 days subsequent to Tl, such as wherein T2 is on day 12 of a treatment cycle and Tl is on day 5 of the treatment cycle.

20. The combination drug for use of any preceding claim, wherein the patient is characterized by nothaving one or more of criteria selected from the group consisting of: a) malabsorption syndrome or previous surgeries with resection of the stomach or small intestine, such as ileostomy; b) difficulty in swallowing tablets; c) clinical symptoms of CNS metastases requiring steroid treatment; d) an active infection requiring parenteral or oral antibiotic treatment; e) HIV; f) hepatitis B or C; g) stroke within < 6 months prior to the treatment; h) transient ischemic attach (TIA) within < 6 months prior to the treatment; i) myocardial infarction within < 6 months prior to the treatment; j) unstable angina; k) New York Heart Association (NYHA) Grade II or greater congestive heart failure (CHF); and l) Serious cardiac arrhythmia requiring medication.

21. The combination drug for use of any preceding claim, wherein, the one or more anti-cancer agents comprise an UGT1A1 and / or an ABCG2 substrate.

22. The combination drug for use of any preceding claim, wherein the one or more anti-cancer agents comprise: a) Irinotecan or its active metabolite SN-38.

23. The combination drug for use of any preceding claim, wherein the anti-cancer agents comprise: a) Irinotecan or its active metabolite SN-38; b) 5-fluorouracil; and c) Folinic acid.

24. The combination drug for use of any preceding claim, wherein the regulator compound is SCO- 101 or a pharmaceutically acceptable salt thereof, the administered anti-cancer agent comprises from 25 mg / m2 to 180 mg / m2, such as from 25 mg / m2 to 170 mg / m2 irinotecan and wherein the SCO-101 is administered in amounts / doses providing an area under the curve (AUC) of SN-38 of more than 385 h*ng / ml from single dose administration of irinotecan or SN-38, such as at least 400 h*ng / ml, such as at least 450 h*ng / ml, such as at least 500 h*ng / ml, such as at least 550 h*ng / ml, such as at least 600 h*ng / ml, such as at least 650 h*ng / ml, such as at least 700 h*ng / ml,such as at least 750 h*ng / ml, such as at least 800 h*ng / ml, such as at least 850 h*ng / ml, such as at least 900 h*ng / ml, such as at least 950 h*ng / ml, such as at least 1000 h*ng / ml, such as at least1050 h*ng / ml, such as at least 1100 h*ng / ml, such as at least 1150 h*ng / ml, such as at least 1200 h*ng / ml, such as at least 1250 h*ng / ml, such as at least 1300 h*ng / ml, such as at least 1350 h*ng / ml, such as at least 1400 h*ng / ml, such as at least 1450 h*ng / ml, such as at least 1500 h*ng / ml, such as at least 1550 h*ng / ml, such as at least 1600 h*ng / ml, such as at least 1650 h*ng / ml, such as at least 1700 h*ng / ml, such as at least 1750 h*ng / ml, such as at least 1800 h*ng / ml, such as at least 1850 h*ng / ml, such as at least 1900 h*ng / ml, such as at least 1950 h*ng / ml, such as at least 2000 h*ng / ml.

25. The combination drug for use of any preceding claim, wherein the regulator compound is SCO- 101 or a pharmaceutically acceptable salt thereof administered in a total daily dose of at least 20 mg, such as at least 30 mg, such as at least 40 mg, such as at least 50 mg, such as at least 60 mg, such as at least 70 mg, such as at least 80 mg, such as at least 90 mg, such as at least 100 mg, such as at least 120 mg, such as at least 140 mg, such as at least 160 mg, such as at least 180 mg, such as at least 200 mg, such as at least 250 mg, such as at least 300 mg, such as at least 350 mg.

26. The combination drug for use of any preceding claim, wherein the regulator compound is SCO-101 or a pharmaceutically acceptable salt thereof administered in a total daily dose of from 20 mg to 400 mg, such as from 50 mg to 350 mg, such as from 100 mg to 300 mg.

27. The combination drug for use of any preceding claim, wherein the regulator compound is SCO- 101 or a pharmaceutically acceptable salt thereof administered in a total daily dose of 100 mg, 150 mg, 200 mg, or 250 mg.

28. The combination drug for use of any preceding claim, wherein the regulator compound is SCO- 101 or a pharmaceutically acceptable salt thereof and administered in a total daily dose of 250 mg.

29. The combination drug for use of claims 22-27, wherein irinotecan is administered in amounts from 20% to 100% of the recommended dose according to the Summary of Product Characteristics, such as from 20% to 25%, such as from 25% to 30%, such as from 30% to 35%, such as from 35% to 40%, such as from 40% to 45%, such as from 45% to 50%, such as from 50% to 55%, such as from 55% to 60%, such as from 60% to 65%, such as from 65% to 70%, such asc from 70% to 75%, such as from 75% to 80%, such as from 80% to 85%, such as from 85% to 90%, such as from 90% to 95%, such as from 95% to 100%.

30. The combination drug for use of claims 22-29, wherein irinotecan is administered in amounts from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, such as from 40 to 41%, such as from 41% to 42%, such as from 42% to 43%, such as from 43% to 44%, such as from 44% to 45%, such as from 45% to 46%, such as from 46% to 47%, such as from 47% to 48%, such as from 48% to 49%, such as from 49% to 50%, such as from 50% to 51%, such as from 51% to 52%, such as from 52% to 53%, such as from 53% to 54%, such as from 54% to 55%, such as from 55% to 56%, such as from 56% to 57%, such as from 57% to 58%, such as from 58% to 59%, such as from 59% to 60%.

31. The combination drug for use of claims 3-30, wherein the one or more anti-cancer agents comprise irinotecan and the treatment comprises administering irinotecan in amounts from 50% to 100% of the total daily irinotecan dosage of the prior treatment, such as from 50% to 55%, such as from 55% to 60%, such as from 60% to 65%, such as from 65% to 70%, such as from 70% to 75%, such as from 75% to 80%, such as from 80% to 85%, such as from 85% to 90%, such as from 90% to 95%, such as from 95% to 100%.

32. The combination drug for use of claim 31, wherein the treatment further comprises 5-fluorouracil and optionally folinic acid.

33. The combination drug for use of claims 22-29, wherein irinotecan is administered in amounts from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, such as from 40 to 41%, such as from 41% to 42%, such as from 42% to 43%, such as from 43% to 44%, such as from 44% to 45%, such as from 45% to 46%, such as from 46% to 47%, such as from 47% to 48%, such as from 48% to 49%, such as from 49% to 50%, such as from 50% to 51%, such as from 51% to 52%, such as from 52% to 53%, such as from 53% to 54%, such as from 54% to 55%, such as from 55% to 56%, such as from 56% to 57%, such as from 57% to 58%, such as from 58% to 59%, such as from 59% to 60%.

34. The combination drug for use of any one of claims 22-30, wherein the irinotecan is administered in a total daily dose of of 170 mg / m2 or less, such as a total daily dose of 160 mg / m2 or less, such as a total daily dose of 150 mg / m2 or less, such as a total daily dose of 140 mg / m2 or less, suchas a total daily dose of 130 mg / m2 or less, such as a total daily dose of 120 mg / m2 or less, such as a total daily dose of 110 mg / m2 or less.

35. The combination drug for use of any one of claims 22-34, wherein the irinotecan is administered in one daily dose of less than 110 mg / m2.

36. The combination drug for use according to any one of the preceding claims, wherein irinotecan is administered in amounts from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, and 5-fluorouracil and folinic acid each administered in amounts from 80% to 100% of the recommended dose according to the Summary of Product Characteristics.

37. The combination drug for use according to any of the preceding claims, wherein the regulator compound is SCO-101 and administered in a total daily dose of 150 mg, 200 mg, or 250 mg.

38. The combination drug for use according to any one of the preceding claims, wherein the treatment cycle comprises administering the regulator compound on day X of the treatment cycle, and then administering the regulator compound each following day for a number of consecutive days, wherein X is 1 or 2.

39. The combination drug for use according to any one of the preceding claims, wherein the number with respect to regulator compound is from 3 to 6, such as from 3 to 4, such as from 4 to 5, or such as from 5 to 6.

40. The combination drug for use according to any one of the preceding claims, wherein the treatment cycle comprises administering the one or more anti-cancer agents on day Y of the treatment cycle, and then administering the one or more anti-cancer agents each following day for a number of consecutive days, wherein Y is any number from 1 to 7, such as from 1 to 2, such as from 2 to 3, such as from 3 to 4, such as from 4 to 5, such as from 5 to 6, such as from 6 to 7.

41. The combination drug for use according to claim 40, wherein the number with respect to one or more anti-cancer agents is from 2 to 5, such as from 2 to 3, such as from 3 to 4, or such as from 4 to 5.

42. The combination drug for use according to any one of the preceding claims, wherein the treatment cycle comprises: a) a total daily dose of 150 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose irinotecan of from 50% to 100% of the total daily dosage of irinotecan of the prior treatment, for example from 50% to 99% of the total daily dosage of irinotecan of the prior treatment, such as from 50% to 90%, for example 65% or 80%, administered each day from day 5 to and including day 7.

43. The combination drug for use according to any one of the preceding claims, wherein the treatment cycle comprises: a) a total daily dose of 100 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose irinotecan of 50% to 100% of the total daily dosage of irinotecan of the prior treatment, for example from 50% to 99% of the total daily dosage of irinotecan of the prior treatment, such as from 50% to 90%, for example 65% or 80%, administered each day from day 5 to and including day 7.

44. The combination drug for use according to any one of the preceding claims, wherein the treatment cycle comprises: a) a total daily dose of 150 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose of irinotecan of from 40% to 95% of the total daily dosage of irinotecan of the prior treatment, for example from 50% to 90%, such as from 50 to 80%, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the total daily dosage of 5-fluorouracil and folinic acid of the prior treatment, administered each day from day 2 to and including day 4.

45. The combination drug for use according to any one of the preceding claims, wherein the treatment cycle comprises: a) a total daily dose of 200 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose of irinotecan of from 40% to 95% of the total daily dosage of irinotecan of the prior treatment, for example from 50% to 90%, such as from 50 to 80%, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the total daily dosage of 5-fluorouracil and folinic acid of the prior treatment, administered each day from day 2 to and including day 4.

46. The combination drug for use according to any one of the preceding claims, wherein the treatment cycle comprises: a) a total daily dose of 200 mg SCO-101 on each day from day 2 to and including day 5; b) a total daily dose of irinotecan of from 40% to 95% of the total daily dosage of irinotecan of the prior treatment, for example from 50% to 90%, such as from 50 to 80%, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the total daily dosage of 5-fluorouracil and folinic acid of the prior treatment, administered each day from day 2 to and including day 4.

47. The combination drug for use according to any one of the preceding claims, wherein the treatment cycle comprises: a) a total daily dose of 250 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose of irinotecan of from 40% to 95% of the total daily dosage of irinotecan of the prior treatment, for example from 50% to 90%, such as from 50 to 80%, for example 50%, and a total daily dose of 5-fluorouracil and folinic acid of from 90% to 100% of the total daily dosage of 5-fluorouracil and folinic acid of the prior treatment, administered each day from day 2 to and including day 4.

48. The combination drug for use according to any one of the preceding claims, wherein the treatment cycle comprises: a) a total daily dose of 150 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose irinotecan, 5-fluorouracil and folinic acid (FOLFIRI) of from 60% to 90% of the recommended dose according to the Summary of Product Characteristics, for example 65% or 80%, administered each day from day 5 to and including day 7.

49. The combination drug for use according to any one of the preceding claims, wherein the treatment cycle comprises: a) a total daily dose of 100 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose irinotecan, 5-fluorouracil and folinic acid (FOLFIRI) of 50% to 90% of the recommended dose according to the Summary of Product Characteristics, for example 50%, administered each day from day 5 to and including day 7.

50. The combination drug for use according to any one of the preceding claims, wherein the treatment cycle comprises:a) a total daily dose of 150 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose of irinotecan of from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, for example 50%, and a total daily dose of 5- fluorouracil and folinic acid of from 90% to 100% of the recommended dose according to the Summary of Product Characteristics, administered each day from day 2 to and including day 4.

51. The combination drug for use according to any one of the preceding claims, wherein the treatment cycle comprises: a) a total daily dose of 200 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose of irinotecan of from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, for example 50%, and a total daily dose of 5- fluorouracil and folinic acid of from 90% to 100% of the recommended dose according to the Summary of Product Characteristics, administered each day from day 2 to and including day 4.

52. The combination drug for use according to any one of the preceding claims, wherein the treatment cycle comprises: a) a total daily dose of 200 mg SCO-101 on each day from day 2 to and including day 5; b) a total daily dose of irinotecan of from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, for example 50%, and a total daily dose of 5- fluorouracil and folinic acid of from 90% to 100% of the recommended dose according to the Summary of Product Characteristics, administered each day from day 2 to and including day 4.

53. The combination drug for use according to any one of the preceding claims, wherein the treatment cycle comprises: a) a total daily dose of 250 mg SCO-101 on each day from day 1 to and including day 6; b) a total daily dose of irinotecan of from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, for example 50%, and a total daily dose of 5- fluorouracil and folinic acid of from 90% to 100% of the recommended dose according to the Summary of Product Characteristics, administered each day from day 2 to and including day 4.

54. The combination drug for use according to any one of the preceding claims, wherein the treatment cycle comprises: a) a total daily dose of 250 mg SCO-101 on each day from day 2 to and including day 5; b) a total daily dose of irinotecan of from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, for example 50%, and a total daily dose of 5- fluorouracil and folinic acid of from 90% to 100% of the recommended dose according to the Summary of Product Characteristics, administered each day from day 2 to and including day 4.

55. The combination drug for use according to any one of the preceding claims, wherein the treatment cycle comprises: a) a total daily dose of 250 mg SCO-101 on each day from day 1 to and including day 4; b) a total daily dose of irinotecan of from 40% to 60% of the recommended dose according to the Summary of Product Characteristics, for example 50%, and a total daily dose of 5- fluorouracil and folinic acid of from 90% to 100% of the recommended dose according to the Summary of Product Characteristics, administered each day from day 1 to and including day 3.

56. The combination drug for use according to any one of the preceding claims, wherein the use comprises from 1 to 30 treatment cycles, such as from 1 to 2, such as from 2 to 3, such as from 3 to 4, such as from 4 to 5, such as from 5 to 6, such as from 6 to 7, such as from 7 to 8, such as from 8 to 9, such as from 9 to 10, such as from 10 to 11, such as from 11 to 12, such as from 12 to 13, such as from 13 to 14, such as from 14 to 15, such as from 15 to 16, such as from 16 to 17, such as from 17 to 18, such as from 18 to 19, such as from 19 to 20, such as from 20 to 21, such as from 21 to 22, such as from 22 to 23, such as from 23 to 24, such as from 24 to 25, such as from 25 to 26, such as from 26 to 27, such as from 1 to 28, such as from 28 to 29, such as from 29 to 30 treatment cycles.

57. The combination drug for use according to any one of the preceding claims, wherein the one or more anti-cancer agents is irinotecan administered in a total daily dose of 50% of the recommended dose according to the Summary of Product Characteristics on a first day, and then subsequently escalated to 65% of the recommended dose according to the Summary of Product Characteristics followed by 80% of the recommended dose according to the Summary of Product Characteristics.c58. The combination drug for use according to any one of the preceding claims, wherein the treatment comprises administering to the patient a Granulocyte colony-stimulating factor (G- CSF).

59. The combination drug for use according to claim 58, wherein the G-CSF is administered prior to, simultaneously with, or subsequently to the administration of the one or more anti-cancer agents.

60. The combination drug for use of any preceding claim, wherein the cancer is a solid tumor, optionally sarcoma, carcinoma and / or lymphoma.

61. The combination drug for use of any preceding claim, wherein the cancer is metastatic cancer.

62. The combination drug for use of any preceding claim, wherein the cancer is selected from the group consisting of colorectal cancer, breast cancer, gastric cancer, lung cancer (including non small cell lung cancer and small cell lung cancer), glioblastomas, head and neck cancers, malignant melanomas, basal cell skin cancer, squamous cell skin cancer, liver cancer, pancreatic cancer, prostate cancer, anal cancer, cervix uteri cancer, bladder cancer, corpus uteri cancer, ovarian cancer, gall bladder cancer, leukemia's (including myeloid and lymphatic leukemia), and / or myelomatosis.

63. The combination drug for use of claim 62, wherein the cancer is colorectal cancer, such as metastatic colorectal cancer.

64. The combination drug for use of claim 62, wherein the cancer is gastric cancer, such as metastatic gastric cancer.

65. The combination drug for use of claim 62, wherein the cancer is pancreatic cancer, such as metastatic pancreatic cancer.

66. The combination drug for use of claim 62, wherein the cancer is breast cancer, such as metastatic breast cancer.

67. The combination drug for use of any preceding claim, wherein the cancer is a resistant cancer which is resistant to the anti-cancer agent when administered alone.

68. The combination drug for use of claim 67, wherein the resistance is de novo resistance.

69. The combination drug for use of claim 67, wherein resistance is acquired resistance.

70. The combination drug for use of any of claims 67 to 69, wherein treatment with the regulator compound re-sensitises the cancer to the anti-cancer agent.

71. The combination drug for use of any one of the preceding claims, wherein the treatment comprises sequential or simultaneous administration of the one or more anti-cancer agents and the regulator compound.

72. The combination drug for use of any one of the preceding claims, wherein the cancer overexpresses ABCG2.

73. The combination drug for use of any one of the preceding claims, wherein the cancer is gastric cancer over-expressing ABCG2.

74. The combination drug for use of any one of the preceding claims, wherein the treatment further comprises administration of a further anti-cancer agent.

75. The combination drug for use of claim 74, wherein the further anti-cancer agent is a Vascular Endothelial Growth Factor (VEGF) inhibitor or an Epidermal Growth Factor Receptor (EGFR) inhibitor.

76. The combination drug for use of claim 75, wherein the EGFR inhibitor is selected from the group consisting of: cetuximab, erlotinib, gefitinib, afatinib, osimertinib, panitumumab, and necitumumab.

77. The combination drug for use of claim 75, wherein the VEGF inhibitor is selected from the group consisting of: bevacizumab, ramucirumab, aflibercept, sunitinib, sorafenib, pazopanib, axitinib, cabozantinib, and lenvatinib.

78. The combination drug for use of any of the preceding claims, wherein: a) the regulator compound is SCO-101; b) the one or more anti-cancer agents comprise Irinotecan or its active metabolite, SN-38, for example as part of FOLFIRI; and wherein the treatment further comprises administration of: c) a VEGF inhibitor, such as bevacizumab.

79. The combination drug for use of any of the preceding claims, wherein: a) the regulator compound is SCO-101; b) the one or more anti-cancer agents comprise Irinotecan or its active metabolite, SN-38, for example as part of FOLFIRI; and wherein the treatment further comprises administration of: c) an EGFR inhibitor, such as cetuximab.

80. The combination drug for use of claim 79, wherein the cancer is characterized as a KRAS wildtype cancer.

81. The combination drug for use of any of claims 74-80, wherein the cancer is metastatic colorectal cancer.

82. The combination drug for use of any of claims 74-80, wherein the cancer is metastatic colorectal cancer and the treatment is provided to the patient as first line treatment, second line treatment, or third line treatment.

83. A combination drug comprising, separately or together, a) irinotecan; and b) a regulator compound, wherein the regulator compound is SCO-101 of the formula:or a pharmaceutically acceptable salt thereof, for use in the treatment of metastatic colorectal cancer in a patient, wherein irinotecan and the regulator compound are administered during a treatment cycle comprising a plurality of days, forexample wherein the regulator compound is administered for from 3 to 5 consecutive days, such as 4 consecutive days.

84. The combination drug of claim 83, wherein the daily dose of SCO-101 is 250 mg.

85. A regulator compound for use in the treatment of gastric cancer in combination with one or more anti-cancer agents.

86. The regulator compound for use of claim 85, wherein the regulator compound is SCO-101 of the formula:or a pharmaceutically acceptable salt thereof.

87. The regulator compound for use of any one of claims 85-86, wherein the one or more anti-cancer agents comprise irinotecan or its active metabolite, SN-38.

88. The regulator compound for use of claim 87, wherein the one or more anti-cancer agents further comprise 5-fluorouracil and optionally folinic acid.

89. A regulator compound for use in increasing the plasma drug exposure (AUC) of an anti-cancer agent in a patient receiving the anti-cancer agent for treatment of a cancer, wherein the regulator compound is an inhibitor of the degradation, clearance, and / or binding of the anti-cancer agent and / or a therapeutically active metabolite thereof, and thereby increasing the plasma drug exposure of an anti-cancer agent.

90. A regulator compound for use in the treatment of a cancer, wherein the treatment comprises combination with one or more anti-cancer agents.

91. A combination drug comprising, separately or together,a) an anti-cancer agent, and b) a regulator compound, wherein an amount of the regulator compound effectively increases the plasma drug exposure (AUC) of the anti-cancer agent when administering the combination drug to a patient.

92. The combination drug of claim 91, wherein the anti-cancer agent is irinotecan and / or its active metabolite SN-38 and the regulator compound is SCO-101 of the formula:or a pharmaceutically acceptable salt thereof.* * *

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