WO2017208019A1

WO2017208019A1 - Dosing regimen for sapacitabin and seliciclib

Info

Publication number: WO2017208019A1
Application number: PCT/GB2017/051597
Authority: WO
Inventors: Judy Chiao
Original assignee: Cyclacel Limited
Priority date: 2016-06-03
Filing date: 2017-06-02
Publication date: 2017-12-07
Also published as: GB201609758D0

Abstract

A first aspect of the invention relates to a method of treating a proliferative disorder in a subject, said method comprising administering to the subject a therapeutically effective amount of (i) sapacitabine, or a metabolite thereof; and (ii) seliciclib; in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises: (a) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on 3 to 5 consecutive days in a first period; and (b) administering a therapeutically effective amount of seliciclib on 2 to 4 consecutive days; (c) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on 3 to 5 consecutive days in a second period; and (d) a rest period of at least about 10 days, or until treatment-related toxicities are resolved, whichever is longer. Further aspects of the invention relate to a kit of parts, and corresponding uses.

Description

DOSING REGIMEN FOR SAPACITABIN AND SELICICLIB

FIELD OF THE INVENTION

The present invention relates to a dosing regimen suitable for the treatment of cancer and other proliferative disorders.

BACKGROUND TO THE INVENTION

Initiation, progression, and completion of the mammalian cell cycle are regulated by various cyclin-dependent kinase (CDK) complexes, which are critical for cell growth. These complexes comprise at least a catalytic (the CDK itself) and a regulatory (cyclin) subunit. Some of the more important complexes for cell cycle regulation include cyclin A (CDK1 - also known as cdc2, and CDK2), cyclin B1-B3 (CDK1 ), cyclin C (CDK8), cyclin D1-D3 (CDK2, CDK4, CDKS, CDK6), cyclin E (CDK2), cyclins K and T (CDK9) and cyclin H (CDK7). Each of these complexes is involved in a particular phase of the cell cycle or in the regulation of transcription.

The activity of CDKs is regulated post-translationally, by transitory associations with other proteins, and by alterations of their intracellular localisation. Tumour development is closely associated with genetic alteration and deregulation of CDKs and their regulators, suggesting that inhibitors of CDKs may be useful anti-cancer therapeutics. Indeed, early results suggest that transformed and normal cells differ in their requirement for e.g. cyclin A/CDK2 and that it may be possible to develop novel antineoplastic agents devoid of the general host toxicity observed with conventional cytotoxic and cytostatic drugs.

The function of CDKs is to phosphorylate and thus activate or deactivate certain proteins, including e.g. retinoblastoma proteins, lamins, histone H1 , and components of the mitotic spindle. The catalytic step mediated by CDKs involves a phospho- transfer reaction from ATP to the macromolecular enzyme substrate. Several groups of compounds {reviewed in e.g. N, Gray, L. Detivaud, C. Doerig, L. Meijer, Curr. Med. Chem. 1999, 6, 859) have been found to possess anti-proliferative properties by virtue of CDK-specific ATP antagonism.

Seliciclib is the compound 6-benzylamino-2-[(R)-1-ethyl-2-hydroxyethylamino]-9- isopropylpurine. Seliciclib has been demonstrated to be a potent inhibitor of cyclin dependent kinase enzymes, particularly CDK2. This compound is currently in development as an anti-cancer agent. CDK inhibitors are understood to block passage of ceils from the G2/M phase of the cell cycle.

It is well established in the art that active pharmaceutical agents can often be given in combination in order to optimise the treatment regime. For example, WO 2005/053699 (Cyclacel Limited) discloses a pharmaceutical combination comprising sapacitabine and seliciclib, and methods of treatment using the same. More specifically, WO 2005/053699 discloses methods of treating proliferative disorders selected from lung, prostate, bladder, head and neck and colon cancer, sarcoma and lymphoma by sequentially administering sapacitabine and seliciclib. WO 2013/171473 (Cyclacel Limited) discloses a dosing regimen for sapacitabine and seliciclib.

The present invention seeks to provide a new dosing regimen for known pharmaceutical agents that is particularly suitable for the treatment of proliferative disorders, especially cancer. More specifically, the invention centres on the surprising and unexpected effects associated with using certain pharmaceutical agents in combination in a particular dosing regimen.

STATEMENT OF INVENTION

In a first aspect, the invention provides a method of treating a proliferative disorder in a subject, said method comprising administering to the subject a therapeutically effective amount of (i) sapacitabine, or a metabolite thereof; and (ii) seliciclib; in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises:

(a) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on 3 to 5 consecutive days in a first period; and

(b) administering a therapeutically effective amount of seliciclib on 2 to 4 consecutive days;

(c) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on 3 to 5 consecutive days in a second period; and

(d) a rest period of at least about 10 days, or until treatment-related toxicities are resolved, whichever is longer.

Advantageously, the Applicant has found that a dosing regimen comprising two dosing periods of sapacitabine (a first and a second period), interleaved with seliciclib dosing, leads to beneficial clinical effects. Without wishing to be bound by theory, it is believed that the presently claimed dosing regimen allows dosing of both drugs at relatively high doses compared to other sapacitabine/seliciclib regimens, wherein one of the two drugs is typically administered at a lower dose. As a result, this leads to better efficacy, in addition, the interleaving regimen optimises the potential for seliciclib to potentiate the activity of sapacitabine when it is given either after or before the sapacitabine doses.

A second aspect of the invention relates to the use of (i) sapacitabine, or a metabolite thereof; and (ii) seliciclib; in the preparation of a medicament for treating a proliferative disorder, wherein the sapacitabine, or metabolite thereof, and the seliciclib are administered in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises:

A third aspect of the invention relates to (i) sapacitabine, or a metabolite thereof; and (ii) seficiclib; for use in treating a proliferative disorder, wherein the sapacitabine, or metabolite thereof, and the seliciclib are administered in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises:

(d) a rest period of at least about 10 days, or until treatment-related toxicities are resolved, whichever is longer. A fourth aspect of the invention relates to a kit of parts comprising:

(i) sapacitabine, or a metabolite thereof;

(ii) seliciclib and

(iii) instructions for administering sapacitabine, or a metabolite thereof, and selicic!ib in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises:

DETAILED DESCRIPTION

The preferred embodiments as set out below are applicable to all the above-mentioned aspects of the invention. As mentioned above, the present invention provides a new dosing regimen for sapacitabine and seliciclib that is particularly effective in the treatment of proliferative disorders. More specifically, the dosing regimen involves interleaving the administration of seliciclib and sapacitabine such that the sapacitabine is administered both before and after the seliciclib. Advantageously, it is understood that this dosing regimen allows seliciclib to enhance the activity of sapacitabine when administered after or before the sapacitabine. it is well known that the effect of drug combinations is inherently unpredictable and there is often a propensity for one drug to partially or completely inhibit the effects of the other. The present invention is based on the surprising observation that administering sapacitabine and seliciclib in combination with a particular dosing regimen does not lead to any adverse interaction between the two agents. The unexpected absence of any such antagonistic interaction is critical for clinical applications. In fact studies by the Applicant have shown that administering sapacitabine and seliciclib in accordance with the above-described dosing regimen gives rise to an enhanced effect as compared to either drug administered alone. The surprising nature of this observation is in contrast to that expected on the basis of the prior art. In particular, the administration of sapacitabine and seliciclib in accordance with the presently claimed dosing regimen maximizes the efficacy of both drugs and does not result in any exacerbation of the toxicities associated with each drug.

1-(2-C-cyano-2-dioxy-p-D-arabino-pentofuranosyi)-N⁴-palmitoyl cytosine (I), also known as 2'-cyano-2-deoxy-N⁴-palmitoyl-1-p-D-arabinofuranosyicytosine (Hanaoka, K., ef al, Int. J, Cancer, 1999:82:226-236 ; Donehower R, ef at, Proc Am Soc Clin Oncol, 2000: abstract 764; Burch, PA, ef al, Proc Am Soc Clin Oncol, 2001 : abstract 364) or "sapacitabine", is an orally administered novel 2'-deoxycytidine antimetabolite prodrug of the nucleoside CNDAC, 1-(2-C-Cyano-2-deoxy-p-D-arabino- pentafuranosyl)-cytosine.

Sapacitabine CNDAC

Sapacitabine has a unique mode of action over other nucleoside metabolites such as gemcitabine in that it has a spontaneous DNA strand breaking action, resulting in potent anti-tumour activity in a variety of cell lines, xenograft and metastatic cancer model. The active metabolite CNDAC generates single strand DNA breaks. It has been demonstrated that DNA single-strand breaks generated following CNDAC incorporation can be transformed into DNA double-strand breaks during subsequent rounds of replication (Liu ef al, Cancer Res 2005; 65 (15) Aug 1 , 6874-6881 ; Liu ef al, Blood, 9 Sept 2010; Col 116; No. 10; 1737-1746). Repair of CNDAC-induced DNA breaks is dependent on components of these DSB repair pathways and, in particular, defects in homologous recombination (HR) repair have been shown to sensitize cell lines to CNDAC (Liu ef al, 2010 ibid).

Sapacitabine has been the focus of a number of studies in view of its oral bioavailability and its improved activity over gemcitabine (the leading marketed nucleoside analogue) and 5-FU (a widely-used antimetabolite drug) based on preclinical data in solid tumours. Recently, investigators reported that sapacitabine exhibited strong anticancer activity in a model of colon cancer. In the same model, sapacitabine was found to be superior to either gemcitabtne or 5-FU in terms of increasing survival and also preventing the spread of colon cancer metastases to the liver (Wu M, er a/, Cancer Research, 2003:63:2477-2482). To date , phase I data from patients with a variety of cancers suggest that sapacitabine is well tolerated in humans, with myelosuppression as the dose limiting toxicity.

Seticiclib (or "CYC202") is a 2,6,9-substituted purine analog having the chemical name 2-(R)-(1 -ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (also known as 2-(1-R-hydroxymethylpropylamino)-6-benzylamino-9-isopropylpurine) and having the structure shown below:

Seliciclib Seliciclib and related purines were first described in WO97/20842. Selicic!ib is a selective and potent inhibitor of CDK2/cyclin E, CDK7/cyclin H and CDK9/cyclin T. The activity against CDK2 results in effects on the cell cycle, while the activity against CDK7/cyclin H and CDK9/cyclin K T1 results in an effect on transcriptional regulation. Treatment of cell lines has wide-ranging effects including: accumulation of cells in G1 and G2 phases, inhibition of rRNA processing, inhibition of RNA polymerase Independent transcription, disruption of nucleoli, and induction of apoptosis from all stages of the cell cycle. In myeloma cells, se!icic!ib causes myeloma cell death by disrupting the balance between cell survival and apoptosis through the inhibition of transcription and down-regulation of myeloid leukemia cell sequence 1 protein (Mcl-1 ). (MacCallum ef al, Cancer Res 2005, June 15, 65(12) 5399-5407). CDK inhibition has also been shown to potentially affect the two major DSB repair pathways - homologous recombination (HR) and non-homologous end-joining (NHEJ) and it has also been demonstrated that CDK inhibition can potentiate the effect of DNA damaging agents such as doxorubicin, sapacitabine and gamma irradiation (Maggiorella ef a/, Cancer Research, 63, 2513-2517, May 15, 2003; Federico ef al, Molecular Cancer 2010; 9: 208). Twenty-four hour treatment of A549 cells with selicic!ib caused significant down regulation of key genes involved in HR (BRCA1 and RAD50) and NHEJ (Ku80, DNA-PK and NHEJ1 ) leading to the inhibition of these DNA repair pathways (Federico ef a/, 20 0 ibid). In vitro studies in cell lines have shown that combination treatments of sapacitabine and seliciclib are most synergistic in inducing cell death when used sequentially rather than concomitantly. However, these studies cannot indicate what adverse effects on the toxicities of the compounds will occur when they are used together (Frame ef al, Proc Am Assoc Cancer Res 2012; 53, Abs 5666). Combination treatments of sapacitabine and seliciclib could be synergistic in ceil lines due to more than one mechanism including: (i) decreased apoptotic threshold through altered expression of apoptotic regulators; (ii) cell cycle effects leading to cell death; and (iii) suppression of DNA repair processes through transcriptional downregulation of repair proteins and additional induction of DNA damage. Each of these mechanisms could require a different clinical dosing schedule of the two drugs to be optimally active.

Surprisingly, the Applicant has found that combining seliciclib and sapacitabine in a dosing regimen where the sapacitabine is administered in two separate periods, interleaved with seliciclib administration does not result in unexpected or exacerbated toxicities due to the combination of the two drugs. Moreover, the presently claimed dosing regimen allows dosing of both drugs at relatively high doses, and more particularly, allows seliciclib to enhance the activity of sapacitabine when administered after or before the sapacitabine. DOSING REGIMEN

As mentioned above, the present invention relates to a method of treating a proliferative disorder in a subject, said method comprising administering to the subject a therapeutically effective amount of (i) sapacitabine, or a metabolite thereof; and (ii) seliciciib; in accordance with a dosing regimen (hereinafter referred to as "Schedule A"), comprising at least one treatment cycle, wherein said treatment cycle comprises:

(b) administering a therapeutically effective amount of seliciciib on 2 to 4 consecutive days;

The treatment cycles may be repeated sequentially and include rest periods between the periods of drug administration. As used herein the term "rest period" means a period during which neither sapacitabine (or a metabolite thereof) nor seliciciib is administered to the subject.

Where there are multiple treatment cycles, there is a rest period between the last day of drug administration of the first treatment cycle and the first day of drug administration of the subsequent treatment cycle. Preferably, the rest period is sufficient to resolve any treatment-related toxicities. Typical treatment-related toxicities include myelosuppression and its associated complications. Myelosuppression refers specifically to a reduction in the ability of the bone marrow to produce red blood cells, platelets and white blood cells. Myelosuppression causes anemia (low levels of red blood cells), neutropenia (low levels of neutrophils) and thrombocytopenia (low levels of platelets). Accordingly, associated complications of myelosuppression include, but are not limited to, fatigue (due to anemia), infections (due to neutropenia) and bruising/bleeding (due to thrombocytopenia).

In one preferred embodiment, steps (a), (b) and (c) are carried out sequentially without a significant gap or rest period in between. For example, in one preferred embodiment, step (b) is carried out sequentially after step (a). Preferably, step (b) is initiated within about 24 hours after step (a) is complete, in another preferred embodiment, step (b) is initiated within about 12 hours after step {a) is complete. In another preferred embodiment, step (b) is initiated within about 36 hours after step (a) is complete. In one preferred embodiment, step (b) is initiated within 24 hours of the last dose of sapacitabine administered in step (a). In one preferred embodiment, step (b) is initiated within about 12 hours after the last dose of sapacitabine administered in step (a). In one preferred embodiment, step (b) is initiated within about 36 hours after the last dose of sapacitabine administered in step (a).

In one preferred embodiment, step (b) is initiated the day after step (a) is complete, i.e. step (a) is completed on one day, and step (b) is initiated the next day. In another preferred embodiment, step (c) is carried out sequentially after step (b). Preferably, step (c) is initiated within about 24 hours after step (b) is complete. In another preferred embodiment, step (c) is initiated within about 12 hours after step (b) is complete. In another preferred embodiment, step (c) is initiated within about 36 hours after step (b) is complete. In one preferred embodiment, step (c) is initiated within 24 hours of the last dose of seliciclib administered in step (b). In one preferred embodiment, step (c) is initiated within about 12 hours after the last dose of seliciclib administered in step (b). In one preferred embodiment, step (c) is initiated within about 36 hours after the last dose of seliciclib administered in step (b). In one preferred embodiment, step (c) is initiated the day after step (b) is complete, i.e. step (b) is completed on one day, and step (c) is initiated the next day.

In one preferred embodiment, step (b) is initiated before step (a) is complete, such that there is partial overlap between steps (a) and (b). For example, in one embodiment, step (b) is initiated on the same day as the last day of administration of sapacitabine in step (a). Preferably, step (b) is initiated no less than about 8 hours after the last dose of sapacitabine administered in step (a). More preferably, step (b) is initiated from about 8 to about 12 hours after the last dose of sapacitabine administered in step (a). In one preferred embodiment, step (b) is initiated from about 12 to about 24 hours after the last dose of sapacitabine administered in step (a). In one preferred embodiment, step (b) is initiated from about 24 to about 36 hours after the last dose of sapacitabine administered in step (a).

In one preferred embodiment, step (c) is initiated before step (b) is complete, such that there is partial overlap between steps (b) and (c). For example, in one embodiment, step (c) is initiated on the same day as the last day of administration of seliciclib in step (b). Preferably, step (c) is initiated no less than about 8 hours after the last dose of seliciclib administered in step (b). More preferably, step (c) is initiated from about 8 to about 12 hours after the last dose of seliciclib administered in step (b). In one preferred embodiment, step (c) is initiated from about 12 to about 24 hours after the last dose of seliciclib administered in step (b). In one preferred embodiment, step (c) is initiated from about 24 to about 36 hours after the last dose of seliciclib administered in step (b). In another preferred embodiment, steps (a) and (b) are separated by an additional rest period, preferably of up to about 7 days, or until treatment-related toxicities are resolved, whichever is longer. More preferably, steps (a) and (b) are separated by an additional rest period of 1 or 2 or 3 or 4 or 5 or 6 or 7 days. Likewise, steps (b) and (c) can also be separated by an additional rest period, preferably of up to about 7 days, or until treatment-related toxicities are resolved, whichever is longer. More preferably, steps (a) and (b) are separated by an additional rest period of 1 or 2 or 3 or 4 or 5 or 6 or 7 days. Even more preferably, the additional rest period is about 7 days, if additional rest periods are present, the rest period between the treatment cycles corresponding to step (d), can be adjusted accordingly.

In one particularly preferred embodiment, steps (b) and (c) are separated by an additional rest period of up to about 7 days or until seiiciclib-related toxicities are resolved, whichever is longer. Selicic!ib-related toxicities include, but are not limited to, fatigue, nausea, vomiting, blood salt imbalance (e.g. low potassium or sodium), and anaemia.

In one preferred embodiment, the treatment cycle comprises:

(b) administering a therapeutically effective amount of seliciclib on 3 consecutive days; (c) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on 3 to 5 consecutive days in a second period; and

The first and second periods of sapacitabine dosing in any one treatment cycle can be of the same or different duration, and may involve the same or different dosages. Preferably, the first and second periods in any one treatment cycle are of the same duration, and involve administering the same dosage.

In one preferred embodiment, step (a) comprises administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on 5 consecutive days.

In another preferred embodiment, step (a) comprises administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on 3 consecutive days.

In one preferred embodiment, step (b) comprises administering a therapeutically effective amount of seliciclib on 3 consecutive days. In one preferred embodiment, step (c) comprises administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, for 5 consecutive days.

In another preferred embodiment, step (c) comprises administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on 3 consecutive days.

In one highly preferred embodiment, the treatment cycle is 28 days in length.

In one highly preferred embodiment, the treatment cycle comprises:

(i) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 1 to 5, and days 9 to 13;

(ii) administering a therapeutically effective amount of seliciclib on days 6 to 8; and (ii) a rest period of at least 10 days, or until treatment-related toxicities are resolved, whichever is longer. Preferably, for this embodiment, the rest period is at least 2 weeks. More preferably, for this embodiment the treatment cycle is 28 days in length and comprises a rest period from days 14 to 28, i.e. the rest period is 15 days (i.e. 15 drug- free days) from the last day of sapacitabine administration of one treatment cycle to the first day of sapacitabine administration of the subsequent treatment cycle.

In another highly preferred embodiment, the treatment cycle comprises:

(i) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 1 to 3, and days 7 to 9;

(ii) administering a therapeutically effective amount of seliciclib on days 4 to 6; and (ii) a rest period of at least 10 days, or until treatment-related toxicities are resolved, whichever is longer.

Preferably, for this embodiment, the rest period is at least 2 weeks. More preferably, for this embodiment the treatment cycle is 28 days in length and comprises a rest period from days 10 to 28, i.e. the rest period is 19 days (i.e. 19 drug- free days) from the last day of sapacitabine administration of one treatment cycle to the first day of sapacitabine administration of the subsequent treatment cycle. In one highly preferred embodiment, there is an additional rest period after administration of the seliciclib and before administration of the sapacitabine in the second period. Preferably, the additional rest period is up to 7 days, more preferably, 1 or 2 or 3 or 4 or 5 or 6 or 7 days, even more preferably, 7 days. In another highly preferred embodiment, said treatment cycle comprises:

(i) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 1 to 3;

(it) administering a therapeutically effective amount of seliciclib on days 4 to 6;

(iii) a rest period on days 7 to 13;

(iv) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 14 to 6; and

(v) a rest period of at least 10 days, or until treatment-related toxicities are resolved, whichever is longer. Preferably, for this embodiment the treatment cycle is 28 days in length and comprises a rest period from days 17 to 28, i.e. the rest period is 12 days (i.e. 12 drug-free days) from the last day of sapacitabine administration of one treatment cycle to the first day of sapacitabine administration of the subsequent treatment cycle.

In one preferred embodiment:

• sapacitabine, or a metabolite thereof is administered on days 1 to 5 and days 9 to 13, followed by a drug-free period of 15 days before the first day of sapacitabine administration in the subsequent treatment cycle; and

· seliciclib is administered on days 6 to 8, followed by a drug-free period of 20 days until the first day of sapacitabine administration in the subsequent treatment cycle.

In another preferred embodiment:

· sapacitabine, or a metabolite thereof is administered on days 1 to 3 and days 7 to 9, followed by a drug-free period of 19 days before the first day of sapacitabine administration in the subsequent treatment cycle; and

• seliciclib is administered on days 4 to 6, followed by a drug-free period of 22 days until the first day of sapacitabine administration in the subsequent treatment cycle.

In another preferred embodiment:

• sapacitabine, or a metabolite thereof is administered on days 1 to 3 and days 14 to 16, followed by a drug-free period of 12 days before the first day of sapacitabine administration in the subsequent treatment cycle; and

• seliciclib is administered on days 4 to 6, followed by a drug-free period of 22 days until the first day of sapacitabine administration in the subsequent treatment cycle. In one preferred embodiment, the dosing regimen comprises two or more of said treatment cycles, more preferably, three or more, four or more, or five or more of said treatment cycles.

In one preferred embodiment, the seliciclib is administered orally. In one preferred embodiment, the seliciclib is administered twice daily (b. i.d.).

In one preferred embodiment, the seliciclib is administered in a dose of from about 200 mg to about 1600 mg per day, more preferably from about 400 mg to about 1600 mg, even more preferably from about 800 to about 1600 mg per day. Preferably, the seliciclib is administered in unit dosage form, wherein said unit dosage is 100 mg, 200 mg or 400 mg, more preferably 200 mg or 400 mg.

In one preferred embodiment, the seliciclib is administered in a dose of about 200 mg to about 800 mg twice a day, more preferably, from about 300 mg to about 800 mg twice a day, more preferably from about 400 mg to about 800 mg twice a day.

In one highly preferred embodiment, the seliciclib is administered in a dose of about 400 mg twice a day.

In another highiy preferred embodiment, the seliciclib is administered in a dose of about 600 mg twice a day.

In another highly preferred embodiment, the seliciclib is administered in a dose of about 800 mg twice a day.

In one preferred embodiment, the dosing regimen comprises two or more of said treatment cycles, and the seliciclib dose is escalated. In one preferred embodiment, the seliciclib dose is escalated with each successive treatment cycle.

In an alternative embodiment, two or more treatment cycles are administered at each dose before escalating. Preferably, two, three or four treatment cycles are administered at each dose before escalating.

Preferably, the seliciclib is initially administered in a dose of 400 mg twice a day, and is escalated to 600 mg twice a day through to 800 mg twice a day. In one preferred embodiment, the seiiciclib dose is escalated in increments of 25 mg, or 50 mg, or 75 mg or 100 mg with each successive treatment cycle.

In one preferred embodiment, the seiiciclib is administered in a dose of 400 mg twice daily for 3 consecutive days on days 6 to 8. Preferably, this is followed by a rest period of 20 days free from seiiciclib.

In one preferred embodiment, the sapacitabine, or metabolite thereof, is administered orally.

In one preferred embodiment, the sapacitabine, or metabolite thereof, is administered in a fixed dose, i.e. the dose is the same in each of the first and second periods of a treatment cycle. Preferably, the dose of sapacitabine, or metabolite thereof, is the same in successive treatment cycles.

In one preferred embodiment, the sapacitabine or metabolite thereof is administered in a dose of about 50 mg to about 350 mg per day, more preferably from about 75 to about 300 mg per day, even more preferably from about 100 to about 300 mg per day, or from about 150 to about 250 mg per day.

In one preferred embodiment, the sapacitabine or metabolite thereof is administered in a dose of about 200 mg to 300 mg per day.

In one preferred embodiment, the sapacitabine or metabolite thereof is administered in a dose of about 250 mg per day.

In one preferred embodiment, the sapacitabine is administered once daily (q. d. ).

In one preferred embodiment, the sapacitabine, or metabolite thereof, is administered in a dose of 250 mg per day once a day for 5 consecutive days, for two weeks (on days 1 to 5 and 9 to 13). Preferably, this is followed by a rest period of 15 days free from sapacitabine, or metabolite thereof.

In one preferred embodiment, the seiiciclib and sapacitabine are each administered in a therapeutically effective amount with respect to the individual components; in other words, the seficiclib and sapacitabine are administered in amounts that would be therapeutically effective even if the components were administered other than in combination, In one preferred embodiment, the seliciclib and sapacitabine are each administered in a sub-therapeutic amount with respect to the individual components; in other words, the seliciclib and sapacitabine are administered in amounts that would be therapeutically ineffective if the components were administered other than in combination.

Preferably, the sapacitabine and seliciclib interact in a synergistic manner. As used herein, the term "synergistic" means that sapacitabine and the seliciclib produce a greater effect when used in combination than would be expected from adding the individual effects of the two components. Advantageously, a synergistic interaction may allow for lower doses of each component to be administered to a patient, thereby decreasing the toxicity of chemotherapy, whilst producing and/or maintaining the same therapeutic effect. Thus, in a particularly preferred embodiment, each component can be administered in a sub-therapeutic amount. One highly preferred embodiment of the invention relates to a method of treating a proliferative disorder in a subject, said method comprising administering to the subject a therapeutically effective amount of (i) sapacitabine; and (ii) seliciclib; in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises:

(a) administering a dose of about 250 mg sapacitabine once a day on days 1 to 5 in a first period; and

(b) administering a dose of about 400 mg seliciclib twice a day on days 6 to 8;

(c) administering a dose of about 250 mg sapacitabine once a day on days 9 to 13 in a second period; and

(d) a rest period of 15 days.

Preferably, the seliciclib dose is escalated from 400 to 600 to 800 mg according to tolerability. Another aspect of the invention relates to the use of (i) sapacitabine, or a metabolite thereof; and (ii) se!iciclib; in the preparation of a medicament for treating a proliferative disorder, wherein the sapacitabine, or metabolite thereof, and the seliciclib are administered in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises:

(d) a rest period of at least 10 days, or until treatment-related toxicities are resolved, whichever is longer. As used herein the phrase "preparation of a medicament" includes the use of the components of the invention directly as the medicament in addition to their use in any stage of the preparation of such a medicament.

Another aspect of the invention relates to (i) sapacitabine, or a metabolite thereof; and (ii) seliciclib; for use in treating a proliferative disorder, wherein the sapacitabine, or metabolite thereof, and the seliciclib are administered in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises:

(d) a rest period of at least 10 days, or until treatment-related toxicities are resolved, whichever is longer.

Another aspect of the invention relates to a kit of parts comprising:

(i) sapacitabine, or a metabolite thereof;

(ii) seliciclib and (iii) instructions for administering sapacitabine, or a metabolite thereof, and seliciclib in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises:

Preferably, the kit of parts is for treating a proliferative disorder in a subject. PROLIFERATIVE DISORDERS

The term "proliferative disorder" is used herein in a broad sense to include any disorder that requires control of the cell cycle, for example cardiovascular disorders such as restenosis and cardiomyopathy, auto-immune disorders such as glomerulonephritis and rheumatoid arthritis, dermatological disorders such as psoriasis, anti-inflammatory, anti-fungal, antiparasitic disorders such as malaria, emphysema and alopecia. In these disorders, the compounds of the present invention may induce apoptosis or maintain stasis within the desired cells as required. Preferably, the proliferative disorder is a cancer or leukaemia, most preferably cancer of the lung, prostate, bladder, head and neck, colon, sarcoma or lymphoma.

In one preferred embodiment, the proliferative disorder is a solid tumor, more preferably selected from breast cancer (including, for example, triple negative breast cancer), ovarian cancer (including, for example, high grade serious ovarian cancer, HGS-OvCa), pancreatic cancer (including, for example, pancreatic ductal adenocarcinoma, PDAC), nasopharyngeal cancer, uterine cancer, colon cancer, lung cancer and leiomyosarcoma.

In one preferred embodiment, the cancer is has a germline mutation. As used herein the term "germline mutation" refers to any detectable and heritable variation in the lineage of germ cells. Mutations in these cells are transmitted to offspring, whereas those in somatic cells are not. A germline mutation gives rise to a constitutional mutation in the offspring, that is, a mutation that is present in virtually every cell. High- risk mutations, for example those which disable an important error-free DNA repair process (homology directed repair), significantly increase a subject's risk of developing certain types of cancers.

In one preferred embodiment, the germline mutation is a deleterious mutation and the change is proven to cause significant risks. Often, these are frameshift mutations that prevent the cell from producing more than the first part of the necessary protein. Deleterious mutations have high, but not complete, genetic penetrance, which means that subjects with the mutation have a high risk of developing disease as a result, but that some subjects will not develop cancer despite carrying a harmful mutation.

In one preferred embodiment, the cancer has a BRCA1 and/or a BRACA2 gene mutation. In one preferred embodiment, the cancer has a BRCA1 gene mutation. In another preferred embodiment, the cancer has a BRACA2 gene mutation. Preferably, the cancer is a breast, ovarian (more preferably HGS-OvCa), pancreatic (more preferably PDAC), prostate, non-small cell lung cancer or colon cancer having a BRCA1 and/or a BRACA2 gene mutation, more preferably, breast cancer having a BRCA1 and/or a BRACA2 gene mutation, even more preferably, triple negative breast cancer.

A BRCA mutation is a mutation in either of the genes BRCA 1 and BRCA2. Both BRCA genes are tumor suppressor genes that produce proteins that are used by the cell in an enzymatic pathway that makes very precise, perfectly matched repairs to DNA molecules that have double-stranded breaks. The pathway requires proteins produced by several other genes, including CHEK2, FANCD2 and A TM. Harmful mutations in any of these genes disable the gene or the protein that it produces and give rise to a hereditary breast-ovarian cancer syndrome in affected families. High-risk mutations significantly increase a subject's risk of developing breast cancer, ovarian cancer and certain other cancers. The cancer risk associated with any given mutation varies significantly and depends on the exact type and location of the mutation and possibly other individual factors. Women with harmful mutations in either BRCA 1 or BRCA2 have risk of breast cancer that is about five times the normal risk, and a risk of ovarian cancer that is about ten to thirty times normal. BRCA 1 mutations typically confer a higher risk of breast and ovarian cancer in women than BRCA2 mutations. BRCA mutations can also increase the risk of other cancers, such as colon cancer, pancreatic cancer, and prostate cancer. The cancer risk caused by BRCA 1 and BRCA2 mutations is inherited in a dominant fashion. A mutated BRCA gene can be inherited from either parent. There are many variations in BRCA genes, and not all changes confer the same risks. In another preferred embodiment, the cancer has a mutation in one or more genes encoding proteins involved in the homology directed repair process, preferably one or more genes selected from PALB2, FANCA, FANCI, FANCL and FANCC, RAD50, RAD51 , RAD51 C and RAD54L. More preferably, the cancer is a breast, ovarian (including, but not limited to, HGS-OvCa), pancreatic (including, but not limited to, PDAC) or prostate cancer having a gene mutation in one or more of the aforementioned genes.

In another preferred embodiment, the cancer has a mutation in one or more DNA damage response genes involved in homology directed repair, preferably one or more genes selected from ATM, ATR, CHEK1 and CHEK2. More preferably, the cancer is a breast, ovarian (including, but not limited to, HGS-OvCa), pancreatic (including, but not limited to, PDAC) or prostate cancer having a gene mutation in one or more of the aforementioned genes. In another preferred embodiment, the cancer has a mutation in one or more genes associated with the homologous recombination (HR) repair pathway. Homologous recombination repair is a type of homology directed repair used by cells to accurately repair double-stranded DNA breaks. Suitable techniques for identifying cancers having such mutations would be familiar to a person skilled in the art. By way of example, in addition to RNA or DNA sequence analysis of genes known to be involved in HR repair, various methods are available to detect tumours with homologous recombination deficiency (HRD). See, for example, Abkevich, V. ei al (British Journal of Cancer (2012) 107, 776-1782), which describes a loss of heterozygosity (LOH) assay in the form of a DNA-based HRD score based on genome-wide LOH analysis. The assay is based on the characteristic that tumours with HR deficiency manifest a specific pattern of LOH. In addition to BRCA1 and BRCA2 defects, high HRD score was significantly associated with RAD51 C deficiency in two data sets. Elevated HRD scores were also seen in PTEN-deficient tumours. Likewise, Popova ef al {Cancer Res (2012) 72(21 ):5454-62) describe an assay using single-nucleotide polymorphism arrays, based on the finding that large scale chromosomal breaks, defined as chromosomal breaks between adjacent regions of at least 10 Mb, are strongly predictive of BRCA1 or BRCA2 inactivation regardless of the mechanism of inactivation. This assay predicted BRCA1/2 inactivation in basal-like breast carcinomas with 100% sensitivity and 90% specificity (97% accuracy).

In a particularly preferred embodiment, the invention relates to the use of the dosing regimen described hereinbefore in the treatment of a CDK-dependent or sensitive proliferative disorder, CDK-dependent disorders are associated with an above normal level of activity of one or more CDK enzymes. Such disorders are preferably associated with an abnormal level of activity of CDK2 and/or CDK4. A CDK sensitive disorder is a disorder in which an aberration in the CDK level is not the primary cause, but is downstream of the primary metabolic aberration. In such scenarios, CDK2 and/or CDK4 can be said to be part of the sensitive metabolic pathway and CDK inhibitors may therefore be active in treating such disorders. Such disorders are preferably cancer or leukemic disorders.

Surprisingly, the administration of seliciclib in accordance with the presently claimed dosing regimen is able to potentiate the effect of sapacitabine in cancers having a BRCA 1 and/or a BRCA2 gene mutation. Cells deficient in HR repair function or components of the HR repair pathway, such as BRCA 1 and BRCA2 are substantially sensitized to CNDAC (the active metabolite of sapacitabine), thus sapacitabine may be particularly effective in patients with BRCA 1/2- or HR repair-deficient tumours, such as subsets of breast cancer (including triple negative breast cancer), ovarian, non-small cell lung cancer, prostate, pancreatic and colon cancer. Moreover, seliciclib has been shown to reduce the expression of BRCA 1 and BRCA2, and has been shown to inhibit DSB repair, and which may contribute to the synergistic activity observed with CNDAC and seliciclib. A phenomenon called "BRCAness" has been reported for cancers that phenotypicaily resemble BRCA1 or BRCA2 mutated cancers but do not result from inactivating germline mutations in BRCA1 or BRCA2. Importantly tumours that display "BRCAness" show a similar deficiency in homology directed repair function. Thus, in one preferred embodiment, the tumour displays BRCAness, but has no mutation in BRCA1 or BRCA2.

In one preferred embodiment, the cancer has a defect in the homology directed repair process caused by alterations in genes other than those directly coding for proteins directly involved in the homology directed repair process, but which are known to modulate the homology directed repair process and indirectly cause a deficiency in homology directed DNA repair. For example, CDK12 is known to promote the transcription of several homology directed repair process genes including BRCA1. Inactivation of CDK12 has been observed in ovarian cancer and leads to suppression of homology directed repair via reduced expression of BRCA1 and other homology directed repair genes. Preferably, the cancer is a breast, ovarian, pancreatic or prostate cancer having a defect in the homology directed repair process.

In one preferred embodiment, the cancer has a defect in the homology directed repair process caused by epigenetic silencing of genes coding for proteins involved in the homology directed repair process. Preferably, the cancer is a breast, ovarian, pancreatic or prostate cancer having an epigenetic defect in the homology directed repair process. For example, epigenetic silencing via promoter hypermethylation of BRCA1 has been observed in epithelial ovarian cancers (EOC) and BRCA1 promoter hypermethylation has been reported in approximately 10-20% of high-grade serous ovarian carcinomas which make up the majority of EOC.

METABOLITE

As used herein, the term "metabolite" encompasses chemically modified entities that are produced by metabolism of sapacitabine.

In one particularly preferred embodiment of the invention, the metabolite of sapacitabine is 2'-C'-cyano-2'-dioxy-1-p-D-arabino-pentofuranosyl cytosine (CNDAC). In another particularly preferred embodiment of the invention, sapacitabine is metabolized intracellular^ to the active metabolite CNDAC-triphosphate (CNDACTP), a process involving both the cleavage of the paimitoyl moiety and activation to CNDACTP by the action of nucleoside kinases.

SALTS/ESTERS

The agents of the present invention can be present as salts or esters, in particular pharmaceutically acceptable salts or esters. Pharmaceutically acceptable salts of the agents of the invention include suitable acid addition or base salts thereof. A review of suitable pharmaceutical salts may be found in Berge et a/, J Pharm Sci, 66, 1-19 (1977). Salts are formed, for example with strong inorganic acids such as mineral acids, e.g. sulphuric acid, phosphoric acid or hydrohalic acids; with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycoiic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (C C₄)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-toluene sulfonic acid.

Esters are formed either using organic acids or alcohols/hydroxides, depending on the functional group being esterified. Organic acids include carboxylic acids, such as alkanecarboxylic acids of 1 to 12 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acid, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycoiic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (C-rC₄)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p- toluene sulfonic acid. Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide. Alcohols include alkanealcohols of 1-12 carbon atoms which may be unsubstituted or substituted, e.g. by a halogen). ENANTIOMERS/TAUTOMERS

The invention also includes where appropriate all enantiomers and tautomers of the agents. The man skilled in the art will recognise compounds that possess an optical properties (one or more chiral carbon atoms) or tautomeric characteristics. The corresponding enantiomers and/or tautomers may be isolated/prepared by methods known in the art.

STEREO AND GEOMETRIC ISOMERS

Some of the agents of the invention may exist as stereoisomers and/or geometric isomers - e.g. they may possess one or more asymmetric and/or geometric centres and so may exist in two or more stereoisomeric and/or geometric forms. The present invention contemplates the use of all the individual stereoisomers and geometric isomers of those inhibitor agents, and mixtures thereof. The terms used in the claims encompass these forms, provided said forms retain the appropriate functional activity (though not necessarily to the same degree).

The present invention also includes all suitable isotopic variations of the agent or pharmaceutically acceptable salts thereof. An isotopic variation of an agent of the present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into the agent and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as ^ZH, ³H, ¹³C, ¹⁴C, ¹⁵N_S ¹⁷0, ¹⁸0, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶CI, respectively. Certain isotopic variations of the agent and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as ³H or ¹⁴C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., ³H, and carbon-14, i.e., ¹¾, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the agent of the present invention and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents. SOLVATES

The present invention also includes solvate forms of the agents of the present invention. The terms used in the claims encompass these forms. POLYMORPHS

The invention furthermore relates to agents of the present invention in their various crystalline forms, polymorphic forms and (an)hydrous forms. It is well established within the pharmaceutical industry that chemical compounds may be isolated in any of such forms by slightly varying the method of purification and or isolation form the solvents used in the synthetic preparation of such compounds.

PRODRUGS

The invention further includes agents of the present invention in prodrug form. Such prodrugs are generally compounds wherein one or more appropriate groups have been modified such that the modification may be reversed upon administration to a human or mammalian subject. Such reversion is usually performed by an enzyme naturally present in such subject, though it is possible for a second agent to be administered together with such a prodrug in order to perform the reversion in vivo. Examples of such modifications include ester (for example, any of those described above), wherein the reversion may be carried out be an esterase etc. Other such systems will be well known to those skilled in the art.

ADMINISTRATION

The pharmaceutical compositions of the present invention may be adapted for oral, rectal, vaginal, parenteral, intramuscular, intraperitoneal, intraarterial, intrathecal, intrabronchial, subcutaneous, intradermal, intravenous, nasal, buccal or sublingual routes of administration.

For oral administration, particular use is made of compressed tablets, pills, tablets, gellules, drops, and capsules. Preferably, these compositions contain from 1 to 2000 mg and more preferably from 50-1000 mg, of active ingredient per dose.

Other forms of administration comprise solutions or emulsions which may be injected intravenously, intraarterially, intrathecal^, subcutaneously, intradermal!y, intraperitoneally or intramuscularly, and which are prepared from sterile or sterilisab!e solutions. The pharmaceutical compositions of the present invention may also be in form of suppositories, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or dusting powders.

An alternative means of transdermal administration is by use of a skin patch. For example, the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. The active ingredient can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilisers and preservatives as may be required.

Injectable forms may contain between 10 - 1000 mg, preferably between 10 - 500 mg, of active ingredient per dose.

Compositions may be formulated in unit dosage form, i.e., in the form of discrete portions containing a unit dose, or a multiple or sub-unit of a unit dose.

DOSAGE

A person of ordinary skill in the art can easily determine an appropriate dose of one of the instant compositions to administer to a subject without undue experimentation. Typically, a physician will determine the actual dosage which will be most suitable for an individual patient and it will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy. The dosages disclosed herein are exemplary of the average case. There can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention. Dosages and frequency of application are typically adapted to the general medical condition of the patient and to the severity of the adverse effects caused, in particular to those caused to the hematopoietic, hepatic and to the renal system. Depending upon the need, the agent may be administered at a dose of from about 0.1 to about 30 mg/kg body weight, more preferably, from about 2 to about 20 mg/kg body weight, even more preferably from 2 to 15 mg/kg body weight. By way of guidance, sapacitabine is typically administered at dosages between 50 mg and 350 mg per dose orally. Sapacitabine is typically administered from about 50 mg to 300 mg per dose, more preferably from about 200 mg to 300 mg per dose, more preferably about 250 mg per dose. Sapacitabine can be administered as a single dose or administered twice a day. Preferabfy, the sapacitabine is administered once daily.

Seliciclib is typically administered in a dose of from about 200 mg to about 1600 mg per day, more preferably from about 800 to about 1600 mg per day. Preferably, the seliciclib is administered in unit dosage form, wherein said unit dosage is 200 mg or 400 mg. In one preferred embodiment, the seliciciib is administered in a dose of about 200 mg to about 800 mg twice a day, more preferably, from about 300 mg to about 800 mg twice a day, more preferably from about 400 mg to about 800 mg twice a day. In a preferred embodiment, the seliciclib is administered in a dose of about 400 mg twice a day, or about 600 mg twice a day, or about 800 mg twice a day. Preferably, seliciclib is administered orally or intravenously. When administered orally, seliciclib is preferably administered in tablets or capsules. Seliciclib can be administered as a single dose or administered twice a day. Preferably, the seliciclib is administered twice daily.

The present invention is further described by way of example.

EXAMPLES

Methods and Materials

Sapacitabine and seliciclib were manufactured by Cyclacel Limited in accordance with known methodology. For example, sapacitabine was prepared in accordance with the methodology described in EP 536936B (Sankyo Company Limited).

Schedule A

Patients were dosed according to the following schedule (one cycle is 28 days)

• 250 mg sapacitabine once daily x 5 consecutive days x 2 weeks (days 1-5, 9- 13) followed by 15 days of rest; • starting dose of seltciclib of 400 mg twice per day x 3 days on days 6-8 followed by 20 days of rest. Seliciclib dose was escalated from 400 to 600 to 800 according to tolerability. Patient criteria: Adult patients with histologically or cytologically confirmed incurable advanced solid tumors no longer responding to conventional therapy or for which no effective therapy exists; must have evaluable disease; Eastern Cooperative Oncology Group performance status 0-1 ; adequate bone marrow, hepatic and renal function; ability to swallow capsules; >3 weeks from prior systemic treatments including investigational anti-cancer therapy, radiation therapy and have recovered from prior toxicities; at least 3 weeks from major surgery. Patients include those with BRCA 1I2- or HRR-deficient tumours, such as subsets of triple negative breast, ovarian, non-small cell lung cancer, pancreatic and colon cancer. For patients with measurable disease, assessment is by tumor imaging studies; tumor response and progression are assessed using the criteria proposed by the Response Evaluation Criteria in Solid Tumors (REC!ST) Committee (Ref: Therasse P, Arbuck SG, Eisenhauer EA ef a/, New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000; 92:205-16).

Various modifications and variations of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the relevant fields are intended to be covered by the present invention.

Claims

1. A method of treating a proliferative disorder in a subject, said method comprising administering to the subject a therapeutically effective amount of (i) sapacitabine, or a metabolite thereof; and (ii) se!iciclib; in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises:

(b) administering a therapeutically effective amount of selicic!ib on 2 to 4 consecutive days;

2. A method according to claim 1 wherein step (b) is carried out sequentially after step (a).

3. A method according to claim 1 or claim 2 wherein step (c) is carried out sequentially after step (b).

4. A method according to any preceding claim wherein step (b) is initiated the day after step (a) is complete.

5. A method according to any preceding claim wherein step (c) is initiated the day after step (b) is complete.

6. A method according to claim 1 or claim 2 wherein steps (b) and (c) are separated by an additional rest period of up to 7 days or until seliciclib-related toxicities are resolved, whichever is longer.

7. A method according to any preceding claim wherein step (a) comprises administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on 5 consecutive days.

8. A method according to any preceding claim wherein step (b) comprises administering a therapeutically effective amount of seliciclib on 3 consecutive days.

9. A method according to any preceding claim wherein step (c) comprises administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on 5 consecutive days.

10. A method according to claim 1 wherein said treatment cycle comprises:

(ii) administering a therapeutically effective amount of seliciclib on days 6 to 8; and

(ii) a rest period of at least about 10 days, or until treatment-related toxicities are resolved, whichever is longer.

11. A method according to any preceding claim wherein said treatment cycle is 28 days in length.

12. A method according to claim 10 wherein the treatment cycle comprises a rest period from days 4 to 28.

13. A method according to any preceding claim wherein the dosing regimen comprises two or more of said treatment cycles, more preferably, three or more, four or more, or five or more of said treatment cycles.

14. A method according to any preceding claim wherein the seliciclib is administered orally.

15. A method according to any preceding claim wherein the seliciclib is administered in a dose of from about 200 mg to about 1600 mg per day, more preferably from about 800 to about 1600 mg per day.

16. A method according to any preceding claim wherein the seliciclib is administered twice daily {b.i.d.).

17. A method according to any preceding claim wherein the seliciclib is administered in a dose of from about 400 mg to about 800 mg twice a day.

18. A method according to claim 15 or claim 16 wherein the dosing regimen comprises two or more of said treatment cycles, and the seliciclib dose is initiated at about 400 mg twice a day and escalated to about 800 mg twice a day. 9. A method according to claim 18 wherein the seliciclib dose is escalated with each successive treatment cycle.

20. A method according to any preceding claim wherein the sapacitabine, or metabolite thereof, is administered orally.

21. A method according to any preceding claim wherein the sapacitabine or metabolite thereof is administered in a dose of about 50 mg to about 350 mg per day, more preferably from about 100 to about 300 mg per day.

22. A method according to any preceding claim wherein the sapacitabine or metabolite thereof is administered in a dose of about 200 mg to 300 mg per day.

23. A method according to any preceding claim wherein the sapacitabine or metabolite thereof is administered in a dose of about 250 mg per day.

24. A method according to any preceding claim wherein the sapacitabine is administered once daily (q.d.).

25. A method according to any preceding claim wherein the proliferative disorder is cancer.

26. A method according to any preceding claim wherein the proliferative disorder is a solid tumor selected from breast cancer, ovarian cancer, pancreatic cancer, nasopharyngeal cancer, uterine cancer, colon cancer, iung cancer and leiomyosarcoma,

27. A method according to claim 25 wherein the cancer has a germline mutation.

28. A method according to claim 25 wherein the cancer has a BRCA1 and/or a BRACA2 gene mutation.

29. A method according to claim 25 wherein the cancer has a mutation in one or more genes encoding proteins involved in the homology directed repair process.

30. A method according to claim 29 wherein the cancer has a mutation in one or more genes selected from PALB2, FANCA, FANCI, FANCL and FANCC, RAD50, RAD51 , RAD51C and RAD54L

31. A method according to claim 25 wherein the cancer has a mutation in one or more DNA damage response genes involved in homology directed repair.

32. A method according to claim 31 wherein the cancer has a mutation in one or more genes selected from ATM, ATR, CHEK1 and CHEK2.

33. A method according to claim 25 wherein the cancer has a defect in the homology directed repair process caused by alterations in one or more genes other than those directly coding for proteins directly involved in the homology directed repair process, but which are known to modulate the homology directed repair process and indirectly cause a deficiency in homology directed DNA repair.

34. A method according to claim 25 wherein the cancer has a defect in the homology directed repair process caused by epigenetic silencing of genes coding for proteins involved in the homology directed repair process.

35. A method according to any preceding claim wherein the metabolite of sapacitabine is 2'-C'-cyano-2^,-dioxy-1-p-D-arabino-pentofuranosyl cytosine (CNDAC).

36. Use of (i) sapacitabine, or a metabolite thereof; and (ii) seliciclib; in the preparation of a medicament for treating a proliferative disorder, wherein the sapacitabine, or metabolite thereof, and the seliciclib are administered in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises:

37. (i) Sapacitabine, or a metabolite thereof; and (ii) seliciclib; for use in treating a proliferative disorder, wherein the sapacitabine, or metabolite thereof, and the seliciclib are administered in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises:

(d) a rest period of at least about 10 days, or until treatment-related toxicities are resolved, whichever is longer. 38, A kit of parts comprising:

(t) sapacitabine, or a metabolite thereof;

(ii) seliciclib and

(iii) instructions for administering sapacitabine, or a metabolite thereof, and seliciclib in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises:

(d) a rest period of at least about 10 days, or until treatment-related toxicities are resolved, whichever is longer,

39. A kit of parts according to claim 38 for treating a proliferative disorder in a subject.