WO2021079129A1

WO2021079129A1 - Dosing regimen

Info

Publication number: WO2021079129A1
Application number: PCT/GB2020/052667
Authority: WO
Inventors: Judy Chiao
Original assignee: Cyclacel Ltd
Current assignee: Cyclacel Ltd
Priority date: 2019-10-24
Filing date: 2020-10-22
Publication date: 2021-04-29
Anticipated expiration: 2022-04-24

Abstract

The present invention provides a method of treating acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in a subject, said method comprising administering to a subject a therapeutically effective amount of (i) sapacitabine, or a metabolite thereof; and (ii) venetoclax; in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises: (a) (i) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, for 3 consecutive days per week, for 2 weeks, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved, whichever is longer; or (ii) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, for 5 consecutive days followed by a rest period of at least 2 weeks, or until treatment-related toxicities are resolved, whichever is longer; and (b) administering a therapeutically effective amount of venetoclax for about 7 to about 14 consecutive days, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved, whichever is longer.

Description

DOSING REGIMEN

The present invention relates to combination therapy for the treatment of acute myeloid leukemia (AML) or myelodyspiastic syndromes (MDS). In particular, the invention relates to a dosing regimen comprising the administration of venetoclax in combination with sapacitabine, or a metabolite thereof.

BACKGROUND TO THE INVENTION

The present invention seeks to provide new therapeutic dosing regimens for the treatment of AML and/or MDS.

AML is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cells. AML is the most common acute leukemia in adults, accounting for around 80 percent of cases in this group. In 2015, AML affected about one million people and resulted in 147,000 deaths globally. AML most commonly occurs in older adults, with the incidence increasing with age, from -1.3 per 100,000 population in patients less than 65 years old, to 12.2 cases per 100,000 population in those over 65 years.

First-line treatment of AML consists primarily of chemotherapy and is divided into two phases: induction and post-remission (or consolidation) therapy. Specific genetic mutations present within the cancer cells may guide therapy, as well as determine how long that patient is likely to survive. Most AML subtypes are treated with induction chemotherapy with cytarabine (ara-C) and an anthracycline (commonly daunorubicin). This induction chemotherapy regimen is known as "7+3" because the cytarabine is given as a continuous IV infusion for seven consecutive days while the anthracycline is given for three consecutive days as an IV push. Alternative induction regimens include high- dose cytarabine alone. The M3 subtype of AML, also known as acute promyelocytic leukemia (APL), is usually treated with all-trans-retinoic acid (ATRA) in addition to induction chemotherapy, usually with an anthracycline.

In view of the toxic effects of therapy, including myelosuppression and an increased risk of infection, induction chemotherapy may not be offered to older patients due to the increased likelihood of poor outcomes and increased toxicities including drug-related deaths, and the options may include less intense chemotherapy or palliative care. Thus, although advances in the treatment of AML have led to significant improvements in outcomes for younger patients, prognosis in the elderly who account for the majority of new cases remains poor. Even with current treatments, as many as 70% of patients 65 years or older will die of their disease within 1 year of diagnosis (I De Kouchkovsky et al, Blood Cancer J. 2016 Jul; 6(7): e441).

Myelodysplastic syndromes (MDS) are a group of cancers in which immature blood cells in the bone marrow do not mature and therefore do not become healthy blood cells. About seven per 100,000 people are affected with about four per 100,000 people newly acquiring the condition each year. The typical age of onset is 70 years. The outlook depends on the type of cells affected, the number of blasts in the bone marrow or blood, and the changes present in the chromosomes of the affected cells. Some types of MDS may develop into acute myeloid leukemia.

MDS is typically treated with supportive care, drug therapy, and stem cell transplantation. Supportive care may include blood transfusions, medications to increase the making of red blood cells, and antibiotics. Lenalidomide, decitabine and 5-azacitidine have all been approved by the FDA for the treatment of MDS. Treatment with decitabine has been shown to give a complete response rate as high as 43%. A phase I study has also shown efficacy in AML when decitabine is combined with valproic acid (Kantarjian H, et al, " Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome ", Cancer, 109 (2): 265-73; Kantarjian H, et al (2006), " Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study¹', Cancer, 106 (8): 1794-803; Kantarjian H, et al. (2007), " Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia", Blood 109 (1): 52-7; Blum W et al, (2007), "Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia", J. Clin. Oncol. 25 (25): 3884-91). Chemotherapy with 5-azacytidine and decitabine has been shown to decrease blood transfusion requirements and to retard the progression of MDS to AML. Lenalidomide has been shown to be effective in reducing red blood cell transfusion requirement in patients with the chromosome 5q deletion subtype of MDS (List A et al, (2006), "Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion",

N. Engl. J. Med. 355 (14): 1456-65). HLA-matched allogeneic stem cell transplantation, particularly in younger (i.e. less than 40 years of age) and more severely affected patients, offers the potential for curative therapy (Oosterveld M, etal, (2003), "The impact of intensive antileukaemic treatment strategies on prognosis of myelodysplastic syndrome patients aged less than 61 years according to International Prognostic Scoring System risk groups", Br J Haematol. 123 (1): 81-9).

Sapacitabine is an orally available nucleoside analogue prodrug of CNDAC that has been evaluated in the treatment of both solid and hematological tumors, including AML. WO 2008/132443 (Cyclacel Limited) describes various sapacitabine dosing regimens for treating proliferative disorders, including AML.

Sapacitabine can also be used in combination with other therapeutic agents. For example, WO 2005/053699 (Cyclacel Limited) discloses a pharmaceutical combination comprising sapacitabine and a CDK inhibitor, and methods of treatment using the same. WO 2013/171473 (Cyclacel Limited) describes specific dosing regimens for sapacitabine and seliciclib.

Combinations of sapacitabine and DNA methyltransferase inhibitors, and their use in treating various proliferative disorders, are described in WO 2009/150405 (Cyclacel Limited). WO 2012/140436 (Cyclacel Limited) describes an alternating dosing regimen for the treatment of AML using sapacitabine and decitabine. Ravandi et al (Abstract 2630; December 2012; American Society of Hematology) describes pooled patient data for a Phase 1/2 trial in AML patients of greater than 70 years of age, treated in accordance with a dosing regimen comprising administering decitabine at a rate of 20 mg/m² for 5 days a week of a 4 week cycle (odd cycles), and administering sapacitabine at a rate of 300 mg b.i.d. for 3 days a week for 2 weeks of 4 week cycle (even cycles). The results of this study indicated that the sequential combination of decitabine and sapacitabine appears to be safe and effective.

WO 2019/081951 (Cyclacel Limited) describes a sapacitabine/decitabine dosing regimen in various patient subgroups defined in terms of their white blood cell count and/or cytogenetic risk classification according to the US Southwest Oncology Group (SWOG) and/or disease classification (antecedent myelodysplastic syndrome, antecedent myeloproliferative neoplasm, and antecedent myelodysplastic/myeloproliferative neoplasm). The present invention seeks to provide a new therapeutic combination for treating AML and/or MDS. In particular, the present invention seeks to optimise combination dosing regimens for sapacitabine in the treatment of AML and/or MDS to maximise drug efficacy, whilst minimising adverse side effects. There is no paradigm for determining the ideal dose and schedule of drugs in general. Due to differences in mechanism and pharmacokinetic/pharmacodynamic properties, it is necessary to experimentally determine the correct schedule for each drug. Often, dosing at the highest level for as long as possible is not always the best solution, and finding the correct balance of dose level and number of consecutive doses depends on the drug in question and the patient population.

STATEMENT OF INVENTION

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

(a) (i) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, for 3 consecutive days per week, for 2 weeks, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved, whichever is longer; or

(ii) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, for 5 consecutive days followed by a rest period of at least 2 weeks, or until treatment-related toxicities are resolved, whichever is longer; and

(b) administering a therapeutically effective amount of venetoclax for about 7 to about 14 consecutive days, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved, whichever is longer.

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 venetoclax in accordance 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 a preferred embodiment, the dosing regimen of the invention produces an enhanced effect as compared to either drug administered alone.

In particular, the administration of sapacitabine and venetoclax 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. Moreover, the presently claimed dosing regimen is well tolerated and gives rise to excellent response rates, good survival rates and absence of cumulative toxicities.

A second aspect of the invention relates to (i) sapacitabine, or a metabolite thereof; and (ii) venetoclax; for use in treating AML or MDS in a subject, wherein the sapacitabine, or a metabolite thereof, and the venetoclax 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 the use of (i) sapacitabine, or a metabolite thereof; and (ii) venetoclax; in the preparation of a medicament for treating AML or MDS, wherein the sapacitabine, or a metabolite thereof, and the venetoclax are administered in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises: (a) (i) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, for 3 consecutive days per week, for 2 weeks, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved, whichever is longer; or

A fourth aspect of the invention relates to a kit of parts comprising: sapacitabine, or a metabolite thereof; venetoclax; and instructions for administering sapacitabine, or a metabolite thereof, and venetoclax in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises:

A fifth aspect of the invention relates to a combination comprising (i) sapacitabine, or a metabolite thereof; and (ii) venetoclax; for use in treating AML or MDS in a subject. DETAILED DESCRIPTION

Aspects of the invention are presented in the accompanying claims. Preferred embodiments are described below in respect of the first aspect of the invention. These preferred embodiments apply equally to the second to fifth aspects of the invention.

The present invention relates to a new dosing regimen for treating AML and/or MDS in a subject which comprises the administration of sapacitabine, or a metabolite thereof, in conjunction with venetoclax.

Sapacitabine

Sapacitabine is the compound 1-(2-C-cyano-2-deoxy-β-D-arabino-pentofuranosyl)-N⁴- palmitoyl cytosine (I), also known as 2'-cyano-2'-deoxy-N⁴-palmitoyl-1-p-D- arabinofuranosylcytosine (Hanaoka, K., etal, Int. J. Cancer, 1999:82:226-236 ; Donehower R, etal, ProcAm Soc Clin Oncol, 2000: abstract 764; Burch, PA, etal, Proc Am Soc Clin Oncol, 2001: abstract 364). 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 or 2'-C-cyano-2'-deoxy-1-p-D-arabino- pentofuranosyl 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-tumor 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 into DNA can be transformed into DNA double-strand breaks during subsequent rounds of replication (Liu etal, Cancer Res 2005; 65 (15) Aug 1, 6874-6881; Liu etal, Blood, 9 Sept 2010; Col 116; No. 10; 1737-1746). This type of DNA damage is different from that caused by other nucleoside analogues such as ara-C and gemcitabine, which terminate or pause DNA synthesis at the site of incorporation. This unique strand-breaking action seems to be the basis of CNDAC's ability to induce cell cycle arrest at the G2 phase, as distinct from the S-phase block seen with ara-C or gemcitabine. Repair of CNDAC- induced DNA breaks is dependent on components of these double-strand break (DSB) repair pathways and, in particular, defects in homologous recombination (HR) repair have been shown to sensitize cell lines to CNDAC (Liu et 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 tumors. 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 gemcitabine or 5-FU in terms of increasing survival and also preventing the spread of colon cancer metastases to the liver (Wu M, et al, Cancer Research, 2003:63:2477- 2482).

To date, clinical data from patients with a variety of cancers suggest that sapacitabine is well tolerated in humans. The phase I studies of single-agent sapacitabine in solid tumors identified myelosuppression as the dose-limiting toxicity (DLT) (Delaunoit T., Burch, P. A., Reid, J. M., et al: “A phase I clinical and pharmacokinetic study of CS-682 administered orally in advanced malignant solid tumors", Invest New Drugs 24:327-333, 2006; Gilbert, J., Carducci, M. A., Baker, S. D., et al “A phase I study of the oral antimetabolite, CS-682, administered once daily 5 days per week in patient with refractory solid tumor malignancies”, Invest New Drugs 24:499-508, 2006). In elderly patients with AML, toxicities were mostly myelosuppression-related. The major non- haematological toxicities were gastrointestinal, and were mostly mild to moderate in nature (Kantarjian, H. et al Lancet Oncology 2012 13:1096-1104, “Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients: a randomised phase 2 study’). Venetoclax

Venetoclax is a selective inhibitor of BCL-2 protein. It is a light yellow to dark yellow solid with the empirical formula C₄₅H₅₀CIN₇O₇S and a molecular weight of 868.44. Venetoclax has very low aqueous solubility. Venetoclax is described chemically as 4-(4-{[2-(4- chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4- [(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5- yloxy)benzamide) or 4-(4-{[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl}-1- piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H- pyrrolo[2,3-b]pyridin-5-yloxy)benzamide, and has the following chemical structure:

Venetoclax

Venetoclax is marketed under the trade names Venclexta and Venclyxto and is a selective and orally bioavailable small-molecule inhibitor of BCL-2, an antiapoptotic protein (Roberts, A; Huang, D (January 2017), "Targeting BCL2 With BH3 Mimetics: Basic Science and Clinical Application of Venetoclax in Chronic Lymphocytic Leukemia and Related B Cell Malignancies: Basic science and clinical application of venetoclax"; Clinical Pharmacology & Therapeutics, 101 (1): 89-98). Overexpression of BCL-2 has been demonstrated in CLL and AML cells where it mediates tumor cell survival and has been associated with resistance to chemotherapeutics. Venetoclax helps restore the process of apoptosis by binding directly to the BCL-2 protein, displacing pro-apoptotic proteins like BIM, triggering mitochondrial outer membrane permeabilization and the activation of caspases. In nonclinical studies, venetoclax has demonstrated cytotoxic activity in tumor cells that overexpress BCL-2.

Venetoclax is approved for for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received one prior therapy. The recommended dosage for CLL/SLL involves a 5 week ramp up to a daily dose of 400 mg (see Venetoclax label; revised 4/2016; https://www.accessdata.fda.gov/drugsatfda docs/label/2016/208573s000Ibl.pdf). Konopleva et al report on the efficacy and biological correlates of response in a Phase 2 study of venetoclax monotherapy in patients with AML (Cancer Discov. 2016 October; 6(10): 1106-1117).

Venetoclax is also approved for use in combination with azacitidine or decitabine or low- dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy. The recommended dosage for combination therapy of AML involves a 4 day ramp up to a daily dose of 400 mg when administered in combination with azacitidine or decitabine, or a 4 day ramp up to a daily dose of 600 mg when administered in combination with low-dose cytarabine (see Venetoclax label; revised 05/2019; https://www.accessdata.fda.gov/drugsatfda docs/label/2019/208573s013Ibl.pdf). Di

Nardo et al report on the safety and efficacy of venetoclax in combination with decitabine or azacitidine in treatment naive elderly patients with AML (Blood, 3 January 2019; Vol 133; No: 1; p7-17). Di Nardo et al also report on venetoclax combination therapy for relapsed and refractory AML and related myeloid malignancies (Am. J. Hematol. 2018; 93; p401-407).

Concomitant use of venetoclax with a strong or moderate CYP3A inhibitor or a Pgp inhibitor increases venetoclax C_max and AUC_inf, which may increase venetoclax toxicities. Venetoclax requires dosage modification based on concomitant use with a strong or moderate CYP3A inhibitor or Pgp inhibitor at initiation, during, or after the ramp-up phase (see Venetoclax label; revised 05/2019; https://www.accessdata.fda.gov/druqsatfda docs/label/2019/208573s013Ibl.pdf) Drug Interactions (7.1)).

EXCIPIENTS, DILUENTS AND CARRIERS

The active agents used in the dosing regimens described herein can be administered alone, or as a mixture with an appropriate pharmacologically acceptable excipient(s), and/or diluent(s) and/or carrier(s). The choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s). The pharmaceutical compositions may be for human or animal usage in human and veterinary medicine.

Examples of suitable may be found in the “Handbook of Pharmaceutical Excipients, 2^nd Edition, (1994), Edited by A Wade and PJ Weller. An example of an excipient includes a sugar derivative such as lactose, sucrose, glucose, mannitol, or sorbitol; a starch derivative such as corn starch, potato starch, alpha -starch, dextrin, carboxy methylstarch; a cellulose derivative such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethyl-cellulose, calcium carboxymethylcellulose, internal-cross-linked sodium carboxymethylcellulose; acacia; dextran; pullulan; a silicate derivative such as light silicic acid anhydride, synthetic aluminum silicate, magnesium aluminate metasilicate; a phosphate derivative such as calcium phosphate; a carbonate derivative such as calcium carbonate; a sulfate derivative such as calcium sulfate; or the like.

Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). Examples of suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like. Examples of suitable diluents include ethanol, glycerol and water.

An example of a disintegrating agent includes an excipient described hereinbefore, a chemically modified starch or cellulose derivative such as sodium cross-carmellose, sodium carboxymethylstarch, cross-linked polyvinylpyrrolidone or the like.

Preservatives, stabilizers, dyes and even flavoring agents may also be included. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be also used. An example of a stabilizing agent includes a para-hydroxybenzoic acid ester derivative such as methylparabene, propylparabene; an alcohol derivative such as chlorobutanol, benzyl alcohol, phenetyl alcohol; benzalkonium chloride; a phenol derivative such as phenol, cresol; thimerosal; acetic anhydride; sorbic acid; or the like. An example of a corrigent includes a sweetening, souring, and flavoring agents or the like all of which are ordinarily used. An example of a solvent includes water, ethanol, glycerin or the like.

Examples of suitable binders include an excipient described hereinbefore; gelatin; polyvinylpyrrolidone; macrogol; or the like, starch, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol.

An example of a lubricating agent includes talc; stearic acid; a metal stearate derivative such as calcium stearate, magnesium stearate, sodium stearate; colloidal silica; veegum; a wax such as beeswax or spermaceti; boric acid; a glycol; a carboxy acid derivative such as fumaric acid, adipic acid; a sodium carboxylate such as sodium benzoate; a sulfate such as sodium sulfate; leucine; a lauryl sulfate such as sodium lauryl sulfate, or magnesium lauryl sulfate; a silicic acid derivative such as silicic acid anhydride, silicic acid hydrate; a starch derivative described above as an excipient; sodium oleate, sodium acetate, sodium chloride, or the like.

DOSING REGIMEN

As mentioned above, one aspect of the invention relates to a method of treating AML or MDS in a subject, said method comprising administering to a subject a therapeutically effective amount of (i) sapacitabine, or a metabolite thereof; and (ii) venetoclax; in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises:

(ii) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, for 5 consecutive days followed by a rest period of at least 2 weeks, or until treatment-related toxicities are resolved, whichever is longer; and (b) administering a therapeutically effective amount of venetoclax for about 7 to about 14 consecutive days, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved, whichever is longer.

In one preferred embodiment, the invention comprises initiating step (a)(i) or (a)(ii) concomitantly with, or one or two days before, or one or two days after, initiating step (b).

As used herein, the term “concomitant” or “concomitantly” refers to administering the two drugs at, or almost at, the same time.

In one preferred embodiment, the invention comprises initiating step (a)(i) or (a)(ii) concomitantly with initiating step (b).

In one preferred embodiment, the invention comprises initiating step (a)(i) or (a)(ii) concurrently with initiating step (b).

In one preferred embodiment, the invention comprises initiating step (a)(i) or (a)(ii) on the same day as initiating step (b).

In one preferred embodiment, the invention comprises initiating step (a)(i) or (a)(ii), one or two days before initiating step (b).

In one preferred embodiment, the invention comprises initiating step (a)(i) or (a)(ii), one day before initiating step (b).

In one preferred embodiment, the invention comprises initiating step (a)(i) or (a)(ii), two days before initiating step (b).

In one preferred embodiment, the invention comprises initiating step (a)(i) or (a)(ii), one or two days after initiating step (b).

In one preferred embodiment, the invention comprises initiating step (a)(i) or (a)(ii), one day after initiating step (b).

In one preferred embodiment, the invention comprises initiating step (a)(i) or (a)(ii), two days after initiating step (b). In one preferred embodiment, the invention comprises administering a therapeutically effective amount of sapacitabine or a metabolite thereof, for 3 consecutive days per week, for 2 weeks followed by a rest period of at least one week, or until treatment- related toxicities are resolved, whichever is longer. In one preferred embodiment, the rest period is at least 1 week. In another preferred embodiment, the rest period is at least 2 weeks.

As used herein, “treatment-related toxicities” include myelosuppression and its associated complications. Myelosuppression is a term commonly used in the art and 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, a type of white blood cell) and thrombocytopenia (low levels of platelets). Associated complications of myelosuppression include fatigue (due to anemia), infections (due to neutropenia) and bruising/bleeding (due to thrombocytopenia).

As used herein, the term “rest period” in step (a)(i) or (a)(ii) refers to a period in which no sapacitabine (or metabolite thereof) is administered. In one preferred embodiment, no other pharmaceutically active agent, aside from venetoclax in accordance with step (b), is administered in the rest period of step (a)(i) or (a)(ii). In an alternative preferred embodiment, no sapacitabine (or metabolite thereof) is administered in the rest period of step (a)(i) or (a)(ii), but one or more other pharmaceutically active agents (in addition to the venetoclax in step (b)) can be administered in the rest period.

In one preferred embodiment, the method is for treating AML.

In another preferred embodiment, the method is for treating MDS.

In one preferred embodiment, the sapacitabine or metabolite thereof is administered orally. In one preferred embodiment, the sapacitabine or metabolite thereof is administered in tablet form. In one highly preferred embodiment, the sapacitabine or metabolite thereof is administered in the form of a liquid fill capsule, for example, as described in WO 2007/072061 (Cyclacel Limited). In one preferred embodiment, the invention comprises administering a therapeutically effective amount of sapacitabine or metabolite thereof for 3 consecutive days per week, for 2 weeks followed by a 2 week rest period.

In another preferred embodiment, the invention comprises administering a therapeutically effective amount of sapacitabine or metabolite thereof for 3 consecutive days per week, for 2 weeks followed by a 1 week rest period.

In one preferred embodiment, the sapacitabine or metabolite thereof is administered b.i.d.. As used herein the term “b.i.d." means twice daily, approximately every 12 hours. In one preferred embodiment, the sapacitabine or metabolite thereof is administered for 3 consecutive days per week, for 2 weeks, in a dose of about 300 to about 400 mg b.i.d., more preferably about 300 to about 350 mg b.i.d..

More preferably, the sapacitabine or metabolite thereof is administered for 3 consecutive days per week, for 2 weeks, in a dose of about 300 mg b.i.d. or about 350 mg b.i.d., more preferably about 300 mg b.i.d..

In another preferred embodiment, the invention comprises administering a therapeutically effective amount of sapacitabine or a metabolite thereof, for 5 consecutive days, followed by a rest period of at least 2 weeks, or until treatment-related toxicities are resolved, whichever is longer. In one preferred embodiment, the rest period is at least 2 weeks. In another preferred embodiment, the rest period is at least 3 weeks.

In one embodiment, the treatment cycle is a 28 day treatment cycle.

In another embodiment, the treatment cycle is a 21 day treatment cycle.

In one highly preferred embodiment, the invention comprises administering a therapeutically effective amount of sapacitabine or metabolite thereof for 5 consecutive days followed by a rest period of 23 days.

In another highly preferred embodiment, the invention comprises administering a therapeutically effective amount of sapacitabine or metabolite thereof for 5 consecutive days followed by a rest period of 16 days. In one highly preferred embodiment, the sapacitabine or metabolite thereof is administered for 5 consecutive days in a dose of about 250 to about 350 mg b.i.d., more preferably from about 250 mg b.i.d. to about 300 mg b.i.d..

Even more preferably, the sapacitabine or metabolite thereof is administered for 5 consecutive days in a dose of about 250 mg b.i.d. or about 300 mg b.i.d., more preferably about 250 mg b.i.d..

Preferably, the sapacitabine or metabolite thereof is 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.

In one preferred embodiment, the sapacitabine or metabolite thereof is administered in unit dosage form, said unit dosage containing from about 25 to about 400 mg of sapacitabine or metabolite thereof.

In a more preferred embodiment, the sapacitabine or metabolite thereof is administered in unit dosage form, said unit dosage containing from about 25 to about 225 mg of sapacitabine or metabolite thereof.

More preferably, the sapacitabine or metabolite thereof is administered in unit dosage form, said unit dosage containing from about 50 to about 125 mg of sapacitabine.

In one especially preferred embodiment, the sapacitabine or metabolite thereof is administered in a unit dosage form containing about 20, 25, 50, 60, 75, 100, 150, 150, 200, 300, 400 or 450 mg of sapacitabine or metabolite thereof.

More preferably, the sapacitabine or metabolite thereof is administered in unit dosage form, said unit dosage containing about 50 mg of sapacitabine or metabolite thereof.

In one preferred embodiment, the total daily dose of sapacitabine or metabolite thereof is made up of one more unit dosages. Where more than one unit dosage is administered, the unit dosages may be the same or different. In one preferred embodiment, the invention comprises administering a therapeutically effective amount of sapacitabine.

In another preferred embodiment, the invention comprises administering a therapeutically effective amount of a metabolite of sapacitabine. 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'-deoxy-1-β-D-arabino-pentofuranosyl cytosine (CNDAC).

In another particularly preferred embodiment of the invention, sapacitabine is metabolized intracellularly to the active metabolite CNDAC-triphosphate (CNDACTP), a process involving both the cleavage of the palmitoyl moiety and activation to CNDACTP by the action of nucleoside kinases.

In one preferred embodiment, the venetoclax is administered orally. In one preferred embodiment, the venetoclax is administered in tablet form. Venetoclax tablets are commercially available, for example, Venclexta® tablets manufactured by AbbVie Inc. North Chicago, IL 60064 and marketed by Genentech USA, South San Francisco, CA 94080-4990.

In one preferred embodiment, the venetoclax is administered q.d.. As used herein the term “q.d" means once a day.

In one preferred embodiment, the invention comprises two or more treatment cycles, more preferably, three or more, four or more, or five or more treatment cycles.

More preferably, the invention comprises two to four treatment cycles.

The invention involves step (b), which comprises administering a therapeutically effective amount of venetoclax for about 7 to about 14 consecutive days, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved, whichever is longer. As used herein, the term “rest period” in step (b) refers to a period in which no venetoclax is administered. In one preferred embodiment, no other pharmaceutically active agent, aside from sapacitabine (or metabolite thereof) in accordance with step (a), is administered in the rest period of step (b). In an alternative preferred embodiment, no venetoclax is administered in the rest period of step (b), but one or more other pharmaceutically active agents (in addition to the sapacitabine or metabolite thereof in step (a)) can be administered in the rest period.

In one preferred embodiment, the method of the invention comprises administering a therapeutically effective amount of venetoclax for 7 to 14 consecutive days, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved, whichever is longer.

In one highly preferred embodiment, the invention comprises administering a therapeutically effective amount of venetoclax for about 14 consecutive days, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved. In another highly preferred embodiment, the invention comprises administering a therapeutically effective amount of venetoclax for 14 ± 2 consecutive days, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved. In a more preferred embodiment, the invention comprises administering a therapeutically effective amount of venetoclax for 14 ± 1 consecutive days, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved. In one preferred embodiment, the rest period is at least 1 week. In another preferred embodiment, the rest period is at least 2 weeks.

In one preferred embodiment, the invention involves administering a therapeutically effective amount of venetoclax for 14 consecutive days, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved. In one preferred embodiment, the rest period is at least 1 week. In another preferred embodiment, the rest period is at least 2 weeks.

More preferably, the invention involves administering a therapeutically effective amount of venetoclax for 14 consecutive days, followed by a rest period of 1 week or 2 weeks.

In one preferred embodiment, the rest period is 1 week. In another preferred embodiment, the rest period is 2 weeks. In another preferred embodiment, the invention comprises administering a therapeutically effective amount of venetoclax for about 7 consecutive days, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved. In one highly preferred embodiment, the invention comprises administering a therapeutically effective amount of venetoclax for 7 ± 2 consecutive days, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved. In a more preferred embodiment, the invention comprises administering a therapeutically effective amount of venetoclax for 7 ± 1 consecutive days, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved. In one preferred embodiment, the rest period is at least 1 week. In another preferred embodiment, the rest period is at least 2 weeks.

In one preferred embodiment, the invention comprises administering a therapeutically effective amount of venetoclax for 7 consecutive days, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved. In one preferred embodiment, the rest period is at least 1 week. In another preferred embodiment, the rest period is at least 2 weeks.

More preferably, the invention comprises administering a therapeutically effective amount of venetoclax for 7 consecutive days, followed by a rest period of 1 week or 2 weeks. In one preferred embodiment, the rest period is 1 week. In another preferred embodiment, the rest period is 2 weeks.

In another preferred embodiment, the invention comprises administering a therapeutically effective amount of venetoclax for about 10 consecutive days, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved. In one highly preferred embodiment, the invention comprises administering a therapeutically effective amount of venetoclax for 10 ± 2 consecutive days, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved. In a more preferred embodiment, the invention comprises administering a therapeutically effective amount of venetoclax for 10 ± 1 consecutive days, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved. In one preferred embodiment, the rest period is at least 1 week. In another preferred embodiment, the rest period is at least 2 weeks. In one preferred embodiment, the invention comprises administering a therapeutically effective amount of venetoclax for 10 consecutive days, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved. In one preferred embodiment, the rest period is at least 1 week. In another preferred embodiment, the rest period is at least 2 weeks.

More preferably, the invention comprises administering a therapeutically effective amount of venetoclax for 10 consecutive days, followed by a rest period of 1 week or 2 weeks. In one preferred embodiment, the rest period is 1 week. In another preferred embodiment, the rest period is 2 weeks.

Preferably, the venetoclax is 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.

In one preferred embodiment, the venetoclax is administered in unit dosage form, said unit dosage containing from about 10 to about 400 mg of venetoclax.

In a more preferred embodiment, the venetoclax is administered in unit dosage form, said unit dosage containing from about 10 to about 200 mg of venetoclax.

More preferably, the venetoclax is administered in unit dosage form, said unit dosage containing from about 10 to about 100 mg of venetoclax.

In one especially preferred embodiment, the venetoclax is administered in a unit dosage form containing about 10, 20, 25, 50, 60, 75 or 100 mg of venetoclax.

More preferably, the venetoclax is administered in unit dosage form, said unit dosage containing about 10, 50 or 100 mg of venetoclax.

In one preferred embodiment, the total daily dose of venetoclax is made up of one more unit dosages. Where more than one unit dosage is administered, the unit dosages may be the same or different.

In one preferred embodiment, the venetoclax is administered in an escalating dosage, preferably over a period of 2, 3, 4, 5, 6 or 7 days, more preferably, over a period of 3 or 4 days. Advantageously, using a ramp-up dosing schedule for venetoclax gradually reduces tumor burden and decreases the risk of tumor lysis syndrome (TLS). TLS is a group of metabolic abnormalities that can occur as a complication during the treatment of cancer, where large amounts of tumor cells are lysed at the same time by the treatment, releasing their contents into the bloodstream.

In one preferred embodiment, the invention comprises administering venetoclax in a dosage according to the directions in the appropriate FDA label (for example, the recommended venetoclax doses for treating AML). The skilled person would understand that the FDA label may be modified on an ongoing basis and any modifications in the recommended dosage would be taken into account by a clinician when selecting an appropriate dosage of venetoclax.

In one preferred embodiment, the venetoclax is administered in an escalating dosing regimen, i.e. the dose of venetoclax is escalated over the time period in which venetoclax is administered within a particular treatment cycle. Preferably, the venetoclax dose is escalated over a period of 2, 3, 4, 5, 6 or 7 days, more preferably, over a period of 3 or 4 days.

In one preferred embodiment, the invention comprises a first treatment cycle comprising administering venetoclax in an escalating dosing regimen, and one or more subsequent treatment cycles each comprising administering venetoclax in a fixed dose. Preferably, the fixed dose of venetoclax in the one or more subsequent treatment cycles corresponds to the escalated (final) dose in the first treatment cycle.

In one preferred embodiment, the invention comprises a first treatment cycle comprising administering venetoclax in an escalating dosing regimen. In one particularly preferred embodiment, the dose of venetoclax is escalated over the first 4 days of the period in which venotoclax is administered during the first treatment cycle. In another preferred embodiment, the dose of venetoclax is escalated over the first 3 days of the period in which venotoclax is administered during the first treatment cycle.

In one highly preferred embodiment, the dose of venetoclax is administered in the first treatment cycle for a 14 day period, and the dose is escalated over the first 4 days of said 14 day period. In one highly preferred embodiment, the dose of venetoclax is administered in the first treatment cycle for a 14 day period, and the dose is escalated over the first 3 days of said 14 day period.

In another highly preferred embodiment, the dose of venetoclax is administered in the first treatment cycle for a 7 day period, and the dose is escalated over the first 4 days of said 7 day period.

In another highly preferred embodiment, the dose of venetoclax is administered in the first treatment cycle for a 7 day period, and the dose is escalated over the first 3 days of said 7 day period.

In one preferred embodiment, the invention comprises a first treatment cycle comprising administering venetoclax in an escalating dosing regimen starting with a dose of from about 10 to about 100 mg q.d. and escalating to a dose of from about 70 to about 400 mg q.d..

In another preferred embodiment, the invention comprises two or more treatment cycles, and wherein the second and subsequent treatment cycles comprise administering venetoclax in a dose of about 70 to 400 mg q.d..

In one preferred embodiment, the invention comprises a first treatment cycle, wherein said first treatment cycle comprises administering venetoclax in an escalating dosing regimen starting with a dose of about 50 to about 100 mg q.d., preferably about 60 to about 100 mg q.d., more preferably about 70 to about 100 mg q.d., even more preferably about 80 to about 100 mg q.d., even more preferably about 90 to about 100 mg q.d.. In a preferred embodiment, the venetoclax dose is escalated to a (final) dose of about 300 to about 400 mg q.d., preferably about 320 to about 400 mg q.d., more preferably about 340 to about 400 mg q.d., more preferably about 350 to about 400 mg q.d., more preferably about 360 to about 400 mg q.d., more preferably about 370 to about 400 mg q.d., more preferably about 380 to about 400 mg, even more preferably about 390 to about 400 mg q.d.. In a preferred embodiment, the venetoclax dose is escalated over a period of 2, 3, 4, 5, 6 or 7 days, more preferably, over a period of 3 or 4 days. More preferably for this embodiment, the invention comprises two or more treatment cycles, wherein the second and subsequent treatment cycles comprise administering venetoclax in accordance with the escalated (final) dose ranges recited above. In one highly preferred embodiment, the invention comprises a first treatment cycle, wherein said first treatment cycle comprises administering venetoclax in an escalating dosing regimen starting with a dose of about 100 mg q.d. and escalating to a dose of about 400 mg q.d.. Preferably, the venetoclax dose is escalated over a period of 2, 3, 4, 5, 6 or 7 days, more preferably, over a period of 3 or 4 days, more preferably 3 days,

In one particularly preferred embodiment, the first treatment cycle comprises administering venetoclax in accordance with the following schedule:

More preferably for this embodiment, the invention comprises two or more treatment cycles, wherein the second and subsequent treatment cycles comprise administering venetoclax in a dose of about 400 mg q.d..

In one preferred embodiment, the subject is not undergoing treatment with a moderate CYP3A inhibitor or a Pgp inhibitor.

In one preferred embodiment, the subject is undergoing treatment with a moderate CYP3A inhibitor or a Pgp inhibitor.

As used herein, “undergoing treatment” means the subject is also being treated with, or has been treated with, or will be treated with, a moderate CYP3A inhibitor or a Pgp inhibitor such that said moderate CYP3A inhibitor or Pgp inhibitor is present in the subject in an amount sufficient to potentially elicit a drug-drug interaction with venetoclax administered in accordance with the present dosing regimen. Treatment with said moderate CYP3A inhibitor or Pgp inhibitor may be prior to, during (including overlapping with or partially overlapping with), or after treatment according to the present dosing regimen as long as the moderate CYP3A inhibitor or Pgp inhibitor is present in the subject in an amount sufficient to potentially elicit a drug-drug interaction with the venetoclax.

As used herein, a moderate CYP3A inhibitor is a compound that increases the AUC of sensitive index substrates of the CYP3A metabolic pathway by ≥ 2 to £ 5-fold. Examples of moderate CYP3A inhibitors include, but are not limited to, aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, dronedarone, erythromycin, fluconazole, fluvoxamine , imatinib, tofisopam and verapamil. See Drug Development and Drug Interactions; Table of Substrates, Inhibitors and Inducers; https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug- interactions-table-substrates-inhibitors-and-inducers#table4-2). The skilled clinician would be able to readily identify other moderate CYP3A inhibitors based on the information published by the regulatory authorities in connection with the registration process for new drugs.

Examples of Pgp inhibitors include, but are not limited to, cyclosporine, elacridar (GF120918), ketoconazole, quinidine, reserpine, ritonavir, tacrolimus, valspodar (PSC833), verapamil and zosuquidar (LY335979). The skilled clinician would be able to readily identify other Pgp inhibitors based on the information published by the regulatory authorities in connection with the registration process for new drugs. See Drug Development and Drug Interactions; Table of Substrates, Inhibitors and Inducers; https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug- interactions-table-substrates-inhibitors-and-inducers#table4-2).

In one highly preferred embodiment, where the subject is undergoing treatment with a moderate CYP3A inhibitor or a Pgp inhibitor, the venetoclax dosage is reduced by at least 60 %, at initiation, during, or after the ramp-up phase.

For example, in one preferred embodiment, the invention comprises a first treatment cycle, wherein the first treatment cycle comprises administering venetoclax in an escalating dosing regimen starting with a dose of about 50 mg q.d. and escalating to a dose of about 200 mg q.d..

In one preferred embodiment, the invention comprises two or more treatment cycles, and wherein the second and subsequent treatment cycles comprise administering venetoclax in a dose of about 200 mg q.d.. In another preferred embodiment, the subject is undergoing treatment with a strong CYP3A inhibitor other than posaconazole. Where the subject is undergoing treatment with a strong CYP3A inhibitor, the dosage of venetoclax should be adjusted according to directions in the appropriate FDA label. The skilled person would understand that the FDA label may be modified on an ongoing basis and any modifications in the recommended dosage would be taken into account by a clinician when adjusting the dosage of venetoclax.

As used herein, “undergoing treatment” means the subject is also being treated with, or has been treated with, or will be treated with, a strong CYP3A inhibitor such that said strong CYP3A inhibitor is present in the subject in an amount sufficient to potentially elicit a drug-drug interaction with venetoclax administered in accordance with the present dosing regimen. Treatment with said strong CYP3A inhibitor may be prior to, during (including overlapping with or partially overlapping with), or after treatment according to the present dosing regimen as long as the strong CYP3A inhibitor is present in the subject in an amount sufficient to potentially elicit a drug-drug interaction with the venetoclax.

As used herein, a strong CYP3A inhibitor is a compound that increases the AUC of sensitive index substrates of the CYP3A metabolic pathway by ≥ 5-fold. Examples of strong CYP3A inhibitors include, but are not limited to, boceprevir, cobicistat, conivaptan, danoprevir and ritonavir, elvitegravir and ritonavir, grapefruit juice, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, paritaprevir and ritonavir and (ombitasvir and/or dasabuvir), ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, troleandomycin, voriconazole, clarithromycin, diltiazem, idelalisib, nefazodone and nelfinavir. Strong inhibitors of CYP3A causing ≥ 10-fold increase in the AUC of sensitive index substrates of the CYP3A metabolic pathway include, but are not limited to, clarithromycin, diltiazem, idelalisib, nefazodone and nelfinavir. See Drug Development and Drug Interactions; Table of Substrates, Inhibitors and Inducers; https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug- interactions-tabie-substrates-inhibitors-and-inducers#table3-2). The skilled clinician would be able to readily identify other strong CYP3A inhibitors based on the information published by the regulatory authorities in connection with the registration process for new drugs. In one highly preferred embodiment, where the subject is undergoing treatment with a strong CYP3A inhibitor other than posaconazole, the venetoclax dosage is reduced at initiation, during, or after the ramp-up phase.

For example, in one preferred embodiment, the invention comprises a first treatment cycle, wherein the first treatment cycle comprises administering venetoclax in an escalating dosing regimen starting with a dose of about 10 mg q.d. and escalating to a dose of about 100 mg q.d..

More preferably for this embodiment, the invention comprises two or more treatment cycles, wherein second and subsequent treatment cycles comprise administering venetoclax in a dose of about 100 mg q.d..

In another preferred embodiment, the subject is undergoing treatment with posaconazole. Where the subject is undergoing treatment with posaconazole, the dosage of venetoclax should be adjusted according to directions in the appropriate FDA label. The skilled person would understand that the FDA label may be modified on an ongoing basis and any modifications in the recommended dosage would be taken into account by a clinician when adjusting the dosage of venetoclax.

As used herein, “undergoing treatment” means the subject is also being treated with, or has been treated with, or will be treated with, posaconazole such that posaconazole is present in the subject in an amount sufficient to potentially elicit a drug-drug interaction with venetoclax administered in accordance with the present dosing regimen. Treatment with posaconazole may be prior to, during (including overlapping with or partially overlapping with), or after treatment according to the present dosing regimen as long as the posaconazole is present in the subject in an amount sufficient to potentially elicit a drug-drug interaction with the venetoclax. In one highly preferred embodiment, where the subject is undergoing treatment posaconazole, the venetoclax dosage is reduced at initiation, during, or after the ramp- up phase.

For example, in one preferred embodiment, the invention comprises a first treatment cycle, wherein the first treatment cycle comprises administering venetoclax in an escalating dosing regimen starting with a dose of about 10 mg q.d. and escalating to a dose of about 70 mg q.d..

More preferably for this embodiment, the invention comprises two or more treatment cycles, wherein the second and subsequent treatment cycles comprise administering venetoclax in a dose of about 70 mg q.d..

In one preferred embodiment, the patient has ≥ 10 % blasts in bone marrow or peripheral blood.

In another preferred embodiment, the patient has ≥ 5% blasts in bone marrow or peripheral blood if AML, or ≥ 10 % blasts in bone marrow or peripheral blood if MDS.

The percentage blasts in bone marrow or peripheral blood can be measured using standard techniques with which the skilled person would be familiar, for example as described in Vardiman J et al, The World Health Organization (WHO) classification of the myeloid neoplasm, Blood 100 (7): 2292-2302, 2002.

In one preferred embodiment, the patient has > 5% blasts in bone marrow if AML, or ≥

10 % blasts in bone marrow if MDS.

In another preferred embodiment, the patient has > 5% blasts in peripheral blood if AML or ≥ 10 % blasts in peripheral blood if MDS. In another preferred embodiment, the subject has received at least one prior therapy for AML or MDS. As used herein, “prior therapy” refers to any therapy the subject has received for AML or MDS.

In one preferred embodiment, the subject has previously been treated for AML or MDS based on WHO classification and has ≥ 10% blasts in bone marrow or peripheral blood and a white blood cell count (WBC) < 25,000/microliter (the use of leukapheresis or hydroxyurea before treatment initiation to achieve this is permitted).

In another preferred embodiment, the subject has previously been treated for AML or MDS based on WHO classification and has > 5% blasts in bone marrow or peripheral blood if AML, or ≥ 10% blasts in bone marrow or peripheral blood if MDS, and a white blood cell count (WBC) < 25,000/microliter (the use of leukapheresis or hydroxyurea before treatment initiation to achieve this is permitted).

In one preferred embodiment, the patient is aged 18 or over.

In one preferred embodiment, the subject is an elderly patient.

In one preferred embodiment, the subject is aged 60 and over.

In one preferred embodiment, the subject is aged 65 and over.

In one preferred embodiment, the subject is aged 70 and over.

In one preferred embodiment, the subject is aged 75 and over.

In one particularly preferred embodiment, the at least one treatment cycle is 28 days in length and comprises:

(a) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 1 to 3 of the treatment cycle; discontinuing said administration (i.e. the administration of sapacitabine, or a metabolite thereof) for days 4 to 7 of the treatment cycle; administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 8 to 10 of the treatment cycle; discontinuing said administration (i.e. the administration of sapacitabine, or a metabolite thereof) for days 11 to 28 of the treatment cycle; and

(b) administering a therapeutically effective amount of venetoclax on days 1 to 14 of the treatment cycle; and discontinuing said administration (i.e. the administration of venetoclax) for days 15 to 28 of the treatment cycle.

In another particularly preferred embodiment, the at least one treatment cycle is 21 days in length and comprises:

(a) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 1 to 3 of the treatment cycle; discontinuing said administration (i.e. the administration of sapacitabine, or a metabolite thereof) for days 4 to 7 of the treatment cycle; administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 8 to 10 of the treatment cycle; discontinuing said administration (i.e. the administration of sapacitabine, or a metabolite thereof) for days 11 to 21 of the treatment cycle; and

(b) administering a therapeutically effective amount of venetoclax on days 1 to 14 of the treatment cycle; and discontinuing said administration (i.e. the administration of venetoclax) for days 15 to 21 of the treatment cycle.

(a) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 1 to 5 of the treatment cycle; discontinuing said administration for days 6 to 28 of the treatment cycle; and

(b) administering a therapeutically effective amount of venetoclax on days 1 to 14 of the treatment cycle; and discontinuing said administration for days 15 to 28 of the treatment cycle.

In one particularly preferred embodiment, the at least one treatment cycle is 21 days in length and comprises:

(a) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 1 to 5 of the treatment cycle; discontinuing said administration for days 6 to 21 of the treatment cycle; and (b) administering a therapeutically effective amount of venetoclax on days 1 to 14 of the treatment cycle; and discontinuing said administration for days 15 to 21 of the treatment cycle.

(a) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 1 to 3 of the treatment cycle; discontinuing said administration for days 4 to 7 of the treatment cycle; administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 8 to 10 of the treatment cycle; discontinuing said administration for days 11 to 28 of the treatment cycle; and

(b) administering a therapeutically effective amount of venetoclax on days 1 to 7 of the treatment cycle; and discontinuing said administration for days 8 to 28 of the treatment cycle.

(a) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 1 to 3 of the treatment cycle; discontinuing said administration for days 4 to 7 of the treatment cycle; administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 8 to 10 of the treatment cycle; discontinuing said administration for days 11 to 21 of the treatment cycle; and

(b) administering a therapeutically effective amount of venetoclax on days 1 to 7 of the treatment cycle; and discontinuing said administration for days 8 to 21 of the treatment cycle.

(a) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 1 to 5 of the treatment cycle; discontinuing said administration for days 6 to 28 of the treatment cycle; and (b) administering a therapeutically effective amount of venetoclax on days 1 to 7 of the treatment cycle; and discontinuing said administration for days 8 to 28 of the treatment cycle.

(a) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 1 to 5 of the treatment cycle; discontinuing said administration for days 6 to 21 of the treatment cycle; and

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

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

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.

Kit

Another aspect of the invention relates to a kit of parts comprising: sapacitabine, or a metabolite thereof; venetoclax; and instructions for administering sapacitabine, or a metabolite thereof, and venetoclax in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises:

Preferably, the kit of parts is for use in treating AML or MDS in a subject.

Combination for use in treating AML or MDS

A further aspect of the invention relates to a combination comprising (i) sapacitabine, or a metabolite thereof; and (ii) venetoclax; for use in treating AML or MDS in a subject.

The present invention is further described with reference to the following non-limiting Examples.

EXAMPLES

Materials & Methods

Sapacitabine was prepared in accordance with the methodology described in EP 536936B (Sankyo Company Limited). Sapacitabine is formulated as a liquid fill capsule in Miglyol 812N Ph. Eur/GRAS, in accordance with Example 3 of WO 2007/072061 (Cyclacel Limited). Venetoclax tablets (Venclexta® tablets) were the commercially approved product, manufactured by AbbVie Inc. North Chicago, IL 60064 and marketed by Genentech USA, South San Francisco, CA 94080-4990.

Clinical Study

Adult patients (aged 18 years or older) with previously treated AML or MDS based on WHO classification with >5% blasts in bone marrow or peripheral blood if AML or ≥ 10% blasts in bone marrow or peripheral blood if MDS and a white blood cell count (WBC) ≤25, 000/microliter (the use of leukapheresis or hydroxyurea before treatment initiation to achieve this is permitted) were selected for the study. Patients with AML of the sub-type of acute promyelocytic leukemia or extramedullary myeloid tumor without bone marrow involvement or known central nervous system (CNS) involvement by leukemia, or known hypersensitivity to venetoclax were excluded.

Dosing Regimen

Patients selected for the study were treated concomitantly with: (a) a dose of between 300 and 400 mg of sapacitabine orally b.i.d. on days 1 to 3 and 8 to 10 of a 28 day treatment cycle (Group 1); or a dose of between 250 and 350 mg sapacitabine orally b.i.d. on days 1 to 5 of a 28 day treatment cycle (Group 2); and

(b) venetoclax on days 1 to 14 of the 28 day treatment cycle in accordance with the dosages set out in the table below based on the patient subgroup:

*Day 1 through Day 14 for second and subsequent treatment cycles

Results

The primary efficacy endpoint of the study was the rate of clinical benefit response, complete response (CR), complete response with incomplete platelet count recovery (CRp), partial response (PR) or haematological improvement (HI) (Cheson B. et. al. Revised recommendation of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes and reporting standards for therapeutic trials in acute myeloid leukemia. J. of Clin. Oncol. 21 : 4642-4649, 2003; Cheson B. et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 108(2):419-25, 2006; Cheson B. et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 96 (12): 3671-74, 2000). Secondary efficacy endpoints were response durations, transfusion requirements, number of hospitalized days, and overall survival. Transfusion requirements for each patient are defined as the number of weeks during which at least one transfusion for red blood cells (RBCs) or platelets is administered and the mean number of units of RBC and platelet transfusions administered per month.

The duration of clinical benefit was measured from the earliest time when the patient achieved any of these responses to the first date when the major HI was lost. Response evaluation was performed within a time frame of 6 cycles of sapacitabine administered concomitantly with venetoclax. The duration of CR, CRp, PR or haematological improvement was measured from the time when response criteria were first met until the first date that recurrent or progressive disease was documented.

Preliminary data for 12 patients is presented in Table 1 below. None of the 12 patients showed any dose limiting toxicity (DLT). Patients #7 and #11 showed stable disease in terms of a lack of significant increase (>50%) in percentage of blasts in peripheral blood or bone marrow for at least 4 cycles of treatment.

Table 1 :

Age at date of consent

Various modifications and variations of the described aspects 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 of carrying out the invention which are obvious to those skilled in the relevant fields are intended to be within the scope of the following claims.

Claims

1. A method of treating acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in a subject, said method comprising administering to a subject a therapeutically effective amount of (i) sapacitabine, or a metabolite thereof; and (ii) venetoclax; in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises:

2. A method according to claim 1 which comprises initiating step (a)(i) or (a)(ii) concomitantly with, or one or two days before, or one or two days after, initiating step (b).

3. A method according to claim 1 which comprises initiating step (a)(i) or (a)(ii) on the same day as initiating step (b).

4. A method according to any preceding claim which comprises administering a therapeutically effective amount of sapacitabine or a metabolite thereof, for 3 consecutive days per week, for 2 weeks followed by a rest period of at least one week, or until treatment-related toxicities are resolved, whichever is longer.

5. A method according to any one of claims 1 to 4 which comprises administering a therapeutically effective amount of sapacitabine or metabolite thereof for 3 consecutive days per week, for 2 weeks followed by a 2 week rest period.

6. A method according to any one of claims 1 to 4 which comprises administering a therapeutically effective amount of sapacitabine or metabolite thereof for 3 consecutive days per week, for 2 weeks followed by a 1 week rest period.

7. A method according to any one of claims 1 to 6 wherein the sapacitabine or metabolite thereof is administered for 3 consecutive days per week, for 2 weeks, in a dose of about 300 to about 400 mg b.i.d..

8. A method according to any one of claims 1 to 7 wherein the sapacitabine or metabolite thereof is administered for 3 consecutive days per week, for 2 weeks, in a dose of about 300 mg b.i.d. or about 350 mg b.i.d..

9. A method according to any one of claims 1 to 3 which comprises administering a therapeutically effective amount of sapacitabine or a metabolite thereof, for 5 consecutive days, followed by a rest period of at least 2 weeks, or until treatment-related toxicities are resolved, whichever is longer.

10. A method according to claim 9 which comprises administering a therapeutically effective amount of sapacitabine or metabolite thereof for 5 consecutive days followed by a rest period of 23 days.

11. A method according to claim 9 which comprises administering a therapeutically effective amount of sapacitabine or metabolite thereof for 5 consecutive days followed by a rest period of 16 days.

12. A method according to any one of claims 9 to 11 wherein the sapacitabine or metabolite thereof is administered in a dose of about 250 to about 350 mg b.i.d..

13. A method according to any one of claims 9 to 12 wherein the sapacitabine or metabolite thereof is administered in a dose of about 250 mg b.i.d. or.about 300 mg b.i.d..

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

15. A method according to any preceding claim which comprises administering a therapeutically effective amount of sapacitabine.

16. A method according to any one of claims 1 to 14 which comprises administering a therapeutically effective amount of a metabolite of sapacitabine, wherein the metabolite is CNDAC.

17. A method according to any preceding claim wherein the venetoclax is administered orally.

18. A method according to any preceding claim wherein the venetoclax is administered q.d..

19 A method according to any preceding claim which comprises two or more treatment cycles, more preferably, three or more, four or more, or five or more treatment cycles.

20. A method according to claim 19 which comprises two to four treatment cycles.

21. A method according to claim 20 which comprises a first treatment cycle comprising administering venetoclax in an escalating dosing regimen starting with a dose of from about 10 to about 100 mg q.d. and escalating to a dose of from about 70 to about 400 mg q.d..

22. A method according to any preceding claim which comprises two or more treatment cycles, and wherein the second and subsequent treatment cycles comprise administering venetoclax in a dose of about 70 to 400 mg q.d..

23. A method according to any preceding claim wherein the subject is not undergoing treatment with a moderate CYP3A inhibitor or a Pgp inhibitor.

24. A method according to claim 23 which comprises a first treatment cycle, wherein said first treatment cycle comprises administering venetoclax in an escalating dosing regimen starting with a dose of about 100 mg q.d. and escalating to a dose of about 400 mg q.d..

25. A method according to claim 24 comprising a first treatment cycle, wherein said first treatment cycle comprises administering venetoclax in accordance with the following schedule:

26. A method according to claim 25 which comprises two or more treatment cycles, and wherein the second and subsequent treatment cycles comprise administering venetoclax in a dose of about 400 mg q.d..

27. A method according to any preceding claim wherein the subject has ≥ 5% blasts in bone marrow or peripheral blood if AML, or ≥ 10 % blasts in bone marrow or peripheral blood if MDS.

28. A method according to any preceding claim wherein the subject has received at least one prior therapy for AML or MDS.

29. A method according to claim 1 wherein the at least one treatment cycle is 28 days in length and comprises:

30. A method according to claim 1 wherein the at least one treatment cycle is 21 days in length and comprises:

(a) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 1 to 3 of the treatment cycle; discontinuing said administration for days 4 to 7 of the treatment cycle; administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 8 to 10 of the treatment cycle; discontinuing said administration for days 11 to 21 of the treatment cycle; and (b) administering a therapeutically effective amount of venetoclax on days 1 to 14 of the treatment cycle; and discontinuing said administration for days 15 to 21 of the treatment cycle.

31. A method according to claim 1 wherein the at least one treatment cycle is 28 days in length and comprises:

32. A method according to claim 1 wherein the at least one treatment cycle is 21 days in length and comprises:

(b) administering a therapeutically effective amount of venetoclax on days 1 to 14 of the treatment cycle; and discontinuing said administration for days 15 to 21 of the treatment cycle.

33. A method according to claim 1 wherein the at least one treatment cycle is 28 days in length and comprises:

(a) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 1 to 3 of the treatment cycle; discontinuing said administration for days 4 to 7 of the treatment cycle; administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on days 8 to 10 of the treatment cycle; discontinuing said administration for days 11 to 28 of the treatment cycle; and (b) administering a therapeutically effective amount of venetoclax on days 1 to 7 of the treatment cycle; and discontinuing said administration for days 8 to 28 of the treatment cycle.

34. A method according to claim 1 wherein the at least one treatment cycle is 21 days in length and comprises:

35. A method according to claim 1 wherein the at least one treatment cycle is 28 days in length and comprises:

36. A method according to claim 1 wherein the at least one treatment cycle is 21 days in length and comprises:

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

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

39. A kit of parts comprising: sapacitabine, or a metabolite thereof; venetoclax; and instructions for administering sapacitabine, or a metabolite thereof, and venetoclax in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises:

40. A kit of parts according to claim 39 for use in treating ALM or MDS in a subject.

41. A combination comprising (i) sapacitabine, or a metabolite thereof; and (ii) venetoclax; for use in treating AML or MDS in a subject.