WO2021037933A1

WO2021037933A1 - Combination of azd2811 nanoparticles, 5-azacitidine and venetoclax for use in the treatment of cancer

Info

Publication number: WO2021037933A1
Application number: PCT/EP2020/073887
Authority: WO
Inventors: Wolfram Brugger
Original assignee: Astrazeneca Ab
Priority date: 2019-08-28
Filing date: 2020-08-26
Publication date: 2021-03-04

Abstract

Disclosed are methods of treating cancer comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a plurality of AZD2811 nanoparticles; an effective amount of 5-azacitidine; and an effective amount of venetoclax.

Description

COMBINATION OF AZD2811 NANOPARTICLES, 5-AZACITIDINE AND VENETOCLAX FOR USE IN THE TREATMENT OF CANCER

BACKGROUND

[001] While much progress has been made in the treatment of hematological malignancies, many of these patients who have such cancers live with an incurable disease. Those patients suffering from acute myeloid leukemia (AML) have limited treatment options, and the five-year survival rate is approximately 25% with patients over 60 responding poorly to treatment, with a median survival of less than 12 months. Accordingly, it’s important to continue to find new treatments for patients with incurable cancer.

SUMMARY

[002] In some embodiments, disclosed is a method of treating cancer comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a plurality of AZD2811 nanoparticles; an effective amount of 5-azacitidine; and an effective amount of venetoclax.

[003] In some embodiments, disclosed is a pharmaceutical composition comprising a plurality of AZD2811 nanoparticles for use in the treatment of cancer, wherein said treatment comprises the separate, sequential, or simultaneous administration of 5-azacitidine and the separate, sequential, or simultaneous administration of venetoclax.

[004] In some embodiments, disclosed is 5-azacitidine for use in the treatment of cancer, wherein said treatment comprises the separate, sequential, or simultaneous administration of a pharmaceutical composition comprising a plurality of AZD2811 nanoparticles and the separate, sequential, or simultaneous administration of venetoclax.

[005] In some embodiments, disclosed is venetoclax for use in the treatment of cancer, wherein said treatment comprises the separate, sequential, or simultaneous administration of a pharmaceutical composition comprising a plurality of AZD2811 nanoparticles and the separate, sequential, or simultaneous administration of 5-azacitidine.

[006] In some embodiments, disclosed is a kit comprising: a first pharmaceutical composition comprising a plurality of AZD2811 nanoparticles and a pharmaceutically acceptable carrier; a second pharmaceutical composition comprising 5-azacitidine and a pharmaceutically acceptable carrier; a third pharmaceutical composition comprising venetoclax and a pharmaceutically acceptable carrier; and instructions for use.

BRIEF DESCRIPTIONS OF THE DRAWINGS

[007] Figure 1 illustrates the survival benefit observed in SCID mice bearing HL-60 AML xenografts treated with (a) vehicle (·), (b) a combination of 5-azacitidine and AZD2811 (■), (c) a combination of 5-azacitidine and venetoclax (▼), (d) a combination of AZD2811 and venetoclax (A), and (e) a combination of AZD2811, 5-azacitidine, and venetoclax (¨).

[008] Figure 2 illustrates the median time to a median overall survival (mOS) endpoint in SCID mice bearing HL-60 AML xenografts treated with (a) vehicle, (b) AZD2811 nanoparticle monotherapy, (c) azacitidine monotherapy, (d) venetoclax (ABT-199) monotherapy, (e) a combination of azacitidine and AZD2811 nanoparticle, (f) a combination of venetoclax and AZD2811 nanoparticle, (g) a combination of azacitidine and venetoclax, and (h) a combination of azacitidine, venetoclax, and AZD2811 nanoparticle. Median time to endpoint (mOS) was calculated from the Kaplan Meier plots shown in Figure 1. Numbers on the bars indicate survival benefit (in days) over median time to endpoint of vehicle group.

DETAILED DESCRIPTION

[009] In some embodiments, disclosed is a method of treating cancer comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a plurality of AZD2811 nanoparticles; an effective amount of 5-azacitidine; and an effective amount of venetoclax,

[0010] The language “AZD2811 nanoparticles” includes nanoparticles that comprise the Aurora kinase B inhibitor 2-(3-((7-(3-(ethyl(2-hydroxyethyl)amino)propoxy)quinazolin-4- yl)amino)-lH-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide (also known as AZD1152 hqpa); about 7 to about 15 weight percent of pamoic acid; and a diblock poly(lactic) acid-poly(ethylene)glycol copolymer; wherein the diblock poly(lactic) acid-poly(ethylene)glycol copolymer has a poly(lactic acid) block having a number average molecular weight of about 16kDa and a poly(ethylene)glycol block having a number average molecular weight of about 5kDa; and wherein the poly(ethylene)glycol block comprises about 10 to 30 weight percent of the therapeutic nanoparticle. Preparation of the AZD2811 nanoparticles is disclosed in International Application Publication No. WO2015/036792. In some embodiments, the AZD2811 nanoparticles are administered intravenously. In some embodiments, the AZD2811 nanoparticles are administered in a dose of up to about 600 mg of AZD2811 (for example, up to about 100 mg, up to about 200 mg, up to about 300 mg, up to about 400 mg, up to about 500 mg, or up to about 600 mg AZD2811). In some embodiments, the AZD2811 nanoparticles are administered intravenously over about 2 hours, over about 3 hours, or over about 4 hours. In some embodiments, the AZD2811 nanoparticles are administered on day 1 and day 4 of a 28-day cycle.

[0011] The term “5-azacitidine” (also known as ladakamycin, 5-azacytidine, azacitidine, or azacytidine) includes the compound having the chemical name of 4-amino- 1-(b-ϋ- ribofuranosyl)-l,3,5-triazin-2(lH)-one and the following structure:

5-Azacitadine is believed to have antineoplastic activity via two mechanisms - at low doses, by inhibition of DNA methyltransferase, causing hypom ethylation of DNA; and at high doses, by its direct cytotoxicity to abnormal hematopoietic cells in the bone marrow through its incorporation into DNA and RNA, resulting in cell death. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising 5-azacitidine and mannitol. In some embodiments, the pharmaceutical composition comprises a 1:1 weight ratio of 5-azacitidine and mannitol ( e.g ., 100 mg each of 5-azacitidine and mannitol). In some embodiments, 5-azacitidine is administered subcutaneously. In some embodiments, 5- azacitidine is administered intravenously. In some embodiments, the 5-azacitidine is administered at 75 mg/m² daily for 7 days, followed by repeat cycles every four weeks, with an increase of 100 mg/m². In some embodiments, 5-azacitidine is administered at a 75 mg/m² dose on day 1 through day 7 of a 28-day cycle. In some embodiments, 5-azacitidine is administered at a 75 mg/m² dose on day 1 through day 5 and days 8 and 9 of a 28-day cycle.

[0012] Venetoclax (also known as ABT-199) is a BCL-2 inhibitor approved for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy. Venetoclax has the structure below and is disclosed as Example 5 in International Application Publication No. 2010/138588:

In some embodiments, venetoclax is orally administered. In some embodiments, venetoclax is administered as an oral pharmaceutical composition comprising 10 mg, 50 mg or 100 mg of venetoclax. In some embodiments, venetoclax is administered at a 20 mg dose once daily for 7 days, followed by a weekly ramp-up dosing schedule over four weeks to a daily dose of 400 mg.

[0013] The language “treat,” “treating,” and “treatment” includes the reduction or inhibition of enzyme or protein activity related to Aurora kinase B, DNA methyltransferase, BCL- 2, or cancer in a subject; amelioration of one or more symptoms of cancer in a subject; or the slowing or delaying of progression of cancer in a subject. The language “treat,” “treating” and “treatment” also includes the reduction or inhibition of the growth of a tumor or proliferation of cancerous cells in a subject.

[0014] The language “inhibit,” “inhibition,” and “inhibiting” includes a decrease in the baseline activity of a biological activity or process.

[0015] The term “cancer” includes, but is not limited to, hematological malignancies such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelomonocytic leukemia (CMML). In some embodiments, the cancer includes cancers that are susceptible to treatment with Aurora kinase B inhibitors (e.g., AZD2811 nanoparticles). In some embodiments, the cancer includes cancers that are susceptible to treatment with DNA- methyltransferase inhibitors (e.g., 5-azacitidine). In some embodiments, the cancer includes cancers that are susceptible to treatment with BCL-2 inhibitors (e.g., venetoclax).

[0016] The language “pharmaceutical composition” includes compositions comprising a plurality of AZD2811 nanoparticles and a pharmaceutically acceptable excipient, carrier, or diluent. The language “pharmaceutically acceptable excipient, carrier or diluent” includes compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, as ascertained by one of skill in the art. Pharmaceutical compositions may be in the form of a sterile injectable solution in one or more aqueous or non-aqueous non-toxic parenterally-acceptable buffer systems, diluents, solubilizing agents, co-solvents, or carriers. A sterile injectable preparation may also be a sterile injectable aqueous or oily suspension or suspension in a non-aqueous diluent, carrier or co-solvent, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents. The pharmaceutical compositions could be a solution for iv bolus/infusion injection or a lyophilized system (either alone or with excipients) for reconstitution with a buffer system with or without other excipients. The lyophilized freeze-dried material may be prepared from non-aqueous solvents or aqueous solvents. The dosage form could also be a concentrate for further dilution for subsequent infusion.

[0017] The term “subject” includes warm-blooded mammals, for example, primates, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a primate, for example, a human. In some embodiments, the subject is suffering from cancer. In some embodiments, the subject is suffering from relapsed AML. In some embodiments, the subject is suffering from relapsed high- risk MDS. In some embodiments, the subject is suffering from cancer and is treatment naive (e.g., has never received treatment for cancer). In some embodiments, the subject is in need of treatment (e.g., the subject would benefit biologically or medically from treatment). In some embodiments, the subject is pretreated with anti -nausea medication.

[0018] The language “effective amount” includes that amount of a pharmaceutical composition comprising AZD2811 nanoparticles, and/or that amount of 5-azacitidine, and/or that amount of venetoclax that will elicit a biological or medical response in a subject, for example, the reduction or inhibition of enzyme or protein activity related to Aurora kinase B, DNA- methyltransferase, BCL-2, or cancer; amelioration of symptoms of cancer; or the slowing or delaying of progression of cancer. In some embodiments, the language “effective amount” includes the amount of a pharmaceutical composition comprising AZD2811 nanoparticles and/or 5-azacitidine and/or veneotclax, is effective to at least partially alleviate, inhibit, and/or ameliorate cancer or inhibit Aurora kinase B, DNA-methyltransferase, BCL-2 and/or reduce or inhibit the growth of a tumor or proliferation of cancerous cells in a subject. [0019] In some embodiments, disclosed is a kit comprising: a first pharmaceutical composition comprising a plurality of AZD2811 nanoparticles and a pharmaceutically acceptable carrier; 5-azacitidine; venetoclax; and instructions for use.

EXAMPLES

[0020] Example 1. Efficacy of AZD281 L a Selective AURKB Inhibitor. Combined with

5-Azacitidine and Venetoclax in a Preclinical Model of Acute Myeloid Leukemia

[0021] Method: 1x107 HL-60 AML cells in 50 % matrigel were implanted subcutaneously on the left flank of adult female SCID mice. Mice were randomized into a group of 12 for the vehicle group and groups of 10 for all other groups. Dosing was started for all drugs and all combinations at day 7 (D7) following implant. AZD2811 nanoparticles were dosed at once weekly with a 20-30 second intravenous infusion at 12.5 mg/kg (25 mg/kg was the maximum tolerated dose of AZD2811 in combination 5-azacitidine at 1 mg/kg and venetoclax at 100 mg/kg); 5- azacitidine was dosed twice-daily for three days by the intraperitoneal route, followed by 4 rest days of no dosing; venetoclax was administered orally daily at 100 mg/kg. All drugs were given for 3 weekly cycles. Tumors were measured twice weekly by single operators, and all dosing was performed by randomized cage to minimize systematic bias. Mice reached study survival endpoint when tumors reached 1.5 cm³.

[0022] Results: As shown in Figure 1, all of the combinations demonstrated a greater percent survival when compared to the vehicle. The triple combination of AZD2811, 5- azacitidine, and venetoclax, however, demonstrated markedly stronger efficacy. The median time to endpoint (median overall survival (mOS)) relative to vehicle for each monotherapy, doublet combination, and triple combination group is shown in Figure 2 and was calculated from the Kaplan Meier plots of Figure 1. The mOS value calculated for the triple combination was 44 days. The sum of the mOS values calculated for each monotherapy and the doublet combination comprising the other two compounds mOS, however, was less than the mOS value calculated for the triple combination in all instances. Specifically, (a) the benefit associated with AZD2811 nanoparticle monotherapy (11 days) added to the benefit associated with the venetoclax + azacitidine doublet combination (27 days) totaled 38 days, (b) the benefit associated with azacitidine monotherapy (6 days) added to the benefit associated with the AZD2811 nanoparticle + venetoclax combination (28 days) totaled 34 days, and (c) the benefit associated with venetoclax monotherapy (16 days) added to the benefit associated with AZD2811 nanoparticle + azacitidine (18 days) totaled 34 days. The monotherapy plus doublet combination totals (38, 34, and 34 days) were all inferior to the triple combination value (44 days), confirming that the benefit of combining all three agents (AZD2811 nanoparticle, venetoclax, and azacitidine) in a single concurrent regimen provided a greater than additive benefit and that such a regimen can be considered synergistic.

Claims

1. A method of treating cancer comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a plurality of AZD2811 nanoparticles; an effective amount of 5-azacitidine; and an effective amount of venetoclax.

2. The method of claim 1, wherein the method comprises administering the pharmaceutical composition comprising a plurality of AZD2811 nanoparticles sequentially, separately, or simultaneously with 5-azacitidine, and sequentially, separately, or simultaneously with venetoclax

3. The method of claim 1, wherein the cancer is a hematological malignancy.

4. The method of claim 3, wherein the hematological malignancy is selected from acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelomonocytic leukemia (CMML).

5. 5-Azacitidine for use in the treatment of cancer, wherein said treatment comprises the separate, sequential, or simultaneous administration of a pharmaceutical composition comprising a plurality of AZD2811 nanoparticles and the separate, sequential, or simultaneous administration of venetoclax.

6. Venetoclax for use in the treatment of cancer, wherein said treatment comprises the separate, sequential, or simultaneous administration of a pharmaceutical composition comprising a plurality of AZD2811 nanoparticles and the separate, sequential, or simultaneous administration of 5-azacitidine.

7. A pharmaceutical composition comprising a plurality of AZD2811 nanoparticles for use in the treatment of cancer, wherein said treatment comprises the separate, sequential, or simultaneous administration of venetoclax and the separate, sequential, or simultaneous administration of 5-azacitadine.

8 The use of any one of claims 5-7, wherein said cancer is a hematological cancer.

9. The use of claim 8, wherein the hematological cancer is selected from acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelomonocytic leukemia (CMML).

10. A kit compri sing : a first pharmaceutical composition comprising a plurality of AZD2811 nanoparticles and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising 5-azacitidine and a pharmaceutically acceptable carrier; a third pharmaceutical composition comprising venetoclax and a pharmaceutically acceptable carrier; and instructions for use; and instructions for use.