HK40040830A - Combination therapy for treating cancer - Google Patents

Description

Combination therapy for the treatment of cancer

RELATED APPLICATIONS

This application claims priority from U.S. provisional patent application No. 62/711,751 filed 2018, 7/30 (e), 35 u.s.c. § 119(e), the contents of which are hereby incorporated by reference in their entirety.

Background

Despite great progress in the treatment of hematological malignancies, many patients with such cancers live with incurable disease. Treatment options for those patients with Acute Myeloid Leukemia (AML) are limited and the 5-year survival rate is about 25%, with patients over 60 years of age responding poorly to treatment with median survival of less than 12 months. Therefore, it is important to continue to search for new treatments for patients with incurable cancer.

Disclosure of Invention

In some embodiments, a method of treating cancer is disclosed, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a plurality of AZD2811 nanoparticles and an effective amount of venetoclax (venetocalax).

In some embodiments, the use of a pharmaceutical composition comprising a plurality of AZD2811 nanoparticles in the treatment of cancer is disclosed, wherein the treatment comprises the separate, sequential or simultaneous administration of vinatoick.

In some embodiments, the use of venetocks in the treatment of cancer is disclosed, wherein the treatment comprises the separate, sequential or simultaneous administration of a pharmaceutical composition comprising a plurality of AZD2811 nanoparticles.

In some embodiments, kits are disclosed comprising: a first pharmaceutical composition comprising a plurality of AZD2811 nanoparticles and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising vinatork, and instructions for use.

Drawings

FIG. 1 illustrates KG1a tumor volumes as a function of time for mice treated with vehicle, AZD2811 alone, Venetok alone (ABT-199), and a combination of AZD2811 and Venetok (ABT-199).

Figure 2 illustrates HL-60 tumor volume over time for mice treated with vehicle, different doses of AZD2811 alone, venetox alone (ABT-199), and different doses of a combination of AZD2811 and venetox (ABT-199).

Figure 3 illustrates the survival benefit of AZD2811 in combination with vinatork (ABT-199) versus a standard of care combination of vinatork (ABT-199) with 5-azacitidine (5-azacitidine) in the disseminated AML xenograft model MOLM-13 for a statistically significant (p 0.01; log rank test).

Detailed Description

In some embodiments, a method of treating cancer is disclosed, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a plurality of AZD2811 nanoparticles and an effective amount of tenectetocel.

The language "AZD 2811 nanoparticles" includes nanoparticles comprising: the Aurora (Aurora) kinase B inhibitor 2- (3- ((7- (3- (ethyl (2-hydroxyethyl) amino) propoxy) quinazolin-4-yl) amino) -1H-pyrazol-5-yl) -N- (3-fluorophenyl) acetamide (also known as AZD1152hqpa), about 7 to about 15 weight percent pamoic acid, and diblock poly (lactic) acid-poly (ethylene) glycol copolymer; wherein the diblock poly (lactic) acid-poly (ethylene) glycol copolymer has a poly (lactic acid) block with a number average molecular weight of about 16kDa and a poly (ethylene) glycol block with a number average molecular weight of about 5 kDa; wherein the poly (ethylene) glycol block comprises about 10 to 30 weight percent of the therapeutic nanoparticle. The preparation of AZD2811 nanoparticles is disclosed in international application publication No. WO 2015/036792.

Venetock (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 deficiency, who had previously received at least one treatment. Venetork has the following structure and is disclosed in International application publication No. 2010/138588 as example 5:

in some embodiments, the tenettor is administered orally. In some embodiments, the tenectetocet is administered in an oral pharmaceutical composition comprising 10mg, 50mg, or 100mg of tenectetocet. In some embodiments, the venetock is administered once daily at a dose of 20mg for 7 days, followed by a weekly ascending dosing regimen over 4 weeks, up to a daily dose of 400 mg.

The language "treating" or "treatment" includes reducing or inhibiting the activity of an enzyme or protein associated with aurora B, BCL-2 or a cancer in a subject, ameliorating one or more symptoms of a cancer in a subject, or slowing or delaying the progression of a cancer in a subject. The language "treating" also includes reducing or inhibiting the growth of a tumor or the proliferation of cancerous cells in a subject.

The language "inhibit" ("inhibit", "inhibition", or "inhibiting") includes a decrease in the baseline activity of a biological activity or process.

The term "cancer" includes, but is not limited to, hematological malignancies, such as Acute Myeloid Leukemia (AML), MDS, CMML, multiple myeloma, Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), burkitt's lymphoma, follicular lymphoma, and Small Lymphocytic Lymphoma (SLL). In some embodiments, the cancer is a cancer susceptible to an aurora kinase B inhibitor (e.g., AZD2811 nanoparticles). In some embodiments, the cancer is a cancer susceptible to a BCL-2 inhibitor (e.g., venetock).

The term "subject" includes warm-blooded mammals, such as primates, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a primate, e.g., a human. In some embodiments, the subject has cancer. In some embodiments, the subject is in need of treatment (e.g., the subject will benefit biologically or medically from treatment).

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 determined by one of ordinary skill in the art. The pharmaceutical composition may be in the form of: one or more aqueous or non-aqueous non-toxic parenterally acceptable buffer systems, diluents, solubilizers, co-solvents, or carriers. The sterile injectable preparation may also be a sterile injectable aqueous or oleaginous suspension or suspension in a non-aqueous diluent, carrier or co-solvent, which may be formulated according to known procedures using one or more suitable dispersing or wetting agents and suspending agents. The pharmaceutical composition may be a solution for intravenous bolus/infusion or a lyophilized system (alone or with excipients) reconstituted with a buffer system with or without other excipients. The lyophilized freeze-dried material may be prepared from a non-aqueous solvent or an aqueous solvent. The dosage form may also be a concentrate that is further diluted for subsequent infusion.

The term "effective amount" includes an amount of a pharmaceutical composition comprising AZD2811 nanoparticles and/or an amount of vernetorks that will elicit a biological or medical response in a subject, e.g., a reduction or inhibition of the activity of an enzyme or protein associated with aurora kinase B, BCL-2 or cancer; improving cancer; or slow or delay the progression of the cancer. In some embodiments, the language "effective amount" includes an amount of a pharmaceutical composition comprising AZD2811 nanoparticles and/or venetocks that is effective to at least partially reduce, inhibit, and/or ameliorate cancer in a subject, or inhibit aurora kinase B, BCL-2, and/or reduce or inhibit growth of a tumor or proliferation of cancerous cells in a subject.

In some embodiments, kits are disclosed comprising: a first pharmaceutical composition comprising a plurality of AZD2811 nanoparticles and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising vinatork, and instructions for use.

Examples of the invention

Example 1: combination of the selective AURKB inhibitor AZD2811 and vinatock in acute myelogenous leukemia Efficacy in the Pre-bed model

KGal：2X 10 in 50% matrigel⁷A single KG1a AML cell was implanted subcutaneously into the left side of an adult female SCID mouse. Mice were randomized into 8 groups based on day 7 tumor volume, with an average tumor volume of 0.2cm³And all administrations are started. AZD2811 nanoparticles were administered once weekly for 20-30 seconds with either 100mg/kg intravenous infusion (100mg/kg is the maximum tolerated dose combined with 100mg/kg of Venetok (ABT-199); Venetok is administered orally at 100mg/kg daily). All drugs were administered for a period of 3 weeks.

HL-60：1X 10 in 50% matrigel⁷Individual HL-60AML cells were implanted subcutaneously into the left side of adult female SCID mice. Mice were randomized into 8 groups based on day 7 tumor volume, with an average tumor volume of 0.2cm³And all administrations are started. AZD2811 nanoparticles were administered once weekly by intravenous infusion for 20-30 seconds at any of 50mg/kg, 25mg/kg, 12.5mg/kg and 6.25mg/kg (100mg/kg is the maximum tolerated dose combined with 100mg/kg of Venetok (ABT-199); Venetok is administered orally at 100mg/kg daily). All drugs were administered for a period of 3 weeks. For both models, a single operator measured tumors twice a week and all dosing was done by randomized cage to minimize systemic bias. For MOLM-13 in situ model, 1X 10⁶Individual MOLM-13 cells were injected into the tail vein of adult female NOG mice. After 3 days, mice were randomized into 8 groups by body weight and treatment was started the following day. AZD2811 nanoparticles were administered once weekly with 25mg/kg intravenous infusion for 20-30 seconds (25mg/kg is the maximum tolerated dose combined with 100mg/kg of venetock (ABT-199); venetock is administered orally at 100mg/kg daily). Administering 5-azacitidine twice daily by intraperitoneal route at 0.5mg/kg for 3 days, followed by rest for 4 days without administration; 5-azacitidine was administered in combination with 100mg/kg of Vernitol per day. All drugs were administered for a 2-week period and the study endpoints were determined from the welfare scoring table.

As a result:as shown in FIG. 1, both AZD2811 nanoparticles and Venetok (ABT-199) monotherapy were moderately effective in the KGla modelAnd the combination with vinatork shows significantly enhanced combined efficacy compared to either agent alone. As shown in figure 2, both AZD2811 nanoparticles and venetock (ABT-199) monotherapy were active in the HL-60 model, and the combination with venetock showed significantly enhanced combined efficacy compared to either agent alone, particularly at the lowest dose of AZD 2811. In figure 3, the combination of AZD2811 and vinatock provided a statistically significant survival benefit over the standard of care regimen vinatock and 5-azacitidine, which itself improved survival compared to vinatock alone.

Claims (9)

1. A method of treating cancer, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a plurality of AZD2811 nanoparticles and an effective amount of tenecterol.

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

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

4. The method of claim 3, wherein the hematologic cancer is selected from Acute Myeloid Leukemia (AML), MDS, CMML, multiple myeloma, Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma, and follicular lymphoma.

5. Use of a pharmaceutical composition comprising a plurality of AZD2811 nanoparticles in the treatment of cancer, wherein said treatment comprises the separate, sequential or simultaneous administration of vinatoick.

6. Use of Venetock 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.

7. The use of claim 4 or 5, wherein the cancer is a hematological cancer.

8. The use of claim 7, wherein the hematologic cancer is selected from Acute Myeloid Leukemia (AML), MDS, CMML, multiple myeloma, Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma, and follicular lymphoma.

9. A kit, comprising:

a first pharmaceutical composition comprising a plurality of AZD2811 nanoparticles and a pharmaceutically acceptable carrier; and

a second pharmaceutical composition comprising vinatock and a pharmaceutically acceptable carrier.