WO2021224381A1

WO2021224381A1 - Combination therapy for treating cancer

Info

Publication number: WO2021224381A1
Application number: PCT/EP2021/061976
Authority: WO
Inventors: Jon TRAVERS
Original assignee: Astrazeneca Ab
Priority date: 2020-05-07
Filing date: 2021-05-06
Publication date: 2021-11-11
Also published as: EP4153180A1

Abstract

Disclosed are methods of treating cancer comprising administering to a subject in need thereof comprising administering to the subject an effective amount of a pharmaceutical composition comprising a plurality of AZD2811 nanoparticles and an effective amount of olaparib.

Description

COMBINATION THERAPY FOR TREATING CANCER

BACKGROUND

[001] While much progress has been made in the treatment of hematological malignancies and solid cancers, many of these patients who have such cancers live with an incurable disease. Those patients suffering from small cell lung cancer (SCLC) have limited treatment options, and the five- year survival rate is approximately 5%, with a median survival of less than 5 to 6 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 and an effective amount of olaparib (AZD2281).

[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 olaparib.

[004] In some embodiments, disclosed is olaparib 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.

[005] In some embodiments, disclosed is a kit comprising: a first pharmaceutical composition comprising a plurality of AZD2811 nanoparticles and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising olaparib and instructions for use.

BRIEF DESCRIPTIONS OF THE DRAWINGS

[006] Fig. 1 illustrates the reduction in tumor volume over time of vehicle (·), olaparib (AZD2281) alone (¨), AZD2811 alone (■), and the combination of AZD2811 and olaparib (0) in a xenograft model of SCLC (NCI-H1048).

[007] Fig. 2 illustrates the reduction in tumor volume over time of vehicle (·), olaparib (AZD2281) alone (¨), AZD2811 alone (■), and the combination of AZD2811 and olaparib (0) in a xenograft model of SCLC (NCI-H69). [008] Fig. 3 illustrates the reduction in tumor volume over time of vehicle (·), olaparib (AZD2281) alone (D), AZD2811 alone (_□), and the combination of AZD2811 and olaparib (❖) in a patient derived xenograft (PDX) model of SCLC (SC61).

[009] Fig. 4 illustrates the reduction in tumor volume over time of vehicle (·), olaparib (AZD2281) alone (D), AZD2811 alone (_□), and the combination of AZD2811 and olaparib (❖) in a patient derived xenograft (PDX) model of SCLC (SC 108).

[0010] Fig. 5 illustrates the reduction in tumor volume over time of vehicle (·), olaparib (AZD2281) alone (D), AZD2811 alone (_□), and the combination of AZD2811 and olaparib (❖) in a patient derived xenograft (PDX) model of SCLC (LC-F-20).

[0011] Fig. 6 illustrates the reduction in tumor volume over time of vehicle (·), olaparib (AZD2281) alone (D), AZD2811 alone (_□), and the combination of AZD2811 and olaparib (❖) in a patient derived xenograft (PDX) model of SCLC (SC101).

[0012] Fig. 7 illustrates the reduction in tumor volume over time of vehicle (·), olaparib (AZD2281) alone (D), AZD2811 alone (_□), and the combination of AZD2811 and olaparib (❖) in a patient derived xenograft (PDX) model of SCLC (SC96).

[0013] Fig. 8 illustrates the reduction in tumor volume over time of vehicle (·), olaparib (AZD2281) alone (D), AZD2811 alone (_□), and the combination of AZD2811 and olaparib ( ·) in a patient derived xenograft (PDX) model of SCLC (SC74).

[0014] Fig. 9 illustrates the reduction in tumor volume over time of vehicle (·), olaparib (AZD2281) alone (D), AZD2811 alone (_□), and the combination of AZD2811 and olaparib (❖) in a patient derived xenograft (PDX) model of SCLC (SC6).

[0015] Fig. 10 illustrates the reduction in tumor volume over time of vehicle (·), olaparib (AZD2281) alone (D), AZD2811 alone (_□), and the combination of AZD2811 and olaparib (❖) in a patient derived xenograft (PDX) model of SCLC (LC-F-22).

DETAILED DESCRIPTION

[0016] 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 and an effective amount of olaparib.

[0017] The language “AZD2811 nanoparticles” includes nanoparticles that comprise the Aurora kinase B inhibitor 2-(3-((7-(3 -(ethyl (2-hydroxy ethyl )amino)propoxy)quinazolin-4-yl)amino)- l//- 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; 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.

[0018] 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 the AZD2811 nanoparticles (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 the AZD2811 nanoparticles). In some embodiments, the AZD2811 nanoparticles are administered in a dose sufficient to give an effective amount of AZDl 152 hqpa of up to about 600 mg (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 AZDl 152 hqpa). In some embodiments, the AZD2811 nanoparticles will be 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 and day 1 of a 21 -day cycle.

[0019] The term “olaparib” refers to a mammalian polyadenosine 5’-diphosphoribose polymerase (PARP) inhibitor with the chemical name to 4-[(3-{[4-cyclopropylcarbonyl)piperazin-l- yljcarobyl }-4-fluorophenyl)methyl]phthalazine- 1 (2//)-one and the structure:

or a pharmaceutically acceptable salt thereof. Olaparib (also known as AZD2281 and LYNPARZA) is described in International Patent Application Publication No. W02002/036576. [0020] In some embodiments, olaparib is administered orally, for example, as a tablet or a capsule. In some embodiments, olaparib is administered as a 50 mg capsule. In some embodiments, olaparib is administered in a 400 mg dose (e.g., eight 50 mg capsules) twice daily.

[0021] In some embodiments, olaparib is administered as a 100 mg or 150 mg tablet. In some embodiments, olaparib is administered in a 200 mg dose (e.g., two 100 mg tablets) twice daily; a 250 mg dose twice daily (e.g., one 100 mg tablet and one 150 mg tablet) twice daily, or a 300 mg dose (e.g., three 100 mg tablets or two 150 mg tablets) twice daily.

[0022] The language “treat,” “treating” and “treatment” includes the reduction or inhibition of enzyme or protein activity related to Aurora kinase B, PARP or cancer in a subject, amelioration of one or more symptoms of cancer in a subj ect, 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.

[0023] 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. [0024] In some embodiments, the subject is suffering from cancer. In some embodiments, the subject is suffering from relapsed small cell lung cancer (SCLC). In some embodiments, the subject is suffering from cancer and is treatment naive (i.e., has never received treatment for cancer). In some embodiments, the subject is in need of treatment (i.e., the subject would benefit biologically or medically from treatment).

[0025] In some embodiments, the subject is in need of maintenance treatment with olaparib. In some embodiments, the subject is suffering from or is in need of maintenance treatment for a deleterious or suspected deleterious germline BRCA-mutated cancer (gBRCAm). In some embodiments, the subject is suffering from or is in need of maintenance treatment for a deleterious or suspected deleterious somatic BRCA-mutated cancer (sBRCAm).

[0026] In some embodiments, the subject is suffering from or is in need of maintenance treatment for a homologous recombination (HR) deficient cancer, such as ovarian cancer, fallopian tube cancer, primary peritoneal cancer, prostate cancer, breast cancer, and/or pancreatic cancer. Examples of genes in the HR pathway, which may cause a homologous recombination (HR) deficient cancer include: BRCA1, BRCA2, ATM, BARDl, BRIP1, CHEK1, CHEK2, CDK12, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D and RAD54L.

[0027] In some embodiments, the subject is suffering from or in need of maintenance treatment for deleterious or suspected deleterious gBRCAm ovarian cancer. In some embodiments, the patient is suffering from or is in need of maintenance treatment for deleterious or suspected deleterious gBRCAm ovarian cancer and has been treated with three or more prior lines of chemotherapy.

[0028] In some embodiments, the subject is suffering from or is in need of maintenance treatment for epithelial ovarian, fallopian tube, or primary peritoneal cancer. In some embodiments, the subject is suffering from or in need of maintenance treatment for deleterious or suspected deleterious gBRCAm epithelial ovarian, fallopian tube, or primary peritoneal cancer. In some embodiments, the subject is suffering from or is in need of maintenance treatment for deleterious or suspected deleterious gBRCAm epithelial ovarian, fallopian tube, or primary peritoneal cancer and is in complete or partial response to first-line platinum-based chemotherapy. In some embodiments, the subject is suffering from or in need of maintenance treatment for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. In some embodiments, the subject is suffering from or in need of maintenance treatment for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer and is in complete or partial response to platinum-based chemotherapy.

[0029] In some embodiments, the subject is suffering from or is in need of maintenance treatment for breast cancer. In some embodiments, the subject is suffering from or is in need of maintenance treatment for deleterious or suspected deleterious gBRCAm, HER2-negative metastatic breast cancer. In some embodiments, the subject is suffering from or is in need of maintenance treatment for deleterious or suspected deleterious gBRCAm, HER2 -negative metastatic breast cancer and has been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. In some embodiments, the subject is suffering from or is in need of maintenance treatment for deleterious or suspected deleterious gBRCAm, HER2 -negative, hormone receptor (HR)-positive breast cancer and has been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting and has been treated with a prior endocrine therapy or been considered inappropriate for endocrine therapy. [0030] In some embodiments, the subject is suffering from or is in need of maintenance treatment for pancreatic adenocarcinoma. In some embodiments, the subject is suffering from or is in need of maintenance treatment for deleterious or suspected deleterious gBRCAm pancreatic adenocarcinoma. In some embodiments, the subject is suffering from or is in need of maintenance treatment for deleterious or suspected deleterious gBRCAm pancreatic adenocarcinoma and the disease has not progressed on at least 16 weeks for a first-line platinum-based chemotherapy regimen. In some embodiments, the subject is in need of first-line maintenance treatment for deleterious or suspected deleterious gBRCAm pancreatic adenocarcinoma.

[0031] In some embodiments, the subject is suffering from or is in need of maintenance treatment for lung cancer. In some embodiments, the subject is suffering from or is in need of maintenance treatment for deleterious or suspected deleterious gBRCAm lung cancer. In some embodiments, the subject is suffering from or is in need of maintenance treatment for deleterious or suspected deleterious gBRCAm small cell lung cancer (SCLC). In some embodiments, the subject is suffering from or is in need of maintenance treatment for deleterious or suspected deleterious gBRCAm non-small cell lung cancer (NSCLC).

[0032] In some embodiments, the subject is suffering from or is in need of maintenance treatment for prostate cancer. In some embodiments, the subject is suffering from or is in need of maintenance treatment for neuroendocrine prostate cancer. In some embodiments, the subject is suffering from or is in need of maintenance treatment for homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer.

[0033] In some embodiments, the subject is suffering from or is in need of maintenance treatment for a neuroendocrine tumor cancer.

[0034] In some embodiments, the subject has been tested with a companion diagnostic for olaparib prior to treatment with olaparib and AZD2811.

[0035] The language “inhibit,” “inhibition,” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process.

[0036] The term “cancer” includes but is not limited to solid cancers such as small cell lung cancer (SCLC), prostate cancer (PC), breast cancer (BC), 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 olaparib. In some embodiments, the cancer is a deleterious or suspected deleterious gBRCAm cancer. [0037] 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.

[0038] The language “effective amount” includes that amount of a pharmaceutical composition comprising AZD2811 nanoparticles and/or that amount of olaparib 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, PARP, 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 olaparib that is effective to at least partially alleviate, inhibit, and/or ameliorate cancer or inhibit Aurora kinase B, olaparib, and/or reduce or inhibit the growth of a tumor or proliferation of cancerous cells in a subject. In some embodiments, the effective amount of olaparib is 400 mg administered by capsule twice daily. In some embodiments, the effective amount of olaparib is 200 mg, 250 mg or 300 mg administered by tablet twice daily.

[0039] In some embodiments, disclosed is a kit comprising: a first pharmaceutical composition comprising a plurality of AZD2811 nanoparticles and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising olaparib and instructions for use. EXAMPLES

[0040] Example 1 : Efficacy of AZD281 L a Selective AURKB Inhibitor. Combined with Olaparib in a Preclinical Model of Small Cell Lung Cancer

[0041] Method: 5xl0⁶ NCI H1048 SCLC cells in 50% matrigel were implanted subcutaneously on the left flank of adult female Nude mice. Mice were randomised into groups when the tumors reached approximately 0.2 cm³ (10 days post implant) and dosing of all compounds started at day 1 (Dl) following randomization. Compound treated group size was of 7 mice and vehicle treated group size was of 10 animals. AZD2811 nanoparticles were dosed once weekly with a 20 to 30 second intravenous infusion at 25 mg/kg. Olaparib was dosed at 200 mg/kg orally on a daily basis. All drugs were given for 4 weekly cycles. Tumors were measured twice weekly by single operator. Mice reached study survival endpoint when tumor volume reached 10% of mouse body weight. [0042] In an additional model, lxlO⁷ NCI H69 SCLC cells in 50% matrigel were implanted subcutaneously on the left flank of adult female Nude mice. Mice were randomised into groups when the tumors reached approximately 0.2 cm³ (13 days post implant) and dosing of all compounds started at day 1 (Dl) following randomization. Compound treated group size was of 8 mice and vehicle treated group size was of 12 animals. AZD2811 nanoparticles were dosed once weekly with a 20 to 30 second intravenous infusion at 25 mg/kg. Olaparib was dosed at 100 mg/kg orally on a daily basis. All drugs were given for 4 weekly cycles. Tumors were measured three times weekly by single operator. Mice reached study survival endpoint when tumor volume reached 10% of mouse body weight.

[0043] Results: As shown in Fig. 1 and Fig. 2, both AZD2811 nanoparticles and PARP inhibitor monotherapy were modestly efficacious in the NCI-H69 model with greater efficacy in the NCI- 111048, and in both models, the combination of agents demonstrated markedly stronger efficacy.

[0044] Example 2: Efficacy of AZD281 L a Selective AURKB Inhibitor. Combined with Olaparib in a Suite of Patient Derived Xenograph Models of Small Cell Lung Cancer

[0045] Method: Fragments of SCLC patient tumors previously grown in mice were implanted on the left flank of adult female athymic nude (Athymic Nude-Foxnl^nu ) mice. Mice were randomised into groups when the tumors reached approximately 0.15 cm³ and dosing of all compounds started at day 1 (Dl) following randomisation. Compound treated group size was of 3 mice and vehicle treated group size was of 2 to 3 animals. AZD2811 nanoparticles were dosed once weekly with a 20 to 30 second intravenous infusion at 25 mg/kg for a total of 4 doses, unless mice reached tumor volume endpoint prior to 28 days. Olaparib was dosed at 200 mg/kg orally on a daily basis for a total of 28 doses, unless mice reached tumor volume endpoint prior to 28 days. Hence, all drugs were given in total for 4 weekly cycles. Tumors were measured twice weekly by single operator. Mice reached study survival endpoint when tumor volume reached 10% of mouse body weight. All treatments were tolerated at the given dose and schedule.

[0046] Results: Figs. 3 to 10 illustrate the reduction in tumor volume over time in eight PDX models (SC61, SC108, LC-F-20, SC101, SC96, SC74, SC6, and LC-F-22). Table 1 below reports the mean tumor growth (TG) values calculated for each treatment and model. The mean tumor growth values were calculated at the last day when at least 2 mice remained on study for all treatment groups. Negative values represent degree of regression where -100% is complete regression. Positive values represent degree of tumor growth compared to control (vehicle) where 100% is no change from vehicle and 0% is stasis.

[0047] TABLE 1

[0048] AZD2811 nanoparticle monotherapy inhibited tumor growth in the majority of the PDX models and provided the highest growth inhibition in the SC61 PDX model (mean tumor growth of -82% on D14; see Table 1 and Fig. 3).

[0049] Olaparib monotherapy inhibited tumor growth in the PDX models to a much lessser extent (mean tumor growth ranging from 58% to 100%; see Table 1 and Figs. 3 to 10) and provided the highest growth inhibition in the SCLC-POU2F3 PDX model LC-F-22 (mean tumor growth of - 58% on D21; see Table 1 and Fig. 10) and the SCLC-ASCL1 PDX model SC96 (mean tumor growth of 58% on D21; see Table 1 and Fig. 7).

[0050] Overall, the following results were obtained in the eight PDX models:

• In the SC61 PDX model (see Fig. 3), AZD2811 monotherapy gave a median tumor growth value -82% (partial tumor regression) and olaparib monotherapy had limited effect. Although this result limits the evaluation of the tumor growth effect for the combination, continued observations past the treatment period of 28 days appeared to indicate a notable delay in tumor regrowth in the combination treatment arm relative to AZD2811 monotherapy which demonstrates that the combination of AZD2811 and olaparib elicited an anti -tumor effect that was greater than the effect of AZD2811 monotherapy alone.

• In the SC 108 PDX model (see Fig. 4), AZD2811 monotherapy and olaparib monotherapy gave median tumor growth values of 11% and no effect, respectively.

In contrast, the combination of AZD2811 and olaparib gave a median tumor growth value of -95% (complete regression).

• In the LC-F-20 PDX model (see Fig. 5), AZD2811 monotherapy and olaparib monotherapy gave median tumor growth values of no effect and 70%, respectively.

In contrast, the combination of AZD2811 and olaparib gave a median tumor growth value of a -79% (partial regression).

• In the SC 101 PDX model (see Fig. 6), AZD2811 monotherapy and olaparib monotherapy gave median tumor growth values of 82% and 89%, respectively. In contrast, the combination of AZD2811 and olaparib gave a median tumor growth value of 33%. Although not reaching stasis, the 33% median tumor growth value achieved was still better than the sum of the individual monotherapy effects.

• In PDX model SC96 (see Fig. 7), AZD2811 monotherapy and olaparib monotherapy gave median tumor growth values of 18% and 58%, respectively. The combination of AZD2811 and olaparib gave a median tumor growth value of -11% (partial regression).

• In PDX models SC74, SC6, and LC-F-22 (see Figs. 8, 9, and 10, respectively), the combination of AZD2811 and olaparib was not effective in controlling tumor growth. [0051] In summary, the PDX models in which the combination of AZD2811 and olaparib affected tumor growth (SC61, SC 108, LC-F-20, SC 101, and SC96) all belong to the SCLC subtype, ASCL1. In fact, the combination of AZD2811 and olaparib showed appreciable activity above the sum of the individual monotherapy activities for tumor growth relative to control (vehicle) in three of the five PDX models belonging to the ASCL1 subtype (SC108, LC-F-20 and SC101). In contrast, the PDX models where the combination of AZD2811 and olaparib was not effective in controlling tumor growth (SC74, SC6, and LC-F-22) all belong to the atypical SCLC subtypes, NEUROD1 and POU2F3. This result suggests that the combination of AZD2811 and olaparib is not universally toxic to cells and that particular populations may benefit from the combination, either in SCLC or other neuroendocrine tumors where similar patterns of transcription factor expression may dictate treatment efficacy.

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 and an effective amount of olaparib.

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 olaparib.

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

4. 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 olaparib.

5. Olaparib 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.

6. The use of claim 4 or 5, wherein said cancer is small cell lung cancer (SCLC).

7. A kit comprising: a first pharmaceutical composition comprising a plurality of AZD2811 nanoparticles and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising olaparib and instructions for use.