EP4153180A1 - Polythérapie pour le traitement du cancer - Google Patents

Polythérapie pour le traitement du cancer

Info

Publication number
EP4153180A1
EP4153180A1 EP21724264.3A EP21724264A EP4153180A1 EP 4153180 A1 EP4153180 A1 EP 4153180A1 EP 21724264 A EP21724264 A EP 21724264A EP 4153180 A1 EP4153180 A1 EP 4153180A1
Authority
EP
European Patent Office
Prior art keywords
olaparib
azd2811
cancer
subject
treatment
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21724264.3A
Other languages
German (de)
English (en)
Inventor
Jon TRAVERS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of EP4153180A1 publication Critical patent/EP4153180A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine

Definitions

  • 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).
  • 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.
  • 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.
  • kits 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.
  • 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).
  • 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).
  • 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).
  • 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).
  • PDX patient derived xenograft
  • 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).
  • PDX patient derived xenograft
  • 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).
  • PDX patient derived xenograft
  • 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).
  • PDX patient derived xenograft
  • 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).
  • PDX patient derived xenograft
  • 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).
  • PDX patient derived xenograft
  • 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).
  • PDX patient derived xenograft
  • 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.
  • 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
  • the AZD2811 nanoparticles are administered intravenously.
  • 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).
  • 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).
  • the AZD2811 nanoparticles will be administered intravenously over about 2 hours, over about 3 hours, or over about 4 hours.
  • the AZD2811 nanoparticles are administered on day 1 and day 4 of a 28- day cycle and day 1 of a 21 -day cycle.
  • 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.
  • PARP polyadenosine 5’-diphosphoribose polymerase
  • Olaparib also known as AZD2281 and LYNPARZA
  • W02002/036576 is described in International Patent Application Publication No. W02002/036576.
  • olaparib is administered orally, for example, as a tablet or a capsule.
  • olaparib is administered as a 50 mg capsule.
  • olaparib is administered in a 400 mg dose (e.g., eight 50 mg capsules) twice daily.
  • 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.
  • a 200 mg dose e.g., two 100 mg tablets
  • a 250 mg dose twice daily e.g., one 100 mg tablet and one 150 mg tablet
  • a 300 mg dose e.g., three 100 mg tablets or two 150 mg tablets
  • 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.
  • the term “subject” includes warm-blooded mammals, for example, primates, dogs, cats, rabbits, rats, and mice.
  • the subject is a primate, for example, a human.
  • the subject is suffering from cancer.
  • the subject is suffering from relapsed small cell lung cancer (SCLC).
  • SCLC small cell lung cancer
  • the subject is suffering from cancer and is treatment naive (i.e., has never received treatment for cancer).
  • the subject is in need of treatment (i.e., the subject would benefit biologically or medically from treatment).
  • 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).
  • gBRCAm deleterious or suspected deleterious germline BRCA-mutated cancer
  • sBRCAm somatic BRCA-mutated cancer
  • 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.
  • HR homologous recombination
  • 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.
  • the subject is suffering from or in need of maintenance treatment for deleterious or suspected deleterious gBRCAm ovarian cancer.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the subject is suffering from or is in need of maintenance treatment for pancreatic adenocarcinoma.
  • the subject is suffering from or is in need of maintenance treatment for deleterious or suspected deleterious gBRCAm pancreatic adenocarcinoma.
  • 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.
  • 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).
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • 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.
  • HRR homologous recombination repair
  • the subject is suffering from or is in need of maintenance treatment for a neuroendocrine tumor cancer.
  • the subject has been tested with a companion diagnostic for olaparib prior to treatment with olaparib and AZD2811.
  • the language “inhibit,” “inhibition,” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process.
  • 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).
  • SCLC small cell lung cancer
  • PC prostate cancer
  • BC breast cancer
  • hematological malignancies such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelomonocytic leukemia (CMML).
  • the cancer includes cancers that are susceptible to treatment with Aurora kinase B inhibitors (e.g., AZD2811 nanoparticles).
  • the cancer includes cancers that are susceptible to treatment with olaparib.
  • the cancer is a deleterious or suspected deleterious gBRCAm cancer.
  • compositions comprising a plurality of AZD2811 nanoparticles and a pharmaceutically acceptable excipient, carrier, or diluent.
  • 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.
  • 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.
  • 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.
  • 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.
  • the effective amount of olaparib is 400 mg administered by capsule twice daily.
  • the effective amount of olaparib is 200 mg, 250 mg or 300 mg administered by tablet twice daily.
  • kits 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.
  • Example 1 Efficacy of AZD281 L a Selective AURKB Inhibitor. Combined with Olaparib in a Preclinical Model of Small Cell Lung Cancer
  • lxlO 7 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 cm 3 (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.
  • 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
  • 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.
  • 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 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.
  • 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).
  • 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).
  • 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).

Abstract

Sont divulguées des méthodes de traitement du cancer consistant à administrer à un sujet qui en a besoin une quantité efficace d'une composition pharmaceutique comprenant une pluralité de nanoparticules d'AZD2811 et une quantité efficace d'olaparib.
EP21724264.3A 2020-05-07 2021-05-06 Polythérapie pour le traitement du cancer Pending EP4153180A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063021389P 2020-05-07 2020-05-07
PCT/EP2021/061976 WO2021224381A1 (fr) 2020-05-07 2021-05-06 Polythérapie pour le traitement du cancer

Publications (1)

Publication Number Publication Date
EP4153180A1 true EP4153180A1 (fr) 2023-03-29

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP21724264.3A Pending EP4153180A1 (fr) 2020-05-07 2021-05-06 Polythérapie pour le traitement du cancer

Country Status (2)

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EP (1) EP4153180A1 (fr)
WO (1) WO2021224381A1 (fr)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100804564B1 (ko) 2000-10-30 2008-02-20 쿠도스 파마슈티칼스 리미티드 프탈라지논 유도체
MY191804A (en) 2013-09-16 2022-07-15 Astrazeneca Ab Therapeutic polymeric nanoparticles and methods of making and using same

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Publication number Publication date
WO2021224381A1 (fr) 2021-11-11

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