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WO2020254299A1 - Combinaison d'un inhibiteur de mcl-1 et d'un standard de traitement de soin pour cancers du sein, utilisations et compositions pharmaceutiques associées - Google Patents

Combinaison d'un inhibiteur de mcl-1 et d'un standard de traitement de soin pour cancers du sein, utilisations et compositions pharmaceutiques associées Download PDF

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WO2020254299A1
WO2020254299A1 PCT/EP2020/066575 EP2020066575W WO2020254299A1 WO 2020254299 A1 WO2020254299 A1 WO 2020254299A1 EP 2020066575 W EP2020066575 W EP 2020066575W WO 2020254299 A1 WO2020254299 A1 WO 2020254299A1
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group
alkyl
branched
linear
hydrogen atom
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Sébastien BANQUET
Alix DERREAL
Florence Binlich
Dale Porter
Ensar HALILOVIC
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Novartis AG
Laboratoires Servier SAS
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Novartis AG
Laboratoires Servier SAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol

Definitions

  • the present invention relates to a combination of a Mcl-1 inhibitor with a second anticancer agent, wherein the second anticancer agent is selected from eribulin (cytotoxic agent) and fulvestrant (hormonal therapy).
  • the invention also relates to the use of said combination in the treatment of cancer, in particular breast cancer, and more particularly luminal breast cancer, HER2 + breast cancer and triple negative breast cancer. Also provided are pharmaceutical formulations suitable for the administration of such combinations.
  • BC is classified into four major molecular subtypes: (i) luminal A (HR + /HER2 ); (ii) HER2 + ; (iii) luminal B (HR + /HER2 + ); and (iv) triple negative (HR7HER2-).
  • Each of these subtypes has different risk factors for incidence, therapeutic response, disease progression, and preferential organ sites of metastases.
  • Luminal BC positive for HR represents the vast majority (60-80%) of BC cases in developed countries (American Cancer Society. Breast Cancer Facts & Figures 2017-18. Atlanta: American Cancer Society, Inc. (2017)).
  • HR + BC endocrine therapy is the mainstay for treatment. Sequential administration of endocrine treatments is recommended until there is a need for rapid response or evidence of clinical resistance, when chemotherapy will be indicated (Reinert et al. Ther. Adv. Med. Oncol. 2015, 7, 304-320). Since endocrine drugs work by different mechanisms, they are generally used in combination for better anticancer efficacy. However, conflicting results have been reported (Michaud et al. Oncologist 2001, 6, 538-546; Bergh et al.
  • TNBC accounts for 10-15% of the BC and is associated with younger age at diagnosis, high histologic grade, and a poor short term prognosis (Lebert, Curr. Oncol. 2018, 25, S142- S150; Stevens et al. Cancer Res. 2013, 73, 2025-2030).
  • standard chemotherapy remains the mainstay of treatment.
  • TNBC is the BC subtype with the higher complete response rate to chemotherapy (22%).
  • recurrence and metastasis rates are higher than those carrying non- TNBC tumors (Liedtke et al. J. Clin. Oncol. 2008, 26, 1275-1281).
  • the median OS (Overall Survival) for patients with metastatic TNBC is about 9-12 months with conventional cytotoxic agents.
  • ER, PR, and HER2 expression precludes the use of targeted therapies in advanced TNBC, and the only approved systemic treatment option is chemotherapy (usually taxanes, anthracyclines and platinum drugs (Berrada et al. Ann. Oncol. 2010, 21, vii30-35) with or without bevacizumab).
  • chemotherapy usually taxanes, anthracyclines and platinum drugs (Berrada et al. Ann. Oncol. 2010, 21, vii30-35) with or without bevacizumab).
  • new therapies for TNBC are still needed.
  • Apoptosis is a highly regulated cell death pathway that is initiated by various cytotoxic stimuli, including oncogenic stress and chemotherapeutic agents. It has been shown that evasion of apoptosis is a hallmark of cancer and that efficacy of many chemotherapeutic agents is dependent upon the activation of the intrinsic mitochondrial pathway (Hanahan et al. Cell 2011, 144, 646-742).
  • Bcl-2 (B-cell lymphoma-2) family proteins play an important role in balancing cell survival and apoptosis (Tsujimoto, Genes to Cells 1998, 3, 697-707).
  • Bcl-2 family proteins have been found to be dysregulated in hematological malignancies but also in solid tumors and are frequently upregulated in acquired chemoresistant cancer cells (Maji et al. Advances in Cancer Research 2017, 137, 37-75). Pro-apoptotic and anti-apoptotic signals are tightly regulated in normal breast epithelial cells. Dysregulation of this balance is required for breast tumorgenesis and to increase acquired resistance to various treatments, including targeted therapies, radiation and chemotherapies (Williams et al. Oncotarget 2014, 6, 3519-3530). In BC, differential expression of pro-survival proteins across tumor subtypes suggest that different members of this protein class could be targeted in distinct tumor subtypes (Merino et al. Sci. Transl. Med. 2017, 9, pii: eaam7049).
  • Bcl-2 is an estrogen-responsive gene, which is overexpressed in about 85% of ER + positive BC (Dawson et al. British J Cancer 2010, 103, 668-675).
  • Pre-clinical data using patient- derived xenograft models of ER + BC suggested that intermittent dosing with a Bcl-2 inhibitor (venetoclax) synergized with tamoxifen (antiestrogenic treatment) to improve tumor response by increasing apoptosis (Vaillant et al. Cancer Cell 2013, 24, 120-129).
  • Mcl-1 was the second member of the Bcl-2 family discovered (Kozopas et al. Proc. Natl. Acad. Sci. USA 1993, 90, 3516-3520). Mcl-1 may also be a therapeutic target because Mcl-1 amplification has been observed in a large-scale high-resolution study of somatic copy number alterations across diverse cancers, including breast cancer, and Mcl-1 can confer resistance to chemotherapy or targeted therapy (Wertz et al. Nature 2011, 471, 110-114; Placzek et al. Cell Death & Disease 2010, 1, e40). Mcl-1 appears to be the main prosurvival protein that is up-regulated in TNBC (Goodwin et al. Cell Death Differ.
  • Mcl-1 amplification was commonly observed in TNBC tumors that failed to achieve a complete pathological response with neoadjuvant chemotherapy (Balko et al. Cancer Discov. 2014, 4, 232-245).
  • Mcl-1 expression was found upregulated in the antiestrogen-resistant cell lines and depletion of Mcl-1 in resistant cells caused decreased viability of cancer cells (Thrane et al. Oncogene 2015, 34, 4199-4210; Dawson et al. 2010).
  • the present invention provides a novel combination of a Mcl-1 inhibitor and a second anticancer agent, wherein the second anticancer agent is eribulin and fulvestrant.
  • the results show that the Mcl-1 inhibitor in combination with eribulin (Table 2) exhibits a strong synergistic pro-apoptotic activity in TNBC and ER + /HER2 breast cancer cell lines.
  • a Phase I/II clinical trial is currently ongoing (Example 2).
  • ⁇ D represents a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group,
  • ⁇ E represents a furyl, thienyl or pyrrolyl ring
  • ⁇ Xi, X 3 , X 4 and X 5 independently of one another represent a carbon atom or a nitrogen atom,
  • ⁇ X2 represents a C-R26 group or a nitrogen atom
  • ⁇ means that the ring is aromatic
  • ⁇ Y represents a nitrogen atom or a C-R 3 group
  • ⁇ Z represents a nitrogen atom or a C-R 4 group
  • ⁇ Ri represents a halogen atom, a linear or branched (Ci-C 6 )alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a linear or branched (Ci-C 6 )haloalkyl group, a hydroxy group, a hydroxy(Ci-C 6 )alkyl group, a linear or branched (Ci-C 6 )alkoxy group, -S-(Ci-C 6 )alkyl group, a cyano group, a nitro group, -Cys , -(Co-C 6 )alkyl-NRnRn’, -0-(Ci-C 6 )alkyl-NRnRn’, -0-(Ci-C 6 )alkyl-Ri 2 , -C(0)-0Rn, -0-C(0)-Rn, -C(0)-
  • R2, R 3 , R 4 and R 5 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-C 6 )alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a linear or branched (Ci-C 6 )haloalkyl, a hydroxy group, a hydroxy(Ci-C 6 )alkyl group, a linear or branched (Ci-C 6 )alkoxy group, a -S-(Ci-C 6 )alkyl group, a cyano group, a nitro group, -(Co-C 6 )alkyl-NRnRn’, -O-Cyi, -(Co-C 6 )alkyl-Cyi,
  • ⁇ 5 and R 7 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-C 6 )alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a linear or branched (Ci-C 6 )haloalkyl, a hydroxy group, a linear or branched (Ci-C 6 )alkoxy group, a -S-(Ci-C 6 )alkyl group, a cyano group, a nitro group, -(Co-C 6 )alkyl-NRnRn’, -0-(Ci-C 6 )alkyl-NRiiRii ⁇ -O-Cyi, -(Co-C 6 )alkyl-Cyi, -(C2-C 6 )alkenyl-Cyi,
  • ⁇ W represents a -CH2- group, a -NH- group or an oxygen atom
  • ⁇ R 8 represents a hydrogen atom, a linear or branched (Ci-Cx)alkyl group, a -CHR a R b group, an aryl group, a heteroaryl group, an aryl(Ci-C 6 )alkyl group, or a heteroaryl(Ci-C 6 )alkyl group,
  • ⁇ R 9 represents a hydrogen atom, a linear or branched (Ci-Ce)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, -Cy2, -(Ci-C 6 )alkyl-Cy 2 , -(C2-C 6 )alkenyl-Cy2, -(C2-C 6 )alkynyl-Cy2, -Cy 2 -Cy 3 , -(C2-C 6 )alkynyl-0-Cy2, -Cy2-(Co-C 6 )alkyl-0-(Co-C 6 )alkyl-Cy3, a halogen atom, a cyano group, -C(0)-Ri4, or -C(0)-NRi4Ri4’,
  • ⁇ Rio represents a hydrogen atom, a linear or branched (Ci-Ce)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, an aryl(Ci-C 6 )alkyl group, a cycloalkyl(Ci-C 6 )alkyl group, a linear or branched (Ci-Ce)haloalkyl, or -(Ci-C 6 )alkyl-0-Cy4,
  • R11 and Rn’ independently of one another represent a hydrogen atom, an optionally substituted linear or branched (Ci-Ce)alkyl group, or -(Co-Ce)alkyl-Cyi, or the pair (Rn, Rn’) together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by from 1 to 2 groups representing a hydrogen atom, or a linear or branched (Ci-C 6 )alkyl group and it being understood that one or more of the carbon atoms of the possible substituents, may be deuterated,
  • ⁇ Ri2 represents -Cys, -Cy5-(Co-C 6 )alkyl-0-(Co-C 6 )alkyl-Cy 6 , -Cy5-(Co-C 6 )alkyl-Cy 6 ,
  • Rn, R 13’ , Ri4 and Ru’ independently of one another represent a hydrogen atom, or an optionally substituted linear or branched (Ci-C 6 )alkyl group,
  • ⁇ R a represents a hydrogen atom or a linear or branched (Ci-C 6 )alkyl group
  • R b represents a -0-C(0)-0-Rc group, a -0-C(0)-NRcR c ’ group, or a -0-P(0)(0Rc)2 group,
  • R c and R e ’ independently of one another represent a hydrogen atom, a linear or branched (Ci-Cs)alkyl group, a cycloalkyl group, a (Ci-C 6 )alkoxy(Ci-C 6 )alkyl group, or a (Ci-C 6 )alkoxycarbonyl(Ci-C 6 )alkyl group,
  • Cyi, Cy2, Cy3, Cy4, Cys, Cy 6 , Cy7, Cys and Cyio independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, ⁇ Cy 9 represents or Cy 9 represents a heteroaryl group which is substituted by a group selected from -0-P(0)(OR 2O ) 2 ; -0-P(0)(0 M + ) 2 ; -(CH 2 ) p -O-(CHRi8-CHRi9-O) q -R 20 ; hydroxy; hydroxy(Ci-C 6 )alkyl; -(CH 2 ) r -U-(CH 2 ) s -heterocycloalkyl; or -U-(CH 2 ) q -NR 2i R 2i ’,
  • ⁇ Ri5 represents a hydrogen atom; a -(CH 2 ) p -0-(CHRi8-CHRi 9 -0) q -R 2 o group; a linear or branched (Ci-C 6 )alkoxy(Ci-C 6 )alkyl group; a -U-(CH 2 ) q -NR 2i R 2i ’ group; or a - (CH 2 ) r -U-(CH 2 ) s -heterocycloalkyl group,
  • Ri 6 represents a hydrogen atom; a hydroxy group; a hydroxy(Ci-C 6 )alkyl group; a -(CH 2 ) r -U-(CH 2 ) s -heterocycloalkyl group; a (CH 2 ) r -U-V-0-P(0)(OR 2 o) 2 group; a -0-P(0)(0 M + ) 2 group; a -0-S(0) 2 OR 2 o group; a -S(0) 2 OR 2 o group; a -S(0) 2 OR 2 o group; a -(CH 2 ) p -0-(CHRi8-CHRi 9 -0)q-R 2 o group; a -(CH 2 ) p -0-C(0)-NR 22 R 23 group; or a -U-(CH 2 ) q -NR 2 I R 2 1’ group,
  • ⁇ Ri7 represents a hydrogen atom; a -(CH 2 ) p -0-(CHRi8-CHRi 9 -0) q -R 2 o group; a -CH 2 -0-P(0)(OR 2O ) 2 group; a -0-P(0)(OR 2 o) 2 group; a -0-P(0)(0 M + ) 2 group; a hydroxy group; a hydroxy(Ci-C 6 )alkyl group; a -(CH 2 ) r -U-(CH 2 ) s -heterocycloalkyl group; a -U-(CH 2 ) q -NR 2i R 2i ’ group; or an aldonic acid,
  • ⁇ M + represents a pharmaceutically acceptable monovalent cation
  • ⁇ U represents a bond or an oxygen atom
  • ⁇ V represents a -(CH 2 ) S - group or a -C(O)- group
  • Ri 8 represents a hydrogen atom or a (Ci-C 6 )alkoxy(Ci-C 6 )alkyl group
  • ⁇ Ri9 represents a hydrogen atom or a hydroxy(Ci-C 6 )alkyl group
  • ⁇ R 2O represents a hydrogen atom or a linear or branched (Ci-C 6 )alkyl group
  • R 2I and R 2I ’ independently of one another represent a hydrogen atom, a linear or branched (Ci-C 6 )alkyl group, or a hydroxy(Ci-C 6 )alkyl group,
  • ⁇ R22 represents a (Ci-C 6 )alkoxy(Ci-C 6 )alkyl group, a -(CH ⁇ p-NR ⁇ I group, or a -(CH 2 ) P -0-(CHRi8-CHRi9-0) q -R2o group,
  • ⁇ R23 represents a hydrogen atom or a (Ci-C 6 )alkoxy(Ci-C 6 )alkyl group
  • ⁇ R24 and R24’ independently of one another represent a hydrogen atom or a linear or branched (Ci-C 6 )alkyl group
  • ⁇ R25 represents a hydrogen atom, a hydroxy group, or a hydroxy(Ci-C 6 )alkyl group
  • ⁇ R26 represents a hydrogen atom, a halogen atom, a linear or branched (Ci-Ce)alkyl group, or a cyano group,
  • ⁇ R27 represents a hydrogen atom or a linear or branched (Ci-Ce)alkyl group
  • ⁇ R28 represents a -0-P(0)(0 )(0 ) group, a -0-P(0)(0 )(OR3o) group, a -0-P(0)(OR 3O )(OR 3O ’) group, a -(CH2) p -0-S(0)20 group; a -(CH2) P -S(0)20 group; a -(CH2) p -0-S(0)20R3o group; -Cyio, a -0-C(0)-R29 group, a -0-C(0)-0R29 group or a -0-C(0)-NR2 9 R2 9 ’ group;
  • R29 and R29’ independently of one another represent a hydrogen atom, a linear or branched (Ci-Ce)alkyl group or a linear or branched amino(Ci-C 6 )alkyl group,
  • ⁇ R30 and R3O’ independently of one another represent a hydrogen atom, a linear or branched (Ci-Ce)alkyl group or an aryl(Ci-C 6 )alkyl group,
  • ⁇ R31 represents the following groups: wherein the ammonium ion optionally exists as a zwitterionic form or has a monovalent anionic counterion,
  • ⁇ n is an integer equal to 0 or 1
  • ⁇ p is an integer equal to 0, 1, 2, or 3,
  • ⁇ q is an integer equal to 1, 2, 3 or 4,
  • ⁇ r and s are independently an integer equal to 0 or 1, it being understood that:
  • aryl means a phenyl, naphthyl, biphenyl, indanyl or indenyl group
  • heteroaryl means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen,
  • cycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members,
  • heterocycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, which may include fused, bridged or spiro ring systems, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy, to be substituted by from 1 to 4 groups selected from optionally substituted linear or branched (Ci-C 6 )alkyl, optionally substituted linear or branched (C2-C6)alkenyl group, optionally substituted linear or branched (C2-C6)alkynyl group, optionally substituted linear or branched (Ci-C 6 )alkoxy, optionally substituted (Ci-C 6 )alkyl-S-, hydroxy, oxo (or L -oxide
  • (Ci-C 6 )haloalkyl, trifluoromethoxy, or halogen it being understood that R’ and R” independently of one another represent a hydrogen atom or an optionally substituted linear or branched (Ci-C 6 )alkyl group, and it being understood that one or more of the carbon atoms of the preceding possible substituents, may be deuterated, or their enantiomers, diastereoisomers, atropisomers, or addition salts thereof with a pharmaceutically acceptable acid or base, and (b) a second anticancer agent, wherein the second anticancer agent is selected from eribulin and fulvestrant,
  • the Mcl-1 inhibitor is Compound 1 (S64315/MIK665):
  • the Mcl-1 inhibitor is Compound 2 (S63845):
  • the invention provides a combination as described herein, for use in the treatment of cancer, more particularly, the treatment of breast cancer.
  • the invention provides a pharmaceutical composition comprising the combination as described herein, and at least one pharmaceutically acceptable carrier.
  • Combination refers to either a fixed dose combination in one unit dosage form (e.g., capsule, tablet, or sachet), non-fixed dose combination, or a kit of parts for the combined administration where a compound of the present invention and one or more combination partners (e.g. another drug as explained below, also referred to as‘therapeutic agent’ or‘co agent’) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect.
  • a combination partners e.g. another drug as explained below, also referred to as‘therapeutic agent’ or‘co agent’
  • co-administration or‘combined administration’ or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • fixed dose combination means that the active ingredients, e.g. a compound of formula (I) and one or more combination partners, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed dose combination means that the active ingredients, e.g. a compound of the present invention and one or more combination partners, are both administered to a patient as separate entities either simultaneously or sequentially, with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • Cancer means a class of disease in which a group of cells display uncontrolled growth. Cancer types include breast cancers including luminal breast cancer, HER2 + breast cancer and triple negative breast cancer.
  • BC means breast cancer.
  • jointly therapeutically effective means that the therapeutic agents may be given separately (in a chronologically staggered manner, especially a sequence-specific manner) in such time intervals that they prefer, in the warm-blooded animal, especially human, to be treated, still show a (preferably synergistic) interaction (joint therapeutic effect). Whether this is the case can, inter alia , be determined by following the blood levels, showing that both compounds are present in the blood of the human to be treated at least during certain time intervals.
  • Standard-of-care drug or‘standard-of-care chemotherapy’ means eribulin and fulvestrant.
  • ‘Synergistically effective’ or‘synergy’ means that the therapeutic effect observed following administration of two or more agents is greater than the sum of the therapeutic effects observed following the administration of each single agent.
  • the term‘treat’,‘treating’ or‘treatment’ of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • ‘treat’,‘treating’ or‘treatment’ refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • ‘treat’,‘treating’ or‘treatment’ refers to modulating the disease or disorder, either physically, ( e.g ., stabilization of a discernible symptom), physiologically, ( e.g ., stabilization of a physical parameter), or both.
  • a subject is‘in need of a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • the term‘remission’ refers to a decrease in or disappearance of signs and symptoms of cancer.
  • Medical means a pharmaceutical composition, or a combination of several pharmaceutical compositions, which contains one or more active ingredients in the presence of one or more excipients.
  • haloalkyl refers to a linear or branched alkyl chain substituted with one or more halogen groups in place of hydrogens along the hydrocarbon chain.
  • halogen groups suitable for substitution in the haloalkyl group include fluorine, bromine, chlorine, and iodine.
  • Haloalkyl groups may include substitution with multiple halogen groups in place of hydrogens in an alkyl chain, wherein said halogen groups can be attached to the same carbon or to another carbon in the alkyl chain.
  • ⁇ Z represents a nitrogen atom or a C-R 4 group
  • ⁇ Ri represents a linear or branched (Ci-C 6 )alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a linear or branched (Ci-C 6 )alkoxy group, -S-(Ci-C 6 )alkyl group, a linear or branched (Ci-C 6 )haloalkyl, a hydroxy group, a cyano, -NRiiRii’, -Cyx or a halogen atom,
  • R2, R 3 and R 4 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-C 6 )alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a linear or branched (Ci-C 6 )haloalkyl, a hydroxy group, a linear or branched (Ci-C 6 )alkoxy group, -S-(Ci-C 6 )alkyl group, a cyano group, a nitro group, -(Co-C 6 )alkyl-NRnRn’, -O-Cyi, -(Co-C 6 )alkyl-Cyi, -(C2-C 6 )alkenyl-Cyi, -(C 2 -C 6 )alkynyl-Cyi, -0-(Ci-C6)al
  • ⁇ 5 and R 7 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-C 6 )alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a linear or branched (Ci-C 6 )haloalkyl, a hydroxy group, a linear or branched (Ci-C 6 )alkoxy group, a -S-(Ci-C 6 )alkyl group, a cyano group, a nitro group, -(Co-C 6 )alkyl-NRnRn’, -O-Cyi, -(Co-C 6 )alkyl-Cyi, -(C2-C 6 )alkenyl-Cyi, -(C2-C 6 )alkynyl-Cyi, -0-(Ci-C 6 )al
  • ⁇ R 8 represents a hydrogen atom, a linear or branched (Ci-Cx)alkyl group, an aryl group, a heteroaryl group, an aryl(Ci-C 6 )alkyl group, or a heteroaryl(Ci-C 6 )alkyl group,
  • R 9 represents a linear or branched (Ci-C 6 )alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, -Cy2, -(Ci-C 6 )alkyl-Cy 2 , -(C2-C 6 )alkenyl-Cy2, -(C2-C 6 )alkynyl-Cy2, -Cy 2 -Cy 3 , -(C2-C 6 )alkynyl-0-Cy2, -Cy2-(Co-C 6 )alkyl-0-(Co-C 6 )alkyl-Cy3, a halogen atom, a cyano group, -C(0)-Ri4, or -C(0)-NRi4Ri4 ⁇
  • ⁇ R11 and Rn’ independently of one another represent a hydrogen atom, an optionally substituted linear or branched (Ci-C 6 )alkyl group, or -(Co-C 6 )alkyl-Cyi,
  • ⁇ R12 represents -Cys, -Cy5-(Co-C 6 )alkyl-Cy 6 , -Cy5-(Co-C 6 )alkyl-0-(Co-C 6 )alkyl-Cy 6 , -Cy 5 -(Co-C6)alkyl-NRii-(Co-C6)alkyl-Cy 6 , -Cy 5 -Cy6-0-(Co-C6)alkyl-Cy7,
  • Ri 3 , R 13 ’ , Ri 4 and R 14’ independently of one another represent a hydrogen atom, or an optionally substituted linear or branched (Ci-Ce)alkyl group,
  • ⁇ R25 represents a hydrogen atom, a hydroxy group, or a hydroxy(Ci-C 6 )alkyl group
  • Cyi, Cy2, Cy 3 , Cys, Cy 6 , Cyi and Cys independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group,
  • ⁇ n is an integer equal to 0 or 1, it being understood that:
  • aryl means a phenyl, naphthyl, biphenyl, indanyl or indenyl group
  • heteroaryl means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen,
  • cycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members,
  • heterocycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, which may include fused, bridged or spiro ring systems, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy, to be substituted by from 1 to 4 groups selected from optionally substituted linear or branched (Ci-Ce)alkyl, optionally substituted linear or branched (C2-C6)alkenyl group, optionally substituted linear or branched (C2-C6)alkynyl group, optionally substituted linear or branched (Ci-C 6 )alkoxy, optionally substituted (Ci-Ce)alkyl-S-, hydroxy, oxo (or L -oxide where appropriate
  • (Ci-Ce)haloalkyl, trifluoromethoxy, or halogen it being understood that R’ and R” independently of one another represent a hydrogen atom or an optionally substituted linear or branched (Ci-Ce)alkyl group, and it being understood that one or more of the carbon atoms of the preceding possible substituents, may be deuterated, or their enantiomers, diastereoisomers, atropisomers, or addition salts thereof with a pharmaceutically acceptable acid or base, and (b) a second anticancer agent, wherein the second anticancer agent is selected from eribulin and fulvestrant,
  • R9, R11, RiT and R12 are as described in El or E2 above.
  • Mcl-1 inhibitor of formula (I) is Compound 1 : (2f?)-2- ⁇ [(5S , a )-5- ⁇ 3-chloro-2-methyl-4-[2-(4-methylpiperazin-l- yl)ethoxy]phenyl ⁇ -6-(4-fluorophenyl)thieno[2,3-£f]pyrimidin-4-yl]oxy ⁇ -3-(2- ⁇ [2-(2- methoxyphenyl)pyrimidin-4-yl]methoxy ⁇ phenyl)propanoic acid, or a pharmaceutically acceptable salt thereof.
  • Mcl-1 inhibitor of formula (I) is Compound 2: (2f?)-2- ⁇ [(5S , a )-5- ⁇ 3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl) ethoxy] phenyl ⁇ -6-(5-fluorofuran-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy ⁇ -3-(2- ⁇ [ 1 -(2,2,2- trifluoroethyl)-l//-pyrazol-5-yl]methoxy [phenyl )propanoic acid, or a pharmaceutically acceptable salt thereof.
  • a second anticancer agent selected from eribulin and fulvestrant
  • Mcl-1 inhibitor and the second anticancer agent are provided in amounts which are jointly therapeutically effective for the treatment of cancer.
  • a pharmaceutical composition comprising the combination according to any of El to El 4, and at least one pharmaceutically acceptable carrier.
  • E22 The use of a combination according to any of El to El 4, in the manufacture of a medicament for the treatment of cancer.
  • E23. The use according to E22, wherein the cancer is breast cancer, more particularly luminal A breast cancer, luminal B breast cancer, HER2 + breast cancer and triple negative breast cancer.
  • a second anticancer agent selected from eribulin and fulvestrant
  • Mcl-1 inhibitor and the second anticancer agent are provided in effective amounts for the treatment of cancer, in particular breast cancer.
  • a second anticancer agent selected from eribulin and fulvestrant.
  • E27 Compound 1 for use in a combination therapy with eribulin or fulvestrant, for the treatment of cancer, in particular breast cancer.
  • E28 Eribulin for use in a combination therapy with Compound 1, for the treatment of cancer, in particular breast cancer.
  • the proportion of active ingredients by weight is from 5 to 50 %.
  • compositions according to the invention there will be more especially used those which are suitable for administration by the oral, parenteral and especially intravenous, per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory route, more specifically tablets, dragees, sublingual tablets, hard gelatin capsules, glossettes, capsules, lozenges, injectable preparations, aerosols, eye or nose drops, suppositories, creams, ointments, dermal gels etc.
  • the compound of formula (I), in particular Compound 1 is administered intravenously, for example, using the formulation as described in WO 2018/078064.
  • compositions according to the invention comprise one or more excipients or carriers selected from diluents, lubricants, binders, disintegration agents, stabilisers, preservatives, absorbents, colorants, sweeteners, flavourings etc.
  • lactose as diluents lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerol,
  • binders magnesium aluminium silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone,
  • the compounds of the combination may be administered simultaneously or sequentially.
  • the administration route is preferably the intravenous infusion or injection, and the corresponding pharmaceutical compositions may allow the instantaneous or delayed release of the active ingredients.
  • the compounds of the combination may moreover be administered in the form of two separate pharmaceutical compositions, each containing one of the active ingredients, or in the form of a single pharmaceutical composition, in which the active ingredients are in admixture.
  • the useful dosage regimen varies according to the sex, age and weight of the patient, the administration route, the nature of the cancer and of any associated treatments and ranges from 25 mg to 1500 mg of Mcl-1 inhibitor per week, more preferably from 50 mg to 1400 mg per week.
  • the dose of the second anticancer agent will be the same as that used when it is administered on its own.
  • the recommended dose of eribulin is 1.4 mg/m 2 which should be administered intravenously over 2 to 5 minutes on day 1 and day 8 during a 21 -day cycle.
  • the recommended dose of fulvestrant is 500 mg once monthly, with an additional 500 mg dose given two weeks after the initial dose only.
  • EXAMPLE 1 In vitro effect on proliferation of combining MCL-1 inhibitors with eribulin in Breast Cancer (BC) cell lines
  • Cell lines were sourced and maintained in the basic media supplemented with FBS as indicated in Table 1. In addition, all media contained penicillin (100 IU/mL), streptomycin (100 pg/mL) and L-glutamine (2 mM).
  • Cell lines were cultured at 37 °C in a humidified atmosphere containing 5% CO2 and expanded in T-150 flasks. In all cases cells were thawed from frozen stocks, expanded through > 1 passage using appropriate dilutions, counted and assessed for viability using a CASY cell counter prior to plating 150 pL/well at the densities indicated in Table 1 into 96-well plates. All cell lines were determined to be free of mycoplasma contamination in- house. Stock solutions of compounds were prepared at a concentration of 5 mM in DMSO and stored at -20 °C.
  • Mcl-1 inhibitors of the invention inhibited the growth of the majority of the 8 BC cell lines tested (IC50 values from 50 nM to 12.4 mM - Table 2).
  • GI synergistic growth inhibition
  • GI > 150% was measured in 5 BC cell lines upon the combined treatment of Mcl-1 inhibitors and eribulin.
  • a multi arm dose escalation Phase part designed with three independent arms
  • Arm 1 combination of Compound 1 with paclitaxel in locally advanced or metastatic TNBC or HR + /HER2 BC.
  • Patient will receive Compound 1 via Intra Venous (IV) infusion, from 30 minutes and up to 3 hours depending on the patient’s body weight and toxicities observed.
  • IV Intra Venous
  • the dose escalation will start at 100 mg and doses up to 1000 mg might be explored.
  • Compound 1 will be administered on D2, D9, D16 and D23 during 28-day cycle.
  • the same patient will receive paclitaxel at 80 mg/m 2 via IV infusion, as one-hour infusion, on Dl, D8 and D15 during 28-day cycle (3 weeks on and 1 week off).
  • the dose of paclitaxel may be adapted.
  • Arm 2 combination of Compound 1 with eribulin in locally advanced or metastatic TNBC or HR + /HER2 BC.
  • Patient will receive Compound 1 via IV infusion, from 30 minutes and up to 3 hours depending on the patient’s body weight and toxicities observed.
  • the dose escalation will start at 100 mg and doses up to 1000 mg might be explored.
  • Compound 1 will be administered on D2, D9 and D16 of a 21 -day cycle.
  • the same patient will receive eribulin at 1.4 mg/m 2 , via IV infusion, over 2 to 5 minutes on Dl and D8 of a 21 -day cycle in accordance with the SmPC of eribulin.
  • the dose of eribulin may be adapted.
  • Arm 3 combination of Compound 1 with fulvestrant in locally advanced or metastatic HR + /HER2 BC, in postmenopausal women.
  • Patient will receive Compound 1 via IV infusion, from 30 minutes and up to 3 hours depending on the patient’s body weight and toxicities observed.
  • the dose escalation will start at 100 mg and doses up to 1000 mg might be explored.
  • Compound 1 will be administered on D2, D8, D15 and D22 in Cycle 1, and on Dl, D8, D15 and D22 in following cycles, during 28-day cycle.
  • IM Intramuscular
  • the arm of treatment will be decided by investigator by taking into account type of BC the stage, and previous lines of treatment.
  • Arm 3 combination of Compound 1 and fulvestrant in locally advanced or metastatic HR + /HER2 BC, in postmenopausal women.
  • patients will be treated at the RDE of Compound 1 + fulvestrant with the administration schedule identified during the escalation Phase I part.
  • the total number of cycles is at the discretion of the investigator. Patients will be treated with Compound 1 in combination with paclitaxel, eribulin or fulvestrant until the disease progresses or patient’ s or physician’ s decision.

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Abstract

L'invention concerne une combinaison comprenant un inhibiteur de Mcl-1 et un second agent anticancéreux, le second agent anticancéreux étant choisi entre l'éribuline et le fulvestrant, et des compositions et des utilisations associées.
PCT/EP2020/066575 2019-06-17 2020-06-16 Combinaison d'un inhibiteur de mcl-1 et d'un standard de traitement de soin pour cancers du sein, utilisations et compositions pharmaceutiques associées Ceased WO2020254299A1 (fr)

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WO2022261301A1 (fr) 2021-06-11 2022-12-15 Gilead Sciences, Inc. Inhibiteurs de mcl-1 en combinaison avec des agents anticancéreux

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Publication number Priority date Publication date Assignee Title
WO2022261310A1 (fr) 2021-06-11 2022-12-15 Gilead Sciences, Inc. Inhibiteurs de mcl-1 en combinaison avec des conjugués anti-corps-médicament
WO2022261301A1 (fr) 2021-06-11 2022-12-15 Gilead Sciences, Inc. Inhibiteurs de mcl-1 en combinaison avec des agents anticancéreux
US11931424B2 (en) 2021-06-11 2024-03-19 Gilead Sciences, Inc. Combination MCL-1 inhibitors with anti-body drug conjugates
US11957693B2 (en) 2021-06-11 2024-04-16 Gilead Sciences, Inc. Combination MCL-1 inhibitors with anti-cancer agents

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