EP4319736A1 - Traitement de néoplasies malignes à l'aide d'une combinaison d'anticorps anti-pd-1 - Google Patents

Traitement de néoplasies malignes à l'aide d'une combinaison d'anticorps anti-pd-1

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Publication number
EP4319736A1
EP4319736A1 EP22785065.8A EP22785065A EP4319736A1 EP 4319736 A1 EP4319736 A1 EP 4319736A1 EP 22785065 A EP22785065 A EP 22785065A EP 4319736 A1 EP4319736 A1 EP 4319736A1
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European Patent Office
Prior art keywords
dose
weeks
administered
antibody
body weight
Prior art date
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EP22785065.8A
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German (de)
English (en)
Inventor
Mariia Stanislavovna SHUSTOVA
Sergei Nikolaevich FOGT
Fedor Borisovich KRYUKOV
Dmitry Valentinovich MOROZOV
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Biocad JSC
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Biocad JSC
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Priority claimed from RU2021109765A external-priority patent/RU2787457C2/ru
Application filed by Biocad JSC filed Critical Biocad JSC
Publication of EP4319736A1 publication Critical patent/EP4319736A1/fr
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule

Definitions

  • the present invention relates to the field of medicine, specifically to methods for treating a malignant neoplasm, comprising administering an antibody to PD-1, in particular prolgolimab, in combination with a chemotherapeutic agent.
  • PD-1 protein is an inhibitor member of the CD28 family of receptors, which includes CD28, CTLA-4, ICOS, PD-1, and BTLA.
  • PD-1 is expressed by activated B cells, T cells, and myeloid cells (Agata et al., supra; Okazaki et al. (2002) Curr. Opin. Immunol. 14: 391779-82; Bennet et al. (2003) J Immunol 170:711-8).
  • the initial members of the family, CD28 and ICOS, were discovered by functional effect on augmenting T cell proliferation following the addition of monoclonal antibodies (Hutloff et al. (1999) Nature 397:263-266; Hansen et al.
  • PD-1 was discovered through screening for differential expression in apoptotic cells (Ishida et al. (1992) EMBO J 11:3887-95).
  • the other members of the family, CTLA-4 and BTLA were discovered through screening for differential expression in cytotoxic T lymphocytes and TH1 cells, respectively.
  • CD28, ICOS and CTLA-4 all have an unpaired cysteine residue allowing for homodimerization.
  • PD-1 is suggested to exist as a monomer, lacking the unpaired cysteine residue characteristic in other CD28 family members.
  • PD-1 is a 55 kDa type I transmembrane protein that is part of the Ig gene superfamily (Agata et al. (1996) Int Immunol 8:765-72).
  • PD-1 comprises a membrane proximal immunoreceptor tyrosine-based inhibitory motif (ITEM) and a membrane distal tyrosine-based switch motif (ITSM) (Thomas, M L. (1995) J Exp Med 181:1953-6; Vivier, E and Daeron, M (1997) Immunol Today 18:286-91).
  • ITEM immunoreceptor tyrosine-based inhibitory motif
  • ITSM membrane distal tyrosine-based switch motif
  • PD-1 lacks the MYPPPY motif that is critical for B7-1 and B7-2 binding.
  • PD-L1 and PD-L2 Two ligands for PD-1 have been identified, PD-L1 and PD-L2, that have been shown to downregulate T cell activation upon binding to PD-l(Freeman et al. (2000) J Exp Med 192:1027-34; Latchman et al. (2001) Nat Immunol 2:261-8; Carter et al. (2002) Eur J Immunol 32:634-43). Both PD-L1 and PD-L2 are B7 homologs that bind to PD-1, but do not bind to other CD28 family members.
  • PD-1 PD-L1
  • PD-L1 One ligand for PD-1, PD-L1 is abundant in a variety of human cancers (Dong et al. (2002) Nat. Med. 8:787-9). The interaction between PD-1 and PD-L1 results in a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and immune evasion by the cancerous cells (Dong et al. (2003) J. Mol. Med. 81:281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54:307-314; Konishi et al. (2004) Clin. Cancer Res. 10:5094-100).
  • Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1, and the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well (Iwai et al. (2002) Proc. Nat’l. Acad. Sci. USA 99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66).
  • PD-1 is an inhibitory member of the CD28 family expressed on activated B cells, T cells, and myeloid cells (Agata et al., supra; Okazaki et al. (2002) Curr Opin Immunol 14: 391779-82; Bennett et al. (2003) J Immunol 170:711-8).
  • PD-1 deficient animals develop various autoimmune phenotypes, including autoimmune cardiomyopathy and a lupus-like syndrome with arthritis and nephritis (Nishimura et al. (1999) Immunity 11:141-51; Nishimura et al. (2001) Science 291:319-22).
  • PD-1 has been found to play a role in autoimmune encephalomyelitis, systemic lupus erythematosus, graft-versus-host disease (GVHD), type I diabetes, and rheumatoid arthritis (Salama et al. (2003) J Exp Med 198:71-78; Prokunina and Alarcon-Riquelme (2004) Hum Mol Genet 13:R143; Nielsen et al. (2004) Lupus 13:510).
  • the ITSM of PD-1 was shown to be essential to block BCR-mediated Ca2+-flux and tyrosine phosphorylation of downstream effector molecules (Okazaki et al. (2001) PNAS 98:13866-71).
  • nivolumab BMS
  • pembrolizumab Merk
  • PD-1 prolgolimab also known as BCD-100
  • BCD-100 a human monoclonal antibody of the IgGl isotype with effectorless mutations L234A, L235A.
  • Prolgolimab has shown increased affinity for PD-1, increased aggregation stability in comparison with antibodies of the IgG4 isotype.
  • prolgolimab is currently under clinical trials for various types of malignant neoplasms, including melanoma, including inoperable/metastatic melanoma, early stages of melanoma before and after definitive treatment; lung cancer, non-small cell lung cancer (NSCLC), including inoperable/metastatic non-small cell lung cancer; cervical cancer, including metastatic cervical cancer, recurrent cervical cancer, progressive cervical cancer, persistent cervical cancer, early stages of cervical cancer before and after definitive treatment.
  • NSCLC non-small cell lung cancer
  • cervical cancer including metastatic cervical cancer, recurrent cervical cancer, progressive cervical cancer, persistent cervical cancer, early stages of cervical cancer before and after definitive treatment.
  • Treatment of malignant neoplasms may combine immunotherapy and chemotherapy. Such therapy may be more effective than immunotherapy or chemotherapy alone.
  • composition refers to a composition and/or formulation containing a therapeutically effective amount of the antibody according to the invention plus excipients or auxiliary substances (carriers, diluents, vehicles, solvents and other excipients).
  • aqueous composition refers to a water-based composition, the water in the composition may be: water, water for injections, physiologic saline (0.9%-1.0% aqueous solution of sodium chloride)
  • parenteral administration refers to administration regimens, typically using injection, and includes, in particular intravenous, intramuscular, intraarterial, intratracheal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, intraarticular, subcapsular, subarchnoid, intraspinal, epidural and intrasternal injection or infusion.
  • the term “use” applies to the possibility to use the antibody of the present invention or a pharmaceutical composition containing thereof to treat, relief the course of the disease, expedite the remission, reduce the recurrence rate following the diseases or disorders mediated by receptors with which the antibody of the present invention can bind.
  • diseases are, without limitation, malignant neoplasms, including melanoma, including inoperable/metastatic melanoma, early stages of melanoma before and after definitive treatment; lung cancer, non-small cell lung cancer (NSCLC), including inoperable/metastatic non-small cell lung cancer, non- squamous cell non-small cell lung cancer, squamous cell lung cancer, small cell lung cancer, including inoperable/metastatic small cell lung cancer, early stage lung cancer before and after definitive treatment; cervical cancer, including metastatic cervical cancer, recurrent cervical cancer, progressive cervical cancer, persistent cervical cancer, early stages of cervical cancer before and after definitive treatment, head and neck cancers, including head and neck squamous cell carcinoma, Hodgkin's lymphoma, gastrointestinal cancer, metastatic esophageal squamous cell carcinoma, bladder cancer, including metastatic urothelial carcinoma, kidney cancer, endometrial cancer, including metastatic endometrial cancer, early stages of endometrial cancer
  • the term “method of treatment” refers to the possibility to use the antibody of the invention or pharmaceutical composition containing same to treat, relief the course of the disease, expedite the remission, reduce the recurrence rate following the diseases or disorders associated with PD1 activity.
  • "Treat” or “treatment” of a disease, disorder or condition may comprise the prevention or delay of the onset of clinical symptoms of a disease, disorder or condition developing in human, the inhibition of a disease, disorder or condition, i.e. stop, reduction or delay of the development of a disease or a relapse thereof (in case of maintenance therapy) or at least one clinical or subclinical symptom thereof, or the alleviation or easement of a disease, i.e.
  • diseases are, without limitation, malignant neoplasms, including melanoma, including inoperable/metastatic melanoma, early stages of melanoma before and after definitive surgical treatment; lung cancer, non-small cell lung cancer (NSCLC), including inoperable/metastatic non-small cell lung cancer.
  • malignant neoplasms including melanoma, including inoperable/metastatic melanoma, early stages of melanoma before and after definitive surgical treatment
  • lung cancer non-small cell lung cancer (NSCLC), including inoperable/metastatic non-small cell lung cancer.
  • NSCLC non-small cell lung cancer
  • a "chemotherapeutic agent” is a chemical compound useful in the treatment of a malignant neoplasm.
  • chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylmelamine; acetogenins (e g.
  • bullatacin and bullatacinone delta-9-tetrahydrocannabinol (dronabinol MARINOL®); beta- lapachone; lapachol; colchicines; betulinic acid; camptothecin (including the synthetic analogue topotecan (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®), acetylcamptothecin, scopolectin, and 9-aminocamptothecin); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); podophyllotoxin; podophyllinic acid; teniposide; cryptophycins (e g.
  • cryptophycin 1 and cryptophycin 8 dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancrati statin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.
  • calicheamicin e.g. calicheamicin gamma II and calicheamicin omega II (see, e.g. Agnew, Chem. Inti. Ed. Engl., 33: 183-186 (1994)); dynemicin, including dynemicin A; esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including ADRIAMYCIN®, morpholino-doxorubicin, cyanomorpholin
  • ELOXATINTM oxaliplatin
  • anti-hormonal agents that act to regulate or inhibit hormone action on tumors, such as anti-estrogens with mixed agonist/antagonist profile, including, tamoxifen (NOLVADEX®), 4-hydroxytamoxifen, toremifene (FARESTON®), idoxifene, droloxifene, raloxifene (EVTSTA®), trioxifene, keoxifene, and selective estrogen receptor modulators (SERMs), such as SERM3; pure anti -estrogens without agonist properties, such as fulvestrant (FASLODEX®), and EM800 (such agents may block estrogen receptor (ER) dimerization, inhibit DNA binding, increase ER turnover, and/or suppress ER levels); aromatase inhibitors, including steroidal aromatase inhibitors, such as formestane and exemestane (AROMASIN®), and nonsteroidal aromatase inhibitors, such as anastrazole
  • tamoxifen NO
  • the subject of treatment, or patient is a mammal, preferably a human subject. Said subject may be either male or female, of any age.
  • AUC area under the pharmacokinetic "concentration-time” curve ("area under the curve") AUMC AUMC — the total area under the curve prepared when product concentration in the organism is multiplied by time Cl — Total clearance Cmax — Maximum concentration
  • ECOG Eastern Cooperative Oncology Group GCP — Good Clinical Practice
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • TNM tumor, node, metastasis
  • SPD sum of the product of the perpendicular diameters for multiple lesions
  • TPS Tumor Proportion Score
  • CPS Combin Positive Score
  • ANC absolute neutrophil count
  • HIV Human immunodeficiency virus
  • G-CSF granulocyte colony-stimulating factor
  • GOST State standard JSC Joint stock company
  • IHC immunohistochemical study
  • ELISA Enzyme immunoassay
  • NSCLC non-small cell lung cancer
  • Echo-CG echocardiography
  • the present invention discloses methods for treating a malignant neoplasm in a subject in need thereof, comprising administering a therapeutically effective amount of antibody to PD-1, in particular prolgolimab, in combination with at least one chemotherapeutic agent, in particular paclitaxel, carboplatin or cisplatin.
  • the present invention discloses methods for treating a malignant neoplasm in a subject in need thereof, comprising administering a therapeutically effective amount of antibody to PD-1 prolgolimab in combination with antibody to VEGF, in particular bevacizumab, and at least one chemotherapeutic agent, in particular paclitaxel, carboplatin or cisplatin.
  • the anti-PD-1 antibody prolgolimab that is a human IgGl monoclonal antibody with effectorless mutations L234A, L235A (referred herein as "antibody of the invention") has shown to have improved aggregation stability, increased affinity and improved pharmacokinetic parameters, such as ⁇ 1/2b (hour) or Cmax (pg/ml) when compared to known anti- PD-1 antibodies that are based on human IgG4 antibody, such as nivolumab.
  • Prolgolimab has a weight average molecular weight around 146 kDa and is specific for human PD-1.
  • Prolgolimab has a heavy chain that contains 459 amino acids (SEQ ID NO: 1), and has a human light chain containing 214 amino acids (SEQ ID NO: 2), the constant portion (Fc) of prolgolimab comprises mutations L234A, L235A.
  • the present invention relates to the use of the antibody to PD-1 in combination with at least one chemotherapeutic agent for treating a malignant neoplasm in a subject in need thereof.
  • the present invention relates to a method for treating a malignant neoplasm in a subject in need thereof, including administering a therapeutically effective amount of the antibody to PD-1 in combination with at least one chemotherapeutic agent.
  • the therapeutically effective amount of the antibody to PD-1 according to the present invention depends on the condition to be treated, the severity of the condition, the previous therapy and the patient's history and response to the therapeutic agent.
  • a suitable dose can be adjusted by the decision of the attending physician so that it can be administered to the patient once or through several injections.
  • the therapeutically effective amount of the antibody to PD-1 per dose for the patient is from about 0.01 to 10 mg/kg of body weight, or about
  • 1 to 10 mg/kg of body weight or about 0.05 mg/kg of body weight, or about 0.25 mg/kg of body weight, or about 0.5 mg/kg of body weight, or about 1 mg/kg of body weight, or about 2 mg/kg of body weight, or about 3 mg/kg of body weight, or about 4 mg/kg of body weight, or about 5 mg/kg of body weight, or about 6 mg/kg of body weight, or about 7 mg/kg of body weight, or about 8 mg/kg of body weight, or about 9 mg/kg of body weight, or about 10 mg/kg of body weight.
  • the antibody to PD-1 is administered at a dose of 1 mg/kg or 3 mg/kg of body weight.
  • the antibody to PD-1 is administered at a fixed dose (in mg).
  • An acceptable dose of the antibody to PD-1 may contain 5-450 mg/dose, or may contain 40 mg, or 50 mg, or 60 mg per dose; or may contain 70 mg, or 80 mg, or 90 mg, or 100 mg per dose; or may contain 110 mg, or 120 mg, or 130 mg, or 140 mg per dose; or may contain 150 mg, or 160 mg, or 170 mg, or 180 mg per dose; or may contain 190 mg, or 200 mg, or 210 mg, or 220 mg per dose; or may contain 230 mg, or 240 mg, or 250 mg, or 260 mg per dose; or may contain 270 mg, or 280 mg, or 290 mg per dose, or may contain 300 mg, or 310 mg, or 320 mg, or 330 mg, or 340 mg, or 350 mg per dose; or may contain 360 mg, or 370 mg, or 380 mg, or 390 mg, or 400 mg, or 410 mg , or 420
  • the antibody to PD-1 is administered at a dose of 100-400 mg.
  • the frequency of dosing may be normally about once per week, or about once every
  • the antibody to PD-1 is administered every 2 weeks, or every 3 weeks, or every 4 weeks. [0032] In some embodiments of the invention, the antibody to PD-1 is administered at a dose of 1 mg/kg of body weight every 2 weeks or every 3 weeks.
  • the antibody to PD-1 is administered at a dose of 3 mg/kg of body weight every 2 weeks or every 3 weeks.
  • the antibody to PD-1 is prolgolimab.
  • prolgolimab is administered parenterally.
  • said parenteral administration may be intravenous, subcutaneous or intramuscular administration.
  • prolgolimab may be administered intravenously as an infusion.
  • prolgolimab may be administered intravenously as an infusion over 60 minutes; in case of good tolerability, the infusion time may be shortened to 30 minutes.
  • the chemotherapeutic agent is selected from a group comprising taxane, a platinum agent.
  • the chemotherapeutic agent is administered every 2 weeks, or every 3 weeks, or every 4 weeks.
  • taxane is selected from paclitaxel, docetaxel.
  • paclitaxel is administered at a dose of 135- 175 mg/m 2 .
  • paclitaxel is administered at a dose of 135 or 175 mg/m 2 .
  • paclitaxel is administered at a dose of 175 mg/m 2 as a 3 -hour intravenous (IV) infusion.
  • paclitaxel is administered at a dose of 135 mg/m 2 as a 24-hour IV infusion.
  • the platinum agent is selected from carboplatin, cisplatin.
  • cisplatin is administered at a dose of 50-100 mg/m 2 .
  • cisplatin is administered at a dose of 50 mg/m 2 , 100 mg/m 2 .
  • cisplatin is administered at a dose of 50-100 mg/m2 as an IV infusion every 3 or every 4 weeks.
  • carboplatin is administered at a dose of AUC 5-7.
  • carboplatin is administered at a dose of AUC 5, AUC 6, AUC 7.
  • AUC area under the curve
  • AUC is a statistical measure, the area limited to a certain curve of drug plasma concentration versus the x-axis (time).
  • paclitaxel is administered at a dose of 175 mg/m 2 as a 3 -hour intravenous (IV) infusion followed by administration of cisplatin every 3 weeks.
  • paclitaxel is administered at a dose of 135 mg/m 2 as a 24-hour IV infusion followed by administration of cisplatin every 3 weeks.
  • chemotherapeutic agent in particular, paclitaxel, carboplatin, cisplatin.
  • Dose reduction may be, for example, 50% or 25%.
  • an antibody to VEGF is further administered.
  • the antibody to VEGF is administered every 2 weeks, or every 3 weeks, or every 4 weeks.
  • the antibody to VEGF is bevacizumab.
  • bevacizumab is administered at a dose of 15 mg/kg of body weight.
  • the present invention relates to the use of the antibody to PD-1 in combination with paclitaxel and carboplatin or cisplatin for treating a malignant neoplasm in a subject in need thereof.
  • the present invention relates to a method for treating a malignant neoplasm in a subject in need thereof, including administering a therapeutically effective amount of the antibody to PD-1 in combination with paclitaxel and carboplatin or cisplatin.
  • the antibody to PD-1 is administered at a dose of 1 mg/kg or 3 mg/kg of body weight.
  • paclitaxel is administered at a dose of 175 mg/m2.
  • carboplatin is administered at a dose of AUC 5 or cisplatin is administered at a dose of 50 mg/m2.
  • the antibody to PD-1 in combination with paclitaxel and carboplatin or cisplatin are administered every 2 weeks or every 3 weeks.
  • the antibody to PD-1 at a dose of 1 mg/kg or 3 mg/kg of body weight is administered in combination with paclitaxel at a dose of 175 mg/m2 and carboplatin at a dose of AUC 5 or cisplatin at a dose of 50 mg/m2 every 2 weeks or every 3 weeks.
  • the antibody to PD-1 at a dose of 1 mg/kg of body weight is administered every 2 weeks, paclitaxel at a dose of 175 mg/m2 and carboplatin at a dose of AUC 5 are administered every 3 weeks.
  • the antibody to PD-1 at a dose of 1 mg/kg of body weight is administered every 2 weeks or every 3 weeks, paclitaxel at a dose of 175 mg/m2 and carboplatin at a dose of AUC 5 are administered every 3 weeks.
  • the antibody to PD-1 at a dose of 3 mg/kg of body weight is administered every 2 weeks or every 3 weeks, paclitaxel at a dose of 175 mg/m2 and carboplatin at a dose of AUC 5 are administered every 3 weeks.
  • the antibody to PD-1 at a dose of 1 mg/kg of body weight is administered every 2 weeks or every 3 weeks, paclitaxel at a dose of 175 mg/m2 and cisplatin at a dose of 50 mg/m2 are administered every 3 weeks.
  • the antibody to PD-1 at a dose of 3 mg/kg of body weight is administered every 2 weeks or every 3 weeks, paclitaxel at a dose of 175 mg/m2 and cisplatin at a dose of 50 mg/m2 are administered every 3 weeks.
  • therapy may include one or more cycles of dose administration.
  • the therapy may include no more than 6 cycles of dose administration, or exactly 6 cycles of dose administration.
  • a cycle as used in the present invention refers to the repetition of previously administered doses of active substances over a certain period of time (every 2 weeks, 3 weeks, 4 weeks, etc.).
  • maintenance therapy is further performed following the above main therapy (antibody to PD-1 in combination with at least one chemotherapeutic agent).
  • Maintenance therapy involves administration of the antibody to PD-1 at a dose of 1 mg/ml or 3 mg/ml every 2 or every 3 weeks. Maintenance therapy is performed until progression.
  • the antibody to PD-1 in combination with paclitaxel and carboplatin is administered for no more than 6 cycles every 3 weeks, followed by administration of the antibody to PD-1 every 2 or every 3 weeks until progression.
  • the antibody to PD-1 in combination with bevacizumab, paclitaxel and cisplatin is administered for no more than 6 cycles every 3 weeks, followed by administration of the antibody to PD-1 every 2 or every 3 weeks until progression.
  • the doses of antibody to PD-1, paclitaxel, carboplatin and cisplatin may be those indicated above.
  • the antibody to PD-1 at a dose of 1 mg/kg or 3 mg/kg in combination with bevacizumab at a dose of 15 mg/kg, paclitaxel at a dose of 175 mg/m 2 and carboplatin at a dose of AUC 5 is administered for 6 cycles every 3 weeks, followed by administration of the antibody to PD-1 at a dose of 1 mg/kg or 3 mg/kg every 2 or every 3 weeks until progression.
  • the antibody to PD-1 at a dose of 1 mg/kg or 3 mg/kg in combination with bevacizumab at a dose of 15 mg/kg, paclitaxel at a dose of 175 mg/m 2 and cisplatin at a dose of 50 mg/m 2 is administered for 6 cycles every 3 weeks, followed by administration of the antibody to PD-1 at a dose of 1 mg/kg or 3 mg/kg every 2 or every 3 weeks until progression.
  • the antibody to PD-1 is prolgolimab.
  • the present invention relates to the use of the antibody to PD-1 in combination with bevacizumab, paclitaxel, carboplatin or cisplatin for treating a malignant neoplasm in a subject in need thereof.
  • the present invention relates to a method for treating a malignant neoplasm in a subject in need thereof, including administering a therapeutically effective amount of the antibody to PD-1 in combination with bevacizumab, paclitaxel, carboplatin or cisplatin.
  • the antibody to PD-1 is administered at a dose of 1 mg/kg or 3 mg/kg of body weight.
  • bevacizumab is administered at a dose of 15 mg/kg of body weight.
  • paclitaxel is administered at a dose of 175 mg/m2.
  • carboplatin is administered at a dose of AUC 5 or cisplatin is administered at a dose of 50 mg/m2.
  • the antibody to PD-1 in combination with bevacizumab, paclitaxel, carboplatin or cisplatin is administered every 2 weeks or every 3 weeks.
  • the antibody to PD-1 at a dose of 1 mg/kg or 3 mg/kg of body weight is administered in combination with bevacizumab at a dose of 15 mg/kg of body weight, paclitaxel at a dose of 175 mg/m2 and carboplatin at a dose of AUC 5 or cisplatin at a dose of 50 mg/m2 every 2 weeks or every 3 weeks.
  • the antibody to PD-1 at a dose of 1 mg/kg of body weight and bevacizumab at a dose of 15 mg/kg of body weight are administered every 2 weeks or every 3 weeks, paclitaxel at a dose of 175 mg/m2 and carboplatin at a dose of AUC 5 are administered every 3 weeks.
  • the antibody to PD-1 at a dose of 3 mg/kg of body weight and bevacizumab at a dose of 15 mg/kg of body weight are administered every 2 weeks or every 3 weeks, paclitaxel at a dose of 175 mg/m2 and carboplatin at a dose of AUC 5 are administered every 3 weeks.
  • the antibody to PD-1 at a dose of 1 mg/kg of body weight and bevacizumab at a dose of 15 mg/kg of body weight are administered every 2 weeks or every 3 weeks, paclitaxel at a dose of 175 mg/m2 and cisplatin at a dose of 50 mg/m2 are administered every 3 weeks.
  • the antibody to PD-1 at a dose of 3 mg/kg of body weight and bevacizumab at a dose of 15 mg/kg of body weight are administered every 2 weeks or every 3 weeks, paclitaxel at a dose of 175 mg/m2 and cisplatin at a dose of 50 mg/m2 are administered every 3 weeks.
  • the antibody to PD-1 is prolgolimab.
  • therapy may include one or more cycles of dose administration until progression.
  • the therapy may include no more than 6 cycles of dose administration, or exactly 6 cycles of dose administration.
  • a cycle as used in the present invention refers to the repetition of previously administered doses of active substances over a certain period of time (every 2 weeks, 3 weeks, 4 weeks, etc.).
  • maintenance therapy is further performed following the above main therapy (antibody to PD-1 in combination with at least one chemotherapeutic agent).
  • Maintenance therapy involves administration of the antibody to PD-1 at a dose of 1 mg/ml or 3 mg/ml every 2 or every 3 weeks. Maintenance therapy is performed until progression.
  • the antibody to PD-1 in combination with bevacizumab, paclitaxel and carboplatin is administered for no more than 6 cycles every 3 weeks, followed by administration of the antibody to PD-1 every 2 or every 3 weeks until progression.
  • the antibody to PD-1 in combination with bevacizumab, paclitaxel and carboplatin is administered for no more than 6 cycles every 3 weeks, followed by administration of the antibody to PD-1 and bevacizumab every 3 weeks until progression.
  • the antibody to PD-1 in combination with bevacizumab, paclitaxel and cisplatin is administered for no more than 6 cycles every 3 weeks, followed by administration of the antibody to PD-1 every 2 or every 3 weeks until progression.
  • the antibody to PD-1 in combination with bevacizumab, paclitaxel and cisplatin is administered for no more than 6 cycles every 3 weeks, followed by administration of the antibody to PD-1 and bevacizumab every 3 weeks until progression.
  • the doses of antibody to PD-1, bevacizumab, carboplatin and cisplatin may be those as indicated above.
  • the antibody to PD-1 at a dose of 1 mg/kg or 3 mg/kg in combination with bevacizumab at a dose of 15 mg/kg, paclitaxel at a dose of 175 mg/m 2 and carboplatin at a dose of AUC 5 is administered for 6 cycles every 3 weeks, followed by administration of the antibody to PD-1 at a dose of 1 mg/kg or 3 mg/kg every 2 or every 3 weeks until progression.
  • the antibody to PD-1 at a dose of 1 mg/kg or 3 mg/kg in combination with bevacizumab at a dose of 15 mg/kg, paclitaxel at a dose of 175 mg/m 2 and carboplatin at a dose of AUC 5 is administered for 6 cycles every 3 weeks, followed by administration of the antibody to PD-1 at a dose of 1 mg/kg or 3 mg/kg and bevacizumab at a dose of 15 mg/kg every 3 weeks until progression.
  • the antibody to PD-1 at a dose of 1 mg/kg or 3 mg/kg in combination with bevacizumab at a dose of 15 mg/kg, paclitaxel at a dose of 175 mg/m 2 and cisplatin at a dose of 50 mg/m 2 is administered for 6 cycles every 3 weeks, followed by administration of the antibody to PD-1 at a dose of 1 mg/kg or 3 mg/kg every 2 or every 3 weeks until progression.
  • the antibody to PD-1 at a dose of 1 mg/kg or 3 mg/kg in combination with bevacizumab at a dose of 15 mg/kg, paclitaxel at a dose of 175 mg/m 2 and cisplatin at a dose of 50 mg/m 2 is administered for 6 cycles every 3 weeks, followed by administration of the antibody to PD-1 at a dose of 1 mg/kg or 3 mg/kg and bevacizumab at a dose of 15 mg/kg every 3 weeks until progression.
  • the antibody to PD-1 is prolgolimab.
  • the malignant neoplasm is selected from the group including melanoma, including inoperable/metastatic melanoma, early stages of melanoma before and after definitive treatment; lung cancer, non-small cell lung cancer (NSCLC), including inoperable/metastatic non-small cell lung cancer, non-squamous cell non-small cell lung cancer, squamous cell lung cancer, small cell lung cancer, including inoperable/metastatic small cell lung cancer, early stage lung cancer before and after definitive treatment; cervical cancer, including metastatic cervical cancer, recurrent cervical cancer, progressive cervical cancer, persistent cervical cancer, early stages of cervical cancer before and after definitive treatment, head and neck cancers, including head and neck squamous cell carcinoma, Hodgkin's lymphoma, gastrointestinal cancer, metastatic esophageal squamous cell carcinoma, bladder cancer, including metastatic urothelial carcinoma, kidney cancer, endometrial cancer, including metastatic endometrial cancer, early
  • the malignant neoplasm is cervical cancer, including metastatic cervical cancer, recurrent cervical cancer, progressive cervical cancer, persistent cervical cancer, early stages of cervical cancer before and after definitive treatment.
  • prolgolimab may be administered as an aqueous pharmaceutical composition comprising:
  • said prolgolimab may be present at a concentration from 15 mg/ml to 25 mg/ml.
  • said prolgolimab may be present at a concentration of 20 mg/ml.
  • said trehalose dihydrate may be present at a concentration from 95 mg/ml to 105 mg/ml.
  • said trehalose dihydrate may be present at a concentration of 100 mg/ml.
  • said sodium acetate trihydrate may be present at a concentration from 1.6 mg/ml to 1.9 mg/ml.
  • said sodium acetate trihydrate may be present at a concentration from 1.7 mg/ml to 1.8 mg/ml.
  • said sodium acetate trihydrate may be present at a concentration of 1.742 mg/ml.
  • said acetic acid may be added to pH 5.0.
  • said acetic acid may be present at a concentration from 0.04 mg/ml to 0.77 mg/ml.
  • said acetic acid may be present at a concentration from 0.40 mg/ml to 0.50 mg/ml. [00118] In some embodiments of the invention, said acetic acid may be present at a concentration of 0.43 mg/ml.
  • prolgolimab may be administered as an aqueous pharmaceutical composition comprising:
  • said prolgolimab may be present at a concentration from 90 mg/ml to 110 mg/ml.
  • said prolgolimab may be present at a concentration of 100 mg/ml.
  • said trehalose dihydrate may be present at a concentration from 75 mg/ml to 85 mg/ml.
  • said trehalose dihydrate may be present at a concentration of 80 mg/ml.
  • said sodium acetate trihydrate may be present at a concentration from 1.6 mg/ml to 1.9 mg/ml.
  • said sodium acetate trihydrate may be present at a concentration from 1.7 mg/ml to 1.8 mg/ml.
  • said sodium acetate trihydrate may be present at a concentration of 1.742 mg/ml.
  • said acetic acid may be added to pH from 5.0 to 5.5.
  • said acetic acid may be added to pH 5.0.
  • said acetic acid may be present at a concentration from 0.045 mg/ml to 0.77 mg/ml.
  • said acetic acid may be present at a concentration from 0.40 mg/ml to 0.50 mg/ml.
  • said acetic acid may be present at a concentration from 0.43 mg/ml.
  • prolgolimab may be administered as an aqueous pharmaceutical composition comprising:
  • prolgolimab may be administered as an aqueous pharmaceutical composition comprising:
  • prolgolimab may be administered as an aqueous pharmaceutical composition comprising:
  • said prolgolimab may be present at a concentration from 15 mg/ml to 40 mg/ml.
  • said prolgolimab may be present at a concentration from 15 mg/ml to 25 mg/ml.
  • said prolgolimab may be present at a concentration of 20 mg/ml.
  • said trehalose dihydrate may be present at a concentration from 95 mg/ml to 105 mg/ml.
  • said trehalose dihydrate may be present at a concentration of 100 mg/ml.
  • said L-histidine may be present at a concentration from 0.7 mg/ml to 1.0 mg/ml.
  • said L-histidine may be present at a concentration of 0.92 mg/ml.
  • said L-histidine hydrochloride may be present at a concentration from 2.8 mg/ml to 3.3 mg/ml.
  • said L-histidine hydrochloride may be present at a concentration of 2.96 mg/ml.
  • said composition may have pH from 5.5 to 6.5.
  • said composition may have pH 5.5.
  • said prolgolimab may be present at a concentration from 90 mg/ml to 110 mg/ml.
  • said prolgolimab may be present at a concentration of 100 mg/ml.
  • said trehalose dihydrate may be present at a concentration from 75 mg/ml to 85 mg/ml.
  • said trehalose dihydrate may be present at a concentration of 80 mg/ml.
  • said L-histidine may be present at a concentration from 0.7 mg/ml to 1.0 mg/ml.
  • said L-histidine may be present at a concentration of 0.92 mg/ml.
  • said L-histidine hydrochloride may be present at a concentration from 2.8 mg/ml to 3.3 mg/ml.
  • said L-histidine hydrochloride may be present at a concentration of 2.96 mg/ml.
  • said composition may have pH from 5.5 to 6.5.
  • said composition may have pH from 5.5 to 6 0
  • said composition may have pH 5.5.
  • prolgolimab may be administered as an aqueous pharmaceutical composition comprising:
  • composition wherein said composition has pH 5.5.
  • prolgolimab may be administered as an aqueous pharmaceutical composition comprising:
  • said composition has pH from 5.5 to 6.0.
  • said aqueous pharmaceutical composition may further comprise a suitable solubilizer.
  • said solubilizer may be Poloxamer 188.
  • said Poloxamer 188 may be present in an amount greater than 0 mg/ml but equal to or less than 1 mg/ml.
  • said Poloxamer 188 may be present in an amount of 0 mg/ml, 0.1 mg/ml, 0.2 mg/ml, 0.3 mg/ml, 0.4 mg/ml, 0.5 mg/ml, 0.6 mg/ml, 0.7 mg/ml, 0.8 mg/ml, 0.9 mg/ml, 1.0 mg/ml.
  • the use of said aqueous pharmaceutical composition of prolgolimab may comprise administering said composition parenterally.
  • said parenteral administration may be intravenous, subcutaneous or intramuscular administration.
  • the use of said aqueous pharmaceutical composition of anti-PD-1 antibody prolgolimab may comprise administering said composition intravenously as an infusion.
  • the aqueous pharmaceutical composition of anti-PD-1 antibody prolgolimab of the invention may be administered intravenously as an infusion over 60 minutes; in case of good tolerability, the infusion time may be shortened to 30 minutes.
  • prolgolimab (BCD-100) for treating patients in combination with platinum-containing chemotherapy and bevacizumab in first-line therapy in female patients with recurrent/persistent or metastatic cervical cancer, phase II trial, BCD- 100-4/CAESURA.
  • BCD- 100-4/CAESURA (CAESURA, NCT03912402) in terms of design thereof is an open-label, single-arm study of efficacy and safety of the BCD- 100 product (JSC "BIOCAD", Russia) in combination with platinum-containing chemotherapy (ChT) and bevacizumab (BEV) in first-line therapy in female patients with recurrent/persistent or metastatic cervical cancer (CC).
  • the trial is carried out in 2 stages.
  • the female patients received BCD-100 + ChT + BEV therapy for up to 6 cycles, either until they developed intolerable toxicity events, or until disease progression.
  • the female patients who demonstrated a positive antitumor effect (stabilization of the disease, partial or complete response) and who had no signs of intolerable toxicity were transferred to the second stage of the trial, the maintenance therapy stage.
  • Cisplatin 50 mg/m2 as a 1-hour Q3W infusion or Carboplatin AUC 5 mg/ml/min as a 1-hour Q3W infusion the choice of Carboplatin or Cisplatin was left to the discretion of the Study Physician based on the risk/benefit ratio for a particular female patient.
  • This stage of the trial consists of maintenance therapy, which is conducted in female patients who have achieved a positive antitumor effect Maintenance therapy regimen:
  • Therapy as part of the second stage of the trial is conducted until disease progression or until development of intolerable toxicity events, but for not more than 12 cycles inclusive.
  • the therapy of the female patients may be continued when stabilization or response to therapy is achieved and provided that there are no intolerable toxicity events.
  • the female patient could further receive up to 12 cycles (inclusive) of the BCD-100 product in combination with bevacizumab (further therapy could continue as part of another trial BCD-100-EXT). Evaluation of efficacy at the second stage of the trial had an ancillary character.
  • the female patients underwent a CT scan every 12 weeks, and unscheduled study was further contemplated if disease progression was suspected.
  • the immunogenicity study was part of the mandatory procedures for monitoring the safety of the therapeutic product and was performed prior to the first administration of the product and then every 42 days of product therapy until the end of the first stage of the trial.
  • 59 patients were enrolled aged 18 and older.
  • the population included female patients with histologically verified (all histological types) primary metastatic cervical cancer, or recurrent/persistent cervical cancer, with the presence of measurable control tumor foci (at least 1 focus), according to the RECIST 1.1 criteria (confirmed by central revision), having a general condition corresponding to a score of 0-1 according to ECOG scale (Table 1).
  • This population included female patients who took the place of those who discontinued prior to first administration of BCD-100, or of those who discontinued as a result of serious deviations from the protocol.
  • the resulting modified ITT population of female patients who received at least one dose of BCD-100 included 58 female patients.
  • the population per protocol included 42 patients who received all 6 cycles of therapy at the first stage.
  • Administration of at least one of the four combination therapy products i.e. prolgolimab, bevacizumab, paclitaxel, cisplatin/carboplatin was assumed as a therapy cycle.
  • the overall response rate in the PP population against the background of combination therapy with prolgolimab was 59.52% in accordance with RECIST 1.1 evaluation criteria and 80.95% in accordance with iRECIST evaluation criteria.
  • the frequency of achieving disease control was 88.10% in accordance with RECIST 1.1 evaluation criteria and 95.24% in accordance with iRECIST evaluation criteria. It should be noted that the indicators of therapy efficacy in the population of female patients who received all 6 therapy cycles are greater as compared to those in the mITT population, thus suggesting a more favorable prognosis in this subgroup of female patients.
  • the median time to achieve response to therapy according to all estimates was about 2.2 months, which corresponds to the time frame of the first control CT study.
  • the median duration of response to therapy was not achieved by any of the evaluations.
  • Safety analysis includes all patients included in the trial and who received at least 1 administration of the test product (mITT).
  • the prolgolimab exposure was 126 days or greater in 68.97% (40 out of 58) of patients.
  • Median (1. quartile; up. quartile) infusions was 6 (5; 6) infusions.
  • Exposure to complete combination of test therapy (all chemotherapy drugs, including bevacizumab and prolgolimab) was 126 days or more in 74.14% (43 out of 58) of patients.
  • Grade 3-4 adverse events according to CTCAE 5.0 were observed in 30 (51.72%) female patients.
  • Table 3 shows data on primary main safety parameters. Table 3 - Main safety parameters in mITT population
  • the platinum-containing chemotherapy regimen in combination with bevacizumab is characterized by safety parameters similar to those obtained in the present trial.
  • the standard therapy regimen in a similar population of patients was characterized by the development of AEs with an incidence of 100%, by the development of SAEs in 45 9% of patients, by the development of grade 3/4/5 AEs in 78.0% of patients, by the discontinuation of therapy due to the development of AEs in 33.0% of patients.
  • the safety profile of combination therapy supplemented with prolgolimab corresponds to the literature data relating to the safety of the standard regimen of platinum-containing chemotherapy in combination with bevacizumab.
  • the addition of prolgolimab to standard therapy was associated with the development of immunotherapy-specific adverse events, i.e. immuno-mediated AEs, that were not observed (according to literature data) against the background of standard therapy, but did not lead to a significant deterioration in the safety profile of the combined therapy regimen as compared to treatment standard.
  • Immunogenicity analysis included data from 55 patients who received at least one prolgolimab administration with no omitted/lost/spoiled blood serum sample taken on day 1 of week 0, as well as at least one of the samples taken at one of the subsequent visits. The immunogenicity study did not reveal the formation of binding antibodies to prolgolimab in any of the patients.

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Abstract

La présente invention concerne l'utilisation d'anticorps anti-PD-1, en particulier le prolgolimab, en combinaison avec au moins un agent chimiothérapeutique, en particulier le paclitaxel, le carboplatine ou le cisplatine, pour traiter un néoplasme malin chez un sujet en ayant besoin, et l'utilisation de l'anticorps anti PD-1 prolgolimab en combinaison avec l'anticorps anti-VEGF, en particulier le bévacizumab, et au moins un agent chimiothérapeutique, en particulier le paclitaxel, le carboplatine, ou le cisplatine, pour traiter un néoplasme malin chez un sujet en ayant besoin. La présente invention concerne en outre un procédé de traitement d'un néoplasme malin chez un sujet en ayant besoin, comprenant l'administration d'une quantité thérapeutiquement efficace d'anticorps anti-PD-1, en particulier le prolgolimab, en combinaison avec au moins un agent chimiothérapeutique, en particulier le paclitaxel, le carboplatine ou le cisplatine, et un procédé de traitement d'un néoplasme malin chez un sujet en ayant besoin, comprenant l'administration d'une quantité thérapeutiquement efficace de l'anticorps anti-PD-1 prolgolimab en combinaison avec un anticorps anti-VEGF, en particulier le bévacizumab, et au moins un agent chimiothérapeutique, en particulier le paclitaxel, le carboplatine ou le cisplatine.
EP22785065.8A 2021-04-08 2022-04-08 Traitement de néoplasies malignes à l'aide d'une combinaison d'anticorps anti-pd-1 Pending EP4319736A1 (fr)

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