WO2016164217A1 - Combinaisons thérapeutiques pour le traitement du cancer - Google Patents

Combinaisons thérapeutiques pour le traitement du cancer Download PDF

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WO2016164217A1
WO2016164217A1 PCT/US2016/024839 US2016024839W WO2016164217A1 WO 2016164217 A1 WO2016164217 A1 WO 2016164217A1 US 2016024839 W US2016024839 W US 2016024839W WO 2016164217 A1 WO2016164217 A1 WO 2016164217A1
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cancer
egfr
radiotherapy
mutant
nsclc
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Andrew D. Simmons
Thomas Christian HARDING
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Clovis Oncology, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine

Definitions

  • the present invention relates to combination treatment methods for treating cancer, particularly non-small cell lung cancer (NSCLC). More specifically, the invention relates to methods of treating or managing cancer, particularly NSCLC, in a subject, comprising administering an irreversible mutant epidermal growth factor receptor (EGFR) inhibitor compound in combination with one or more other therapies, particularly
  • NSCLC non-small cell lung cancer
  • EGFR epidermal growth factor receptor
  • the present invention relates to pharmaceutical compositions and methods comprising said irreversible mutant EGFR inhibitor compounds for treating cancer in combination with one or more other therapies, such as Radiotherapy, administered simultaneously, separately, or sequentially.
  • lung cancer remains the most common cancer worldwide with approximately 1.35 million new cases annually and non- small cell lung cancer (NSCLC) accounting for almost 85% of all lung cancers (Herbst RS et al., N Engl J Med. 2008; 359: 1367-80). Additionally, lung cancer continues to be the most common cause of cancer-related deaths worldwide with a 5-year survival rate of less than 10% in patients with advanced disease.
  • NSCLC non- small cell lung cancer
  • EGFR epidermal growth factor receptor
  • TKIs first-generation reversible EGFR tyrosine kinase inhibitors
  • Toxicity associated with both erlotinib and gefitinib includes skin rash and diarrhea related to inhibition of wild-type EGFR (WT EGFR) in skin and intestine, respectively (Herbst et al, Clin Lung Cancer. 2003; 4:366- 9).
  • T790M mediates resistance to first-generation EGFR inhibitors by acting as a "gatekeeper" mutation, inducing steric hindrance in the ATP binding pocket and preventing inhibitor binding (Pao et al, PLoS Med. 2005;2:e73; Kwak et al, Proc Natl Acad Sci U S A.
  • CO- 1686 is a potent, small- molecule, irreversible tyrosine kinase inhibitor (TKI) that selectively targets the common EGFR mutations (L858R, dell9, T790M) and has minimal inhibitory activity towards WT EGFR (Walter, A. et al., Cancer Discovery. 2013;3: 1404-15). Oral administration of CO- 1686 leads to tumor regressions in cell-based and patient- derived xenograft models as well as a transgenic mouse model expressing mutant forms of EGFR.
  • TKI irreversible tyrosine kinase inhibitor
  • CO-1686 is currently being evaluated in several ongoing clinical studies, including: 1) Study to Evaluate Safety, Pharmacokinetics, and Efficacy of Rociletinib (CO- 1686) in Previously Treated Mutant EGFR in NSCLC Patients (NCT01526928), 2) TIGER- 1: Safety and Efficacy Study of Rociletinib (CO-1686) or Erlotinib in Patients With Mutant EGFR NSCLC Who Have Not Had Any Previous EGFR Directed Therapy (NCT02186301), 3) TIGER-2: A Phase 2, Open-label, Multicenter, Safety and Efficacy Study of Oral CO-1686 as 2nd Line EGFR-directed TKI in Patients With Mutant EGFR NSCLC (NCT02147990), and 4) TIGER- 3: Open Label, Multicenter Study of Rociletinib (CO-1686) Mono Therapy Versus Single-agent Cytotoxic Chemotherapy in Patients With Mutant EGFR NSCLC Who Have Failed
  • the initial area of clinical study for CO-1686 is the treatment of patients with mutant EGFR NSCLC who have received prior EGFR-directed therapy. Expansion of CO- 1686 into the front-line setting of mutant EGFR NSCLC patients is currently ongoing considering the equivalent potency observed between erlotinib and CO-1686 in biochemical, cellular, and in vivo xenograft studies using NSCLC cell lines and models with an EGFR activating mutation.
  • Toxicity associated with erlotinib and gefitinib includes skin rash and diarrhea related to inhibition of WT EGFR in skin and intestine, respectively (Herbst RS et al., N Engl J Med. 2008;359: 1367-80).
  • Use of a WT EGFR sparing, mutant selective inhibitor such as CO-1686 has the potential for preventing some of these side-effects observed with first- generation EGFR inhibitors and therefore improving patient quality-of-life.
  • CO- 1686 has shown a manageable safety profile and it is notable that adverse events (AEs) typical of WT EGFR inhibition (rash and chronic diarrhea) have typically not been observed at doses up to 2000 mg daily (Soria et al., presented at EORTC-NCI-AACR, November 18- 21, 2014, Barcelona, Spain).
  • AEs adverse events
  • BM brain metastases
  • EGFR inhibitors can enhance the anti-tumor activity of radiotherapy (RT) through multiple mechanisms (Chinnaiyan et al. Cancer Res. 2005; 65(8):3328-35; Mehta, Front Oncol. 2012 Apr 10;2:31; Sato et al. Anticancer Res. 2012; 32(11):4877-81).
  • RT radiotherapy
  • the combination of erlotinib and RT in vitro reduced the number of cells in S-phase and enhanced the induction of apoptosis in NSCLC and SCC (squamous cell carcinoma) cell lines.
  • erlotinib and RT increased tumor growth inhibition as compared to either monotherapy in NSCLC and SCC xenograft models.
  • WBRT may disrupt the blood brain barrier (BBB), allowing for greater penetration of erlotinib into the brain (Rubin et al. Disruption of the blood-brain barrier as the primary effect of CNS irradiation. Radiother Oncol 1994; 31(1): 51-60).
  • BBB blood brain barrier
  • the rate of rash was higher in the WBRT and erlotinib combination group as compared to the WBRT and placebo combination group.
  • 40 unselected NSCLC patients were treated with erlotinib monotherapy (150 mg daily) for one week, then concurrently with WBRT, followed by erlotinib maintenance (Welsh et al. J Clin Oncol. 2013; 31(7):895-902).
  • the overall response rate was 86% with a median survival time of 11.8 months.
  • Ionizing radiation results in skin injury (radiation dermatitis) in 95% of patients receiving radiation therapy for cancer, resulting from the activation of numerous cytokines and chemokines produced from immune cells in the dermis and epidermis (Ryan et al. J Invest Dermatol. 2012; 132(3 Pt 2):985-93).
  • the present invention is directed to the combination of WT sparing EGFR inhibitors and RT that provide better therapeutic profiles than current single agent therapies or other combination therapies utilizing EGFR inhibitors.
  • combination therapies of an irreversible mutant EGFR inhibitor compound with one or more other therapies, particularly radiotherapy, that have at least an additive potency or at least an additive therapeutic effect.
  • the invention is directed to combination therapies where the therapeutic efficacy is greater than additive, e.g., a synergistic efficacy exists between an irreversible mutant EGFR inhibitor compound and one or more other therapies, particularly radiotherapy.
  • such combination therapies also reduce or avoid unwanted or adverse effects.
  • the combination therapies of the invention provide an improved overall therapy relative to the administration of the therapeutic agents by themselves.
  • doses of existing therapeutic agents can be reduced or administered less frequently in using the combination therapies of the invention, thereby increasing patient compliance, improving therapy and reducing unwanted or adverse effects.
  • this invention is directed to combination therapies designed to treat or manage cancer, particularly NSCLC, in a subject, wherein the combination therapies comprise administering an irreversible mutant EGFR inhibitor to the subject in need thereof in combination with one or more other therapies, particularly radiotherapy.
  • this invention is directed to methods of treating or managing cancer, particularly NSCLC, in a subject, comprising administering a therapeutically effective amount of an irreversible mutant EGFR inhibitor in combination with the administration of therapeutically effective amount of one or more other therapies, particularly radiotherapy.
  • the present invention provides methods for treating cancer, particularly NSCLC, in a subject comprising administering an Mutant EGFR inhibitor compound that covalently modifies Cysteine 797 in EGFR, wherein said compound exhibits at least 2-fold greater inhibition of a drug resistant Mutant EGFR relative to wild type EGFR, and an additional therapy, particularly radiotherapy.
  • the present invention provides methods for treating drug resistant cancer, particularly NSCLC, in a subject comprising administering an Mutant EGFR inhibitor compound that covalently modifies Cysteine 797 in EGFR, wherein said compound exhibits at least 2-fold greater inhibition of a drug resistant Mutant EGFR relative to wild type EGFR, and an additional therapy, particularly radiotherapy.
  • Radiotherapy treatment using high-energy radiation to kill cancer cells such as x- rays, gamma rays, and charged particles.
  • Radiotherapy includes, but is not limited to, external-beam radiation therapy (IMRT, IGRT, Tomotherapy, stereotactic radiosurgery, stereotactic body radiation therapy, and proton therapy), internal radiation therapy (brachytherapy), and systemic radiation therapy such as radioactive iodine or radioactive substance bound to an antibody or protein.
  • IMRT external-beam radiation therapy
  • IGRT Tomotherapy
  • stereotactic radiosurgery stereotactic body radiation therapy
  • proton therapy proton therapy
  • brachytherapy internal radiation therapy
  • systemic radiation therapy such as radioactive iodine or radioactive substance bound to an antibody or protein.
  • the present invention provides methods for treating cancer, particularly NSCLC, comprising irreversible mutant EGFR inhibitor compounds in combination with one or more other therapies, particularly radiotherapy, administered simultaneously, separately, or sequentially.
  • the present invention provides pharmaceutical compositions of compounds or pharmaceutically acceptable salts of one or more compounds described herein and a pharmaceutically acceptable carrier or excipient.
  • FIGURE 1 Impact of CO- 1686, afatinib, and RT as single agents and in combination with radiation on body weight in the NCI-H1975 xenograft model.
  • Mice were implanted with NCI-H1975 (L858R/T790M EGFR) cells by subcutaneous injection, and then treated with afatinib (20 mg/kg daily), CO- 1686 (50 mg/kg twice daily), and radiation (2 Gy on a 5-days on, 2-day off cycle) as single agents or in combinations.
  • irreversible mutant EGFR inhibitor or “covalent mutant EGFR inhibitor” refers to a third generation EGFR inhibitor that covalently binds to a mutant form of epidermal growth factor receptor (EGFR).
  • an irreversible mutant EGFR inhibitor covalently binds to cysteine 797 of mutant EGFR and exhibits at least 2-fold greater inhibition of a drug-resistant mutant EGFR relative to wild type EGFR.
  • Irreversible mutant EGFR inhibitors include, but are not limited to, CO- 1686, WZ4002, AZD9291, CNX2006, ASP8273, EGF816, HM61713, TAS-2913, AZ5104 and others. Structures of a few exemplary irreversible mutant EGFR inhibitors are shown in Table 1.
  • Radiotherapy refers to any treatment using high-energy radiation to kill cancer cells such as x-rays, gamma rays, and charged particles.
  • Radiotherapy includes, but is not limited to, external-beam radiation therapy (IMRT, IGRT, Tomotherapy, stereotactic radiosurgery, stereotactic body radiation therapy, and proton therapy), internal radiation therapy (brachytherapy), and systemic radiation therapy such as radioactive iodine or radioactive substance bound to an antibody or protein.
  • Radiotherapy may be used to treat localized solid tumors cancers of the skin, tongue, larynx, brain, breast, lung or uterine cervix. It can also be used to treat leukemia and lymphoma, i.e., cancers of the blood-forming cells and lymphatic system, respectively.
  • Whole brain radiation therapy is radiation given to the whole brain, usually over a period of weeks.
  • non-small cell lung cancer or “NSCLC” refers to any type of epithelial lung cancer other than small cell lung cancer (SCLC).
  • kinase inhibitor refers to any type of enzyme inhibitor that specifically blocks the action of one or more kinases responsible for cancer, particularly NSCLC.
  • a kinase inhibitor of the present invention refers to a small molecule, a protein/peptide or an antibody.
  • the quantity and/or magnitude of the symptoms in the treated subject is at least 10% lower than, at least 25% lower than, at least 50% lower than, at least 75% lower than, and/or at least 90% lower than the quantity and/or magnitude of the symptoms in the untreated subject.
  • inhibitory compound refers to any compound capable of interacting with (i.e., for example, attaching, binding etc.) to a binding partner under conditions such that the binding partner becomes unresponsive to its natural ligands.
  • Inhibitory compounds may include, but are not limited to, small organic molecules, antibodies, and proteins/peptides.
  • inhibitor or "covalent inhibitor” as used herein, refers to an inhibitor that covalently modifies an enzyme, and inhibition therefore cannot be reversed.
  • drug refers to any pharmacologically active substance capable of being administered which achieves a desired effect.
  • Drugs or compounds can be synthetic or naturally occurring, non-peptide, proteins or peptides, oligonucleotides or nucleotides, polysaccharides or sugars.
  • administered refers to any method of providing a composition to a patient such that the composition has its intended effect on the patient.
  • An exemplary method of administering is by a direct mechanism such as, local tissue administration (i.e., for example, extravascular placement), oral ingestion, transdermal patch, topical, inhalation, suppository etc.
  • a therapeutically effective amount refers to that amount of therapeutic agent sufficient to destroy, modify, control or remove cancer tissue.
  • a therapeutically effective amount may refer to the amount of therapeutic agent sufficient to delay or minimize the spread of cancer.
  • a therapeutically effective amount may also refer to the amount of therapeutic agent that provides a therapeutic benefit in the treatment or management of cancer.
  • a therapeutically effective amount with respect to an irreversible mutant EGFR inhibitor of the combination therapies of the invention means that amount of an irreversible mutant EGFR inhibitor in combination with one or more other therapies, particularly an Radiotherapy that provides a therapeutic benefit in the treatment or management of cancer, particularly NSCLC, including amelioration of symptoms associate with cancer, such as NSCLC.
  • the term can encompass an amount that improves overall therapy, reduces or avoids unwanted effects, or enhances the therapeutic efficacy of or synergizes with one or more other therapies, such as Radiotherapy, utilized in combination therapies of the invention.
  • the "therapeutically effective amount” may vary depending, for example, on the kinase inhibitors selected, the stage of the cancer, the age, weight and/or health of the patient and the judgment of the prescribing physician. An appropriate amount in any given instance may be readily ascertained by those skilled in the art or capable of determination by routine experimentation .
  • a combination therapy of the invention refers to the beneficial effects that a patient derives from a combination therapy of the invention, which does not result in a cure of cancer, such as NSCLC.
  • a combination therapy of the invention "manages” cancer, particularly NSCLC, so as to prevent the progression or worsening of the cancer.
  • the terms “treat”, “treating”, and “treatment” refer to the eradication, removal, modification or control of cancer, particularly NSCLC, that results from the combination therapy of the invention. In certain embodiments, such terms refer to minimizing or delaying of the spread of cancer, particularly NSCLC.
  • combination therapy or “combination treatment” refers to methods of treating cancer, particularly NSCLC, in a subject comprising an irreversible mutant EGFR inhibitor compound with one or more other therapies, particularly
  • Radiotherapy encompass administering an irreversible mutant EGFR inhibitor and one or more other therapies simultaneously, separately or sequentially.
  • patient is a human or animal and need not be hospitalized.
  • out-patients persons in nursing homes are "patients.”
  • a patient may comprise any age of a human or non-human animal and therefore includes both adult and juveniles (i.e., children). It is not intended that the term "patient” connote a need for medical treatment, therefore, a patient may voluntarily or involuntarily be part of
  • subject refers to a vertebrate, preferably a mammal, more preferably a primate, still more preferably a human. Mammals include, without limitation, humans, primates, wild animals, feral animals, farm animals, sports animals, and pets.
  • pharmaceutically or “pharmacologically acceptable”, as used herein, refer to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human.
  • pharmaceutically acceptable carrier includes any and all solvents, or a dispersion medium including, but not limited to, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils, coatings, isotonic and absorption delaying agents, liposome, commercially available cleansers, and the like. Supplementary bioactive ingredients also can be incorporated into such carriers.
  • salts refers to any salt that complexes with identified compounds contained herein.
  • examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as, but not limited to, acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic, acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and
  • Salt compounds can also be administered as pharmaceutically acceptable quaternary salts known by a person skilled in the art, which specifically include the quaternary ammonium salts of the formula— NR,R',R"+Z -, wherein R, R', R" is independently hydrogen, alkyl, or benzyl, and Z is a counter ion, including, but not limited to, chloride, bromide, iodide, alkoxide, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate).
  • quaternary salts known by a person skilled in the art, which specifically include the quaternary ammonium salts of the formula— NR,R',R"+Z -, where
  • Salt compounds can also be administered as pharmaceutically acceptable pyridine cation salts having a substituted or unsubstituted partial formula: wherein Z is a counter ion, including, but not limited to, chloride, bromide, iodide, alkoxide, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate).
  • Z is a counter ion, including, but not limited to, chloride, bromide, iodide, alkoxide, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fum
  • prodrug refers to a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of the invention.
  • Prodrugs may only become active upon some reaction under biological conditions, but they may have activity in their unreacted forms.
  • Examples of prodrugs contemplated herein include, without limitation, analogs or derivatives of compounds of the invention, and/or their salts when salt formation is possible, but in particular, derivatives of zinc binding thiol moiety.
  • prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties, (e.g., propionic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl- lower alkyl esters (e.g., benzyl ester), heteroaryl esters (nicotinate ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower- alkyl amides, di-lower alkyl esters
  • Prodrugs and their uses are well known in the art (see, e.g., Berge et al. 1977). Prodrugs can typically be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (Manfred E. Wolff ed.1995) and (Rautio, 2008).
  • the term "activity” refers to the activation, production, expression, synthesis, intercellular effect, and/or pathological or aberrant effect of the referenced molecule, either inside and/or outside of a cell.
  • the terms “comprises,” “comprising,” “includes,” “including,” “contains,” “containing,” and any variations thereof, are intended to cover a non-exclusive inclusion, such that a process, method, product-by-process, or composition of matter that comprises, includes, or contains an element or list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, product-by-process, or composition of matter.
  • cancer can be a metastatic cancer.
  • additional cancers related to the methods described herein include, but are not limited to, breast, ovarian, pancreatic, sarcoma, prostate cancer, colon cancer (such as a colon carcinoma, including small intestine cancer), glioma, leukemia, liver cancer, melanoma (e.g., metastatic malignant melanoma), acute myeloid leukemia, kidney cancer, bladder cancer, renal cancer (e.g., renal cell carcinoma), glioblastoma, brain tumors, chronic or acute leukemias including acute lymphocytic leukemia (ALL), adult T-cell leukemia (T-ALL), chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphomas (e.g., Hodgkin's and non-Hodgkin's lymphoma, lymphomas (e.g., Hodgkin's and non-Hodgkin's lymphoma,
  • methods described herein can be useful for treating a combination of two or more types of cancer. In some aspects the methods are useful to treat individual patients diagnosed with cancer.
  • the present invention provides pharmaceutical compositions comprising at least one pharmaceutically-acceptable carrier, in addition to one or more compounds described herein.
  • the composition can take any suitable form for the desired route of administration. Where the composition is to be administered orally, any suitable orally deliverable dosage form can be used, including without limitation tablets, capsules (solid or liquid filled), powders, granules, syrups and other liquids, elixirs, inhalants, troches, lozenges, and solutions. Injectable compositions or i.v. infusions are also provided in the form of solutions, suspensions, and emulsions.
  • the administration of an irreversible mutant epidermal growth factor receptor (EGFR) inhibitor compound may be prior to, immediately prior to, during, immediately subsequent to or subsequent to the administration of radiotherapy.
  • EGFR epidermal growth factor receptor
  • Radiation may be selected from any type suitable for treating cancer. Radiation may come from a machine outside the body (external radiation), may be placed inside the body (internal radiation), or may use unsealed radioactive materials that go throughout the body (systemic radiation therapy). The type of radiation to be given depends on the type of cancer, its location, how far into the body the radiation will need to penetrate, the patient's general health and medical history, whether the patient will have other types of cancer treatment, and other factors. In certain embodiments, radiation is delivered in more than one manner, e. g., internal radiation and external radiation.
  • Radiotherapy can be administered in any therapeutically effective dose.
  • the cumulative dose is less than 90 Gy, such as less than 80 Gy, such as less than 70 Gy, such as less than 60 Gy, such as less than 50 Gy, such as less than 40 Gy, such as less than 30 Gy, such as less than 20 Gy.
  • the cumulative dose is between about 10 to 100 Gy, such as about 20 to 80 Gy, such as about 30 to 70 Gy, such as about 40 to 60 Gy.
  • the irradiation dose is selected from 5-25 Gy, such as from 10-20 Gy.
  • the total dosage of radiotherapy may be fractionated into several smaller doses delivered over a period of time to allow normal cells time to recover, to allow tumor cells that were in a relatively radio-resistant phase of the cell cycle during one treatment to cycle into a sensitive phase of the cycle before the next fraction is given, or to allow hypoxic tumor cells to reoxygenate between fractions, improving the tumor cell kill.
  • the summed value of individual fractionized dose should add up to about the total dose of radiation therapy prescribed.
  • Fractionated doses of radiotherapy may be administered at intervals.
  • the fractionized doses are administered over a period of minutes, hours, or weeks such as 1 to 26 weeks, such as from about 1 to 15 weeks, such as from 2 to 12 weeks.
  • the fractionized doses are administered over a period less than about 15 weeks, such as less than about 14 weeks such as less than about 13 weeks, such as less than about 12 weeks, such as less than about 11 weeks, such as about less than about 10 weeks, such as less than about 9 weeks, such as less than about 8 weeks, such as less than about 7 weeks, such as less than about 6 weeks, such as less than about 5 weeks, such as less than about 4 weeks.
  • the cumulative external irradiation is a therapeutically effective amount of radiation for killing cells.
  • Example 1 Tolerability and efficacy of CO- 1686, afatinib, and RT in the NCI- HI 975 xenograft model
  • NCI-H1975 human NSCLC adenocarcinoma cells were obtained from the American Type Culture Center (Manassas, VA), and were grown in RPMI 1640 (Life Technologies; Carlsbad, CA) supplemented with 10% FBS (HyClone; South Logan, UT), 2mM L-glutamine, and 1% Penicillin- Streptomycin (Mediatech; Corning, NY) at 37°C in a humidified 5% C0 2 incubator. Cells were harvested and resuspended in PBS at a
  • External X-ray beam radiation therapy was performed using a Faxitron CP- 160 cabinet irradiator, and given daily for 5 days with 2 days off except for the treatment group afatinib plus radiation which received radiation for 5 days with 9 days off due to toxicity.
  • Afatinib was administered intraperitoneally daily for twenty-one days at a dosage of 20 mg/kg.
  • CO-1686 was administered orally twice daily for twenty-one days at a dosage of 50 mg/kg.
  • Animals treated with localized radiation received a 2 gray (Gy) dose for five consecutive days followed by a two day dosing holiday. This schedule was repeated for three cycles.
  • the radiation regimen was also combined with the afatinib and CO- 1686 regimens described previously.
  • a vehicle treated group served as the control group for efficacy analysis.
  • Tumors were measured twice per week until the study was ended on Day 60. Each mouse was euthanized when its tumor reached the endpoint volume of 1500 mm 3 or on the final day, whichever came first. The time-to-endpoint (TTE) was calculated for each mouse. The primary treatment outcome was determined from an analysis of percent tumor growth delay (%TGD), defined as the percent increase in median TTE of treated versus control mice, with differences between two groups deemed significant at P ⁇ 0.05 using logrank survival analysis. Short-term efficacy was determined from an analysis of tumor growth inhibition (TGI) on Days 12 and 22.
  • TGI tumor growth inhibition
  • TGI was defined as the percent difference between the median tumor volumes (MTVs) of treated and control mice, with results analyzed for statistical significance at P ⁇ 0.05 using the Mann-Whitney U-test. A treatment that produced at least 60% TGI was considered potentially therapeutically active. Animals were also monitored for partial regression (PR) and complete regression (CR) responses. Treatment tolerability was assessed by frequent observation for clinical signs of treatment-related (TR) side effects and by body weight (BW) measurements.
  • MTVs median tumor volumes
  • the median TTE for vehicle-treated controls was 13.8 days, establishing a maximum possible TGD of 46.2 days (335%) for the 60-day study.
  • the MTV for all animals in the vehicle group was 1183 mm 3 , with a range of 446 to 1800 mm 3 .
  • the Day 22 MTV of three remaining animals was 1352 mm 3 , with a range of 221 to 1800 mm 3 .
  • the CO- 1686 monotherapy produced a significant survival difference versus controls (P ⁇ 0.01, logrank) with seven PRs. Additionally, an analysis of TGI at Day 12 and at Day 22 found a significant effect on tumor growth versus controls (P ⁇ 0.01, Mann- Whitney test). [0074] The afatinib monotherapy regimen produced a significant survival difference versus controls (P ⁇ 0.001, logrank) with four PRs. An analysis of TGI at Day 12 found a significant effect on tumor growth versus controls (P ⁇ 0.001, Mann- Whitney test).
  • the CO- 1686 / radiation combination therapy produced a significant survival difference versus controls (P ⁇ 0.001, logrank) with all ten animals being classified as PRs.
  • the combination therapy also produced a significant survival difference to both

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Abstract

La présente invention concerne des méthodes de traitement combiné pour traiter le cancer, notamment le cancer du poumon non à petites cellules (CPNPC). Plus spécifiquement, l'invention concerne des méthodes de traitement ou de gestion du cancer, en particulier du CPNPC, chez un sujet, consistant à administrer un composé inhibiteur de l'EGFR, irréversible, mutant, en combinaison avec une ou plusieurs thérapies, en particulier la radiothérapie.
PCT/US2016/024839 2015-04-09 2016-03-30 Combinaisons thérapeutiques pour le traitement du cancer WO2016164217A1 (fr)

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CN108033950A (zh) * 2017-08-23 2018-05-15 哈尔滨医科大学 具有抗肿瘤活性的egfr酪氨酸激酶抑制剂bf3-azd9291及其制备方法和应用
WO2018234556A1 (fr) * 2017-06-23 2018-12-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés de prévention ou de traitement de la résistance du cancer à l'inhibition de l'egfr
US10513509B2 (en) 2016-05-26 2019-12-24 Recurium Ip Holdings, Llc EGFR inhibitor compounds
RU2795089C2 (ru) * 2018-04-18 2023-04-28 Новартис Аг Назартиниб для применения в лечении метастаза в цнс

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10513509B2 (en) 2016-05-26 2019-12-24 Recurium Ip Holdings, Llc EGFR inhibitor compounds
US11098030B2 (en) 2016-05-26 2021-08-24 Recurium Ip Holdings, Llc EGFR inhibitor compounds
WO2018234556A1 (fr) * 2017-06-23 2018-12-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés de prévention ou de traitement de la résistance du cancer à l'inhibition de l'egfr
CN108033950A (zh) * 2017-08-23 2018-05-15 哈尔滨医科大学 具有抗肿瘤活性的egfr酪氨酸激酶抑制剂bf3-azd9291及其制备方法和应用
RU2795089C2 (ru) * 2018-04-18 2023-04-28 Новартис Аг Назартиниб для применения в лечении метастаза в цнс

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