WO2017110764A1 - Procédé de test permettant de prédire l'efficacité et la sécurité d'un inhibiteur multikinase, kit de test et biomarqueur - Google Patents

Procédé de test permettant de prédire l'efficacité et la sécurité d'un inhibiteur multikinase, kit de test et biomarqueur Download PDF

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WO2017110764A1
WO2017110764A1 PCT/JP2016/087859 JP2016087859W WO2017110764A1 WO 2017110764 A1 WO2017110764 A1 WO 2017110764A1 JP 2016087859 W JP2016087859 W JP 2016087859W WO 2017110764 A1 WO2017110764 A1 WO 2017110764A1
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treatment
concentration
vegf
ccl
regorafenib
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PCT/JP2016/087859
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Japanese (ja)
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光邦 末永
信之 水沼
哲夫 馬島
啓之 清宮
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公益財団法人がん研究会
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor

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  • the present invention relates to a method for predicting the effectiveness and safety of a multikinase inhibitor targeting tumor cells, and a test kit.
  • the present invention particularly relates to the effectiveness of regorafenib, a method for predicting the risk of side effects, biomarkers used therefor, and kits.
  • Chemotherapy using an anticancer drug is a treatment method that is widely used together with surgery and radiation therapy as a tumor treatment method.
  • Chemotherapy using anticancer drugs involves treating cancer cells that may spread throughout the body or cancer cells that have the potential to metastasize by administering anticancer drugs orally or by injection. It is aimed.
  • Anticancer drugs include platinum agents, alkylating agents, plant alkaloids that act on mitotic cells, and specific properties of cancer cells at the molecular level. There are various types such as targeted drugs.
  • side effects often occur because any anticancer agent acts on normal cells. Symptoms that often appear as side effects include decreased white blood cells and platelets, vomiting / nausea, hair loss, general malaise, and stomatitis. Since side effects occur with most anticancer agents, anticancer agents with reduced side effects and pharmaceuticals that reduce side effects have been developed. As a result, side effects have been reduced compared to before, but the side effects caused by the administration of anticancer agents are a major problem in chemotherapy.
  • Patent Documents 1 and 2 disclose a method for predicting the risk of side effects of docetaxel used for treatment of refractory breast cancer, non-small cell lung cancer, ovarian cancer, etc. by detecting single nucleotide polymorphisms present on SLCO1B3 gene and ABCC2 gene. Is described.
  • Patent Document 2 describes a method for predicting side effects by analyzing the correlation between side effects caused by fluorouracil and cisplatin used in a wide variety of treatments and cytokine gene polymorphisms.
  • Non-patent document 1 describes that the therapeutic effect of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) administration on non-small cell lung cancer patients is correlated with serum HGF concentration. It is disclosed.
  • Non-Patent Document 2 FOLFIRI therapy for patients with colorectal cancer (Fol nic acid, F luorouracil, Iri notecan) performs a therapy plus bevacizumab, analyzes the correlation between efficacy and biomarker for therapeutic It is described. In particular, it has been disclosed that changes in serum VEGF-A concentration correlate with therapeutic efficacy.
  • EGFR-TKI epidermal growth factor receptor tyrosine kinase inhibitor
  • Patent Documents 1 and 2 require that DNA is extracted from serum and PCR is performed, so that protein in serum is directly measured by immunoassay represented by ELISA. Compared to the method, there are many processes and complicated.
  • Regorafenib is a multikinase inhibitor that inhibits multiple protein kinase activities.
  • Legorafenib is an angiogenesis-related kinase (VEGFR1-3, TIE2), a tumor microenvironment-related stromal kinase (PDGFR ⁇ , FGFR), a tumorigenesis-related kinase (KIT, RET, RAF-1, BRAF) Have been shown to inhibit multiple protein kinase activities.
  • VEGFR1-3 angiogenesis-related kinase
  • PDGFR ⁇ tumor microenvironment-related stromal kinase
  • KIT tumorigenesis-related kinase
  • RET RAF-1
  • BRAF tumorigenesis-related kinase
  • Regorafenib is a side effect (including abnormal laboratory values) in 465 cases (93.0%) of 500 cases (including 65 Japanese) in a global phase III clinical trial for patients with colorectal cancer Was recognized.
  • the number of cases of incidence of major side effects (incidence rate) was 225 cases of hand-foot syndrome (45.0%), 169 cases of diarrhea (33.8%), 152 cases of decreased appetite (30.4%), and 145 cases of fatigue (29 0.0%), dysphonia 142 cases (28.4%), hypertension 139 cases (27.8%), and rash 113 cases (22.6%).
  • limb syndrome toxic epidermal necrolysis (TEN), mucocutaneous eye syndrome (Stevens-Johnson syndrome), erythema multiforme, fulminant hepatitis, liver failure, liver dysfunction, Jaundice, bleeding (gastrointestinal bleeding, hemoptysis, pulmonary bleeding, intraperitoneal bleeding, vaginal bleeding, cerebral bleeding, nasal bleeding, hematuria, etc.), interstitial lung disease, thromboembolism (myocardial ischemia, myocardial infarction, etc.), hypertension, hypertension Crisis, post-plastic leukoencephalopathy, gastrointestinal perforation, gastrointestinal fistula, thrombocytopenia may occur.
  • the object of the present invention is to extract a marker for predicting the effect of regorafenib and a marker relating to the onset of an adverse event, and to use it for actual clinical treatment. It is another object of the present invention to provide an inspection method and an inspection kit using the marker.
  • the present invention relates to the following test method, test kit, and biomarker related to the effect prediction of regorafenib.
  • a test method for predicting the effect of administration of Regorafenib comprising measuring CCL-5 concentration in a sample collected from a patient.
  • the test method according to (1) wherein the sample is blood, plasma, serum, urine, ascites, or pleural effusion.
  • the test method according to (3) wherein when the CCL-5 concentration is lower than a predetermined value, it is determined that improvement in progression-free survival (PFS) and overall survival (OS) can be expected Method.
  • PFS progression-free survival
  • OS overall survival
  • a VEGF-A concentration in a patient sample is measured before the start of treatment and early after the start of the first treatment.
  • test method according to any one of (1) to (6), wherein at least one of Ang-2, bFGF, and CCL-2 in a patient sample before the start of treatment is measured, A test method to determine the risk of adverse events.
  • a test kit for predicting the effect of regorafenib administration comprising a reagent for measuring CCL-5 concentration in a patient sample.
  • the reagent is an immunoassay reagent.
  • a biomarker for predicting the effect of regorafenib administration which is CCL-5 and / or VEGF-A.
  • a biomarker for predicting an adverse event caused by administration of regorafenib wherein the biomarker comprises at least one of CCL-5, VEGF-A, Ang-2, bFGF, and CCL-2.
  • the present invention provides a marker for predicting the effects of regorafenib and a marker for the onset of adverse events, which can be used for actual clinical treatment.
  • a marker for predicting the effects of regorafenib and a marker for the onset of adverse events which can be used for actual clinical treatment.
  • serum CCL-5 Chemokine (CC motif) ligand-5)
  • VEGF-A vascular endothelial growth factor-A, vascular endothelial growth factor-A
  • the effect can be predicted more accurately at an early stage of treatment. be able to.
  • FIG. 3 (A) shows the ROC curve of tumor shrinkage and CCL-5 value.
  • FIG. 3 (B) shows CCL-5 ⁇ 59.96 (ng / mL), CCL-5> 59.96 (ng / mL).
  • the progression-free survival period is shown in FIG. 3 (C).
  • FIG. 4 (A) shows the relationship between the decrease on day 21 after the start of VEGF-A treatment and progression-free survival
  • FIG. 4 (B) shows the decrease on day 21 after the start of treatment with VEGF-A and the primary disease. The relationship between the increase in exacerbation and progression-free survival is shown.
  • FIG. 5 (A) shows that the CCL-5 concentration before the start of treatment is less than or equal to the cut-off value, the VEGF-A concentration after the start of treatment decreases, and the CCL-5 concentration before the start of treatment is higher than the cut-off value.
  • concentration after a treatment start increases is shown.
  • FIG. 5B further shows a group not classified into both. The figure which analyzed the total survival time combining the CCL-5 density
  • FIG. 6A shows that the CCL-5 concentration before the start of treatment is less than or equal to the cut-off value, the VEGF-A concentration after the start of treatment decreases, and the CCL-5 concentration before the start of treatment is higher than the cut-off value.
  • concentration after a treatment start increases is shown.
  • FIG. 6B further shows a group that is not classified into both. The figure which analyzed the progression-free survival time combining CCL-5 density
  • FIG. 7A shows a group in which the CCL-5 concentration before the start of treatment is below the cut-off value, the VEGF-A concentration after the start of treatment decreases, and the VEGF-A concentration in the exacerbation stage increases, and the CCL before the start of treatment.
  • the comparison is made with the group in which the -5 concentration is higher than the cut-off value, the VEGF-A concentration is increased after the start of the treatment, and the VEGF-A concentration is decreased in the exacerbation stage.
  • FIG. 7B further shows a group that is not classified into both.
  • FIG. 8A shows a group in which the CCL-5 concentration before the start of treatment is below the cut-off value, the VEGF-A concentration after the start of treatment decreases, the VEGF-A concentration in the exacerbation stage increases, and the CCL before the start of treatment.
  • the comparison is made with the group in which the -5 concentration is higher than the cut-off value, the VEGF-A concentration is increased after the start of the treatment, and the VEGF-A concentration is decreased in the exacerbation stage.
  • FIG. 8B further shows a group not classified into both.
  • an adverse event refers to any undesirable or unintended sign, symptom, or illness that has occurred in a patient to whom a drug has been administered, including those in which the causal relationship with the drug is not clear. It is not limited to side effects with known causal relationships.
  • progression-free survival Progression Free; Survival, PFS
  • overall survival Overall Survival; OS
  • the progression-free survival period is from the date of start of administration to the date on which the exacerbation (PD) is determined or the death date due to any cause (regardless of cause of death), whichever comes first.
  • Surviving cases that are not judged to be exacerbated are treated as censored on the last day when it is confirmed that there is no exacerbation. In other words, if an exacerbation is not confirmed when the event is canceled due to an adverse event, it is treated as being terminated.
  • “Overall survival period (OS)” means the total survival period from the start date of administration to the date of death due to any cause. In surviving cases, the date of confirmation of final survival is censored, and in the case of inability to follow up, the censored date is determined to be the last date of confirmation of survival before becoming untraceable.
  • the sample refers to blood, plasma, serum, urine, ascites, pleural effusion. This is because it is already known that the marker of the present invention is contained in these samples (Non-Patent Documents 4 to 8).
  • blood, plasma, and serum are preferable as samples because the biomarker of the present invention can be measured with high sensitivity.
  • the sample before starting treatment refers to a sample before starting treatment with regorafenib for patients who have become refractory or intolerant to standard chemotherapy.
  • the sample of the 21st day is used for the sample at the early stage after the start of the first treatment in the Examples, the first cycle is one cycle (one cycle is provided with a one week rest period after oral administration for 3 weeks every day). Any sample may be used as long as it is a sample. Considering the effect of drug administration, the samples on the 14th to 28th days are preferable.
  • any measurement method may be used as long as the protein amount of the biomarker in the sample can be measured. Measurement is preferably performed by immunoassay because measurement sensitivity is high and testing can be performed relatively easily.
  • immunoassay for example, radioimmunoassay (RIA), fluorescence immunoassay (FIA), fluorescence polarization immunoassay (FPIA), chemiluminescence immunoassay (CLIA), and the like can be used.
  • the “cut-off value” is a value that can satisfy both high diagnostic sensitivity (adverse event rate) and high diagnostic specificity when a disease is determined based on the value. For example, a value showing a high positive rate in an individual who has developed an adverse event and a high negative rate in an individual who has not developed an adverse event can be set as the cutoff value. Since the specific cut-off value varies depending on the sample and assay system used, it can be appropriately determined according to each assay system.
  • the cut-off value calculation method may be determined by a method known in this field (for example, see Non-Patent Documents 9 to 11).
  • the kit of the present invention can contain an antibody for detecting CCL-5 and VEGF-A, which are biomarkers found in the present invention, a reagent for detecting this, and the like.
  • the detection reagent includes a secondary antibody, a substrate agent, and a labeling substance (for example, fluorescent dye, enzyme). Moreover, these elements can also be mixed beforehand as needed. Further, it may include a solid phase such as a microtiter plate, a reaction container, a buffer for diluting a washing solution or an antibody, a positive control, a negative control, an instruction describing a protocol, and the like.
  • Regorafenib is a multikinase inhibitor, as described above, and has been suggested to act on cancer cell environmental signals related to signal transduction and angiogenesis. However, it was not clear which of these factors was directly affected by regorafenib treatment. Therefore, the present inventors analyzed changes in factors secreted from cancer cells detected by microarray gene expression analysis or ELISA method, in addition to candidates selected from factors involved in angiogenesis and inflammatory cytokines. .
  • HCT-15, HCT-116 and HT-29 available from ATCC were used as human colon cancer cell lines.
  • the above colon cancer cell lines were seeded at a cell density of 9000 cells / mL using 10% FBS-RPMI medium, 24 hours later, regorafenib was added to a concentration of 0 ⁇ M, 1 ⁇ M, and 3 ⁇ M and cultured for 72 hours. Cell proliferation was analyzed by MTS assay (Promega). The results are shown in FIG.
  • cell growth is suppressed in a concentration-dependent manner by adding regorafenib.
  • the HT-29 and HCT-116 cell lines are extremely strong and suppress cell growth and are highly sensitive to regorafenib.
  • the HCT-15 cell line is a cell line that is less resistant to cell growth than other cell lines and has resistance to regorafenib. It became clear.
  • VEGF-A was found as a factor having a significant change in the secretion amount in correlation with the regorafenib sensitivity of the cells (FIG. 2).
  • Regorafenib was added to colorectal cancer cell lines HCT-15, HCT-116, and HT-29, and VEGF-A concentration secreted into the culture medium was measured 48 hours later by ELISA (Quantikine ELISA kit from R & D Systems) ).
  • the VEGF-A concentration is shown with the VEGF-A concentration in the culture medium being 100% when cultured without adding regorafenib in each cultured cell line.
  • VEGF-A in colon cancer cells Information on the expression of VEGF-A in colon cancer cells can be obtained from Oncomine database (https://www.oncomine.org/resource/login.html). According to this, expression of VEGF-A is increased in colon cancer cells.
  • Kumar et al. Non-patent Document 12
  • the concentration of VEGF-A is significantly higher in the serum of colorectal cancer patients than in the healthy human serum, and the VEGF-A level is higher in advanced cancer.
  • VEGF-A In addition to VEGF-A, CCL-2, CCL-5, IL-8 (interleukin-8), PlGF (Placent Growth Factor), Ang-1 (angiopoietin-1), Ang-2 (angiopoietin-2), bFGF ( Analysis was performed using patient serum using basic fibroblast growth factor), SDF-1 (stromal cell-derived factor 1), and PDGF ⁇ (platelet-derived growth factor beta) as candidate factors.
  • IL-8 interleukin-8
  • PlGF Placent Growth Factor
  • Ang-1 angiopoietin-1
  • Ang-2 angiopoietin-2
  • bFGF Analysis was performed using patient serum using basic fibroblast growth factor
  • SDF-1 stromal cell-derived factor 1
  • PDGF ⁇ platelet-derived growth factor beta
  • the amount of cytokines such as CCL-5 and VEGF-A in the serum was determined according to the attached protocol by the sandwich ELISA method using Quantikine ELISA kit of R & D Systems.
  • the buffer attached to the kit was added to a 96-well plate coated with an antibody against each cytokine, and then a serum sample and a cytokine preparation for preparing a calibration curve (dilution series) were added and reacted at room temperature for 2 hours. . Thereafter, after washing three times with a washing buffer, an HRP-labeled antibody against each cytokine was added, and further reacted at room temperature for 1-2 hours. Thereafter, after washing three times with a washing buffer, a coloring solution was added, and after reacting at room temperature for 20-25 minutes, a reaction stop solution was added, and OD450 and OD570 (background) were measured using a plate reader. . Each sample was tested in triplicate, and the cytokine concentration was calculated based on the calibration curve for the value obtained by subtracting the background.
  • ELISA was conducted at 3 points before the start of the first treatment of regorafenib, 21 days after the start of the first treatment, and at the time of the decision to stop the treatment, and whether each candidate factor was correlated with the occurrence of an adverse event was analyzed. .
  • CCL-5 and VEGF-A were correlated with efficacy and adverse events.
  • CCL-5 and VEGF-A levels in the sample are related to efficacy and incidence of adverse events that are particularly common in Japanese, ie hand-foot syndrome, hypertension, liver dysfunction, hyperbilirubinemia, thrombocytopenia It became clear that it was an effective predictive marker. The results will be described in detail below.
  • FIG. 3 (A) shows an ROC curve created for tumor shrinkage and serum CCL-5 concentration. From this result, if the CCL-5 concentration in the serum before the start of treatment is CCL-5 ⁇ 59.96 (ng / mL), a tumor reducing effect can be expected by administration of regorafenib.
  • the VEGF-A concentration decreased on the 21st day, and the pattern of increase during exacerbation of the original disease improved the progression-free survival period, and the average value of the progression-free survival period was 146 days.
  • FIG. 4 (B) There was a statistically significant correlation between the VEGF-A concentration on day 21 after the start of treatment and the concentration at the time of exacerbation of the original disease.
  • it was not statistically significant it was recognized that the same tendency was shown also in the whole survival period. That is, it became clear that the change in serum VEGF-A level after the start of treatment is a factor predicting the therapeutic effect.
  • the patient group which is not classified into the above was analyzed as a Medium group. From the Kaplan-Meier curve, the progression-free survival period of the Medium group was a result intermediate between the Good group and the Poor group (FIG. 5B). Mean values of progression-free survival in the Good group, Medium group, and Poor group were 188 days, 69 days, and 70 days, respectively.
  • serum CCL-5 and VEGF-A can be used alone or in combination as a marker for predicting the effect of regorafenib monotherapy before treatment or at the beginning of treatment.
  • AE indicates an adverse event (Adverse Event)
  • T-Bil indicates the total amount of bilirubin.
  • AST is an abbreviation for aspartate aminotransferase and ALT is an abbreviation for alanine aminotransferase, both of which are test values serving as indicators of liver function.
  • HT represents hypertension
  • HFS represents hand-foot syndrome.
  • Ang-2, bFGF, and CCL-2 are as described above.
  • Ang-2, bFGF, and CCL-2 concentrations before the start of treatment can be predictive markers for the onset of adverse events involved in treatment performance.
  • AST values of grade 2 ⁇ were particularly correlated when CCL-5 concentration decreased after treatment, and liver function abnormalities were frequently developed.
  • Combination of CCL-5 concentration (below CO value) before treatment start and change in VEGF-A concentration after treatment start is associated with the development of hyperbilirubinemia (grade2 ⁇ ) and thrombocytopenia (grade1 ⁇ , grade2 ⁇ ) It became clear that Similar results were obtained with VEGF alone.
  • CCL-5 and VEGF-A can be used as predictive markers for the effect of pretreatment or early treatment onset of adverse events with high incidence in Japanese in regorafenib monotherapy in salvage therapy.
  • the correlation between these adverse events and CCL-5 and VEGF-A is not inconsistent with the correlation between progression-free survival and overall survival.
  • Treatment can be performed.
  • an adverse event can be predicted by measuring the Ang-2, bFGF, and CCL-2 concentrations before starting treatment.
  • regorafenib was analyzed in detail, but application to other multikinase inhibitors such as sorafenib and sunitinib which are multikinase inhibitors having similar structures and activities of the compounds can also be expected.
  • anticancer drug treatment is performed only on patients who are effective in treatment by selecting patients who respond well to anticancer drug administration and chemotherapy. The risk of serious side effects can be avoided.

Abstract

La présente invention porte sur un procédé de test permettant de prédire l'effet d'administration du Régorafénib, et sur un kit de test. Des mesures sont réalisées concernant la concentration en CCL-5 et la concentration en VEGF-A dans un échantillon prélevé chez un patient de telle sorte que l'efficacité du traitement sur le patient et le risque d'évènements indésirables soient estimés.
PCT/JP2016/087859 2015-12-24 2016-12-20 Procédé de test permettant de prédire l'efficacité et la sécurité d'un inhibiteur multikinase, kit de test et biomarqueur WO2017110764A1 (fr)

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