WO2011083391A2 - Biomarqueurs pour une thérapie du cancer par un anti-igf-1r - Google Patents

Biomarqueurs pour une thérapie du cancer par un anti-igf-1r Download PDF

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WO2011083391A2
WO2011083391A2 PCT/IB2010/056071 IB2010056071W WO2011083391A2 WO 2011083391 A2 WO2011083391 A2 WO 2011083391A2 IB 2010056071 W IB2010056071 W IB 2010056071W WO 2011083391 A2 WO2011083391 A2 WO 2011083391A2
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igf
patient
igfbp
insulin
ratio
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PCT/IB2010/056071
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WO2011083391A3 (fr
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Stephanie Janet Green
Antonio Gualberto
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Pfizer Inc.
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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
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4745—Insulin-like growth factor binding protein
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/575—Hormones
    • G01N2333/62—Insulins
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/575—Hormones
    • G01N2333/65—Insulin-like growth factors (Somatomedins), e.g. IGF-1, IGF-2
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/71—Assays involving receptors, cell surface antigens or cell surface determinants for growth factors; for growth regulators
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the insulin-like growth factor (IGF) system comprises two types of unrelated receptors, the insulin-like growth factor receptor 1 (IGF-IR; CD221 ) and insulin-like growth factor receptor 2 (IGF-2R; CD222); two ligands, insulin-like growth factor 1 (IGF-1 ) and insulin-like growth factor 2 ( IGF-2); six IGF binding proteins (IGFBPs), IGFBP-1 to IGFBP- 6.
  • IGFBP proteases e.g.: caspases, metalloproteinases, prostate-specific antigen
  • IGF-1 also known as somatomedin C, is a polypeptide hormone similar in molecular structure to insulin.
  • IGF-1 consists of 70 amino acids in a single chain and has a molecular weight of 7649 daltons. IGF-1 is produced primarily by the liver as an endocrine hormone as well as in target tissues in a paracrine/autocrine fashion. IGFBPs are 24 to 45 kDa proteins. All six IGFBPs share 50% homology with each other and have binding affinities for IGF-I and IGF- II at the same order of magnitude as the ligands have for the IGF-IR. Approximately 98% of IGF-1 is bound to one of 6 binding proteins (IGF-BP). IGFBP-3, the most abundant protein, accounts for about 80% of all IGF binding. IGF-1 binds to IGFBP-3 in a 1 :1 molar ratio. IGFs play a crucial role in regulating cell proliferation, differentiation and apoptosis.
  • IGF-IR mediated signaling has been shown to reduce tumor growth rate, increase apoptosis, increase killing of tumors by chemotherapy and other molecular target therapies (reviewed in Pollak et al, Nature Reviews Cancer. 2004. 4:505-516; Zhang et al, Breast Cancer Res. 2000. 2:170-75; Chakravarti et al, Cancer Res.2002. 62:200-07).
  • IGF-1 R antagonist therapies for various cancers have been clinically investigated, which include anti-IGF-1 R antibodies, such as figitumumab, and small molecule inhibitors.
  • the present invention provides a method of predicting efficacy of an IGF-1 R antagonist therapy for cancer in a patient.
  • the method comprises determining the concentration of free IGF-1 in the blood of the patient, where a concentration of free IGF-1 in the blood that is equal to, or greater than, a predetermined value is predictive or prognostic of better efficacy of the therapy in the patient compared with patients with lower free IGF-1 concentrations.
  • the method comprises determining the insulin/IGFBP-1 ratio in the blood of the patient, wherein the insulin/IGFBP-1 ratio that is equal to, or greater than, a predetermined value is predictive or prognostic of better efficacy of the therapy in the patient compared to patients with lower ratios.
  • the present invention provides a method of selecting a cancer patient for therapy with an IGF-IR antagonist (the "patient selection method").
  • the method comprises determining the concentration of free IGF-1 in the blood of the patient and selecting the patient who has a concentration of free IGF-1 that is equal to, or greater than, a predetermined value.
  • the method comprises determining the insulin/IGFBP-1 ratio in the blood of the patient and selecting the patient who has an insulin/IGFBP-1 ratio that is equal to, or greater than, a predetermined value.
  • the present invention provides a method of monitoring the effectiveness of an IGF-1 R antagonist therapy for cancer in a patient.
  • the method comprises monitoring the change of the free IGF-1 concentration in the blood of the patient after initiation of the IGF-1 R antagonist therapy in the patient, where an increase in the free IGF-1 concentration after initiation of the therapy is indicative of effectiveness of the therapy.
  • the method comprises monitoring the change of insulin/IGFBP-1 ratio in the blood of the patient after the initiation of the IGF-1 R antagonist therapy in the patient, where an increase in the insulin/IGFBP-1 ratio after initiation of the therapy is indicative of effectiveness of the therapy.
  • Particular IGF-1 R antagonist therapies includes molecules that inhibit binding of IGF-1 to IGF-1 R, for examples, anti-IGF-1 R antibodies, such as figitumumab and antibodies disclosed in WO 02/053596, and small molecule inhibitors.
  • the present invention provides a method of treating cancer in a patient with an IGF-1 R antagonist therapy (the "therapeutic method").
  • the method comprises (1 ) identifying a patient who has a concentration of free IGF-1 in the blood that is equal to, or greater than, a predetermined value, and (2) administering to the patient an therapeutically effective amount of an IGF-1 R antagonist.
  • the method comprises (1 ) identifying a patient who has an insulin/IGFBP-1 ratio in the blood that is equal to, or greater than, a predetermined value, and (2) administering to the patient an therapeutically effective amount of an IGF-1 R antagonist.
  • Table 1 shows the ROC area under the curve (AUC) and significance level (P) for each marker for PFS rates at 3 and 6 months in patients treated with paclitaxel plus carboplatin (PC) and figitumumab (F10 - 10 mg/kg dose or F20 - 20 mg/kg dose).
  • AUC area under the curve
  • P significance level
  • Table 2 shows the ROC area under the curve (AUC) and significance level (P) for each marker ratio for PFS rates at 3 and 6 months in patients treated with PCF20.
  • Figure 1 shows a Kaplan Meier analysis of PFS in patients enrolled in study A4021002 who had a baseline free IGF-1 level below 0.7 ng/mL.
  • Figure 2 shows a Kaplan Meier analysis of PFS in patients enrolled in study
  • Figure 3 shows a Kaplan Meier analysis of PFS in patients enrolled in study A4021002 who received PCF20 and had a baseline free IGF-1 level either below 0.7 or equal to or above 0.7 ng/mL.
  • Figure 4 shows a Kaplan Meier analysis of PFS in patients enrolled in study
  • Figure 5 shows a Kaplan Meier analysis of PFS in patients enrolled in study A4021002 who had a baseline insulin/IGFBP-1 ratio equal to or above 0.8.
  • Figure 6 shows a Kaplan Meier analysis of PFS in patients enrolled in study
  • Figure 7 represents the baseline median free IGF-1 plasma levels in patients with a baseline insulin/IGFBP-1 ratio below 0.8 versus those with a baseline insulin/IGFBP-1 ratio equal to and higher than 0.8.
  • Figure 8 shows the increase in free IGF-1 levels relative to baseline from at 1 week the first dose of figitumumab for doses equal or above 0.1 mg/kg
  • an element means one element or more than one element.
  • free IGF-1 refers to the IGF-1 that is not bound to IGF binding proteins and encompass the fraction of IGF-1 that can be readily dissociated from IGFBPs under the specific assay conditions.
  • a biological sample refers to a sample of tissue or fluid isolated from a subject, including but not limited to, for example, plasma, serum, spinal fluid, lymph fluid, the external sections of the skin, respiratory, intestinal, and genitourinary tracts, tears, saliva, sputum, milk, whole blood or any blood fraction, blood derivatives, blood cells, tumors, neuronal tissue, organs or any type of tissue, any sample obtained by lavage (for example of the bronchial system), and sample of in vivo cell culture constituents.
  • the Concentration of free IGF-1 may be measured in a biological sample from the patient.
  • the concentration of free IGF-1 may be measured in a sample of whole blood, or in a sample of a liquid component of the blood, such as serum or plasma.
  • the free IGF-1 concentration in the blood of a patient is preferably measured in samples of EDTA plasma using the ACTIVE Free IGF-I ELISA kit (DSL-10-9400, marketed by Diagnostic Systems Laboratories, Inc, Fullerton, CA 92834-3100 USA). In some cases, such concentration is a baseline concentration.
  • baseline concentration refers to the concentration of free IGF-1 in the blood of a patient before the patient receives the first dose of a therapy.
  • insulin/IGFBP-1 ratio refers to the ratio of insulin concentration to IGFBP- 1 concentration calculated by dividing the insulin concentration expressed as mU/L, with the IGFBP-1 concentration expressed as ng/mL. For example, if the insulin concentration is 100 mll/L and the IGFBP-1 concentration is 100 ng/mL, the insulin/IGFBP-1 ratio is 1.0 .
  • the concentrations of insulin and IGFBP-1 in the blood may be measured in a sample of whole blood, or in a sample of a liquid component of the blood, such as serum or plasma. In some cases, such ratio is obtained from the baseline concentration of both parameters, insulin and IGFBP-1.
  • baseline insulin/IGFBP-1 ratio refers to the ratio between the concentrations of insulin and IGFBP-1 in the blood of a patient before the patient receives the first dose of anti-IGF-IR therapy.
  • IGF-1 R antagonist refers to any molecule that blocks, suppresses, inhibits, or reduces a biological activity of IGF-1 R, including downstream pathways mediated by IGF-1 R signaling.
  • antagonist implies no specific mechanism of biological action whatsoever, and expressly includes and encompasses all possible pharmacological, physiological, and biochemical interactions with IGF-1 R.
  • IGF-1 R antagonist includes (1 ) agent that is a competitive inhibitor or a noncompetitive inhibitor of IGF-1 R binding to its ligands, thus interfering with the binding of an IGF-1 R with its ligands; (2) an agent that does not interfere with the binding of the IGF-1 R with its natural ligand but, instead, inhibits or decrease the activities caused by binding of the IGF- 1 R to its ligands; (3) an agent that decreases the expression of IGF-1 R.
  • agents include antibodies (including antigen binding portions thereof), nucleic acid molecules (such as anti-sense or interfering RNA molecules), peptides, non-peptide small organic molecules, and so on.
  • IGF-1 R antagonist therapy refers to the administration of an IGF-1 R antagonist to a patient for the management of a medical condition.
  • antibody refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding portion thereof.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as V H ) and a heavy chain constant region.
  • the heavy chain constant region is comprised of three domains, Cm, C H 2 and C H 3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as V L ) and a light chain constant region.
  • the V H and V L regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • treating cancer refers to causing a desirable or beneficial effect in a patient diagnosed with a cancer.
  • the desirable or beneficial effect may include: (1 ) inhibition of further growth or spread of cancer cells, (2) death of cancer cells, (3) inhibition of reoccurrence of cancer, (4) alleviation, reduction, mitigation, inhibition, or reducing the frequency, of symptoms associated with the cancer (such as pain), or (5) improved survival of the patient.
  • Inhibition of reoccurrence of cancer includes inhibition of cancer growth at initial cancer sites and surrounding tissue that have previously been treated by radiation, chemotherapy, surgery, or other techniques, as well as absence of cancer growth at new distant sites.
  • the desirable or beneficial effect can be either patientive or objective.
  • the human may note improved vigor or vitality or decreased pain as patientive symptoms of improvement or response to therapy.
  • the clinician may notice a decrease in tumor size or tumor burden based on physical exam, laboratory parameters, tumor markers or radiographic findings. Some laboratory signs that the clinician may observe for response to treatment include normalization of tests, such as white blood cell count, red blood cell count, platelet count, erythrocyte sedimentation rate, and various enzyme levels. Additionally, the clinician may observe a decrease in a detectable tumor marker. Alternatively, other tests can be used to evaluate objective improvement, such as sonograms, nuclear magnetic resonance testing and positron emissions testing.
  • the present invention provides a method of predicting efficacy of an IGF-1 R antagonist therapy for cancer in a patient.
  • the method comprises determining the concentration of free IGF-1 in the blood of the patient, where a concentration of free IGF-1 in the blood that is equal to, or higher than, a predetermined value is predictive or prognostic of better efficacy of the therapy in the patient compared with patients with lower free IGF-1 concentrations.
  • the method comprises determining the insulin/IGFBP-1 ratio in the blood of the patient, wherein the insulin/IGFBP-1 ratio in the blood that is equal to, or higher than, a predetermined value being predictive or prognostic of better efficacy of the therapy in the patient compared to patients with lower ratios.
  • the free IGF-1 , insulin, and IGFBP-1 concentrations are typically measured in samples of plasma or serum, but preferably in plasma. They may be measured in samples taken either prior to or after the initiation of the therapy; however, it is preferred that they are measured in samples taken prior to initiation of the therapy (the "baseline concentrations"). In addition, they may be measured on a single sample, or on multiple samples taken at predetermined time intervals. Where the free IGF-1 , insulin, and IGFBP-1 concentrations are measured on multiple samples, the average of the concentrations in the samples may be used.
  • the predetermined value of the free IGF-1 or insulin/IGFBP-1 ratio may slightly vary depending a number of factors, such as the assay method used, type of samples in which free IGF-1 is measured, storage conditions (such as temperature and duration) of the samples, ethnic identity of the patient, as so on.
  • the predetermined value for free IGF-1 is usually the baseline concentration of free IGF-1 in plasma in the range of about 0.45 ng/L to 0.9 ng/L, such as 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, and 0.9 ng/mL.
  • the predetermined value for free IGF-1 is the baseline plasma concentration of free IGF-1 of 0.5 ng/mL.
  • the predetermined value for free IGF-1 is a baseline plasma concentration of 0.7 ng/mL.
  • the predetermined value for free IGF-1 is a baseline plasma concentration of 0.8 ng/mL.
  • the predetermined value for the insulin/IGFBP-1 ratio is usually a baseline insulin/IGFBP-1 ratio in plasma in the range of about 0.5 to 1.5, such as 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1 , 1.05, 1.1 , 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, and 1.5.
  • the predetermined value for insulin/IGFBP-1 is a baseline insulin/IGFBP-1 ratio of 0.5 in the plasma.
  • the predetermined value for insulin/IGFBP-1 is a baseline insulin/IGFBP-1 ratio of 0.8 in the plasma. In still another embodiment, the predetermined value for insulin/IGFBP-1 is a baseline insulin/IGFBP-1 ratio of 1 in the plasma.
  • the present invention provides a method of selecting a cancer patient for therapy with an IGF-IR antagonist (the "patient selection method").
  • the method comprises determining the concentration of free IGF-1 in the blood of the patient and selecting the patient who has a concentration of free IGF-1 that is equal to, or greater than, a predetermined value.
  • the method comprises determining the insulin/IGFBP-1 ratio in the blood of the patient and selecting the patient who has an insulin/IGFBP-1 ratio that is equal to, or greater than, a predetermined value.
  • the predetermined values for free IGF-1 and insulin/IGFBP ratio, as well as their measurement and selections, are as described previously above.
  • the present invention provides a method of monitoring the effectiveness of an IGF-1 R antagonist therapy for cancer in a patient.
  • the method comprises monitoring the change of the free IGF-1 concentration in the blood of the patient after initiation of the IGF-1 R antagonist therapy in the patient, where an increase in the free IGF-1 concentration after initiation of the therapy is indicative of effectiveness of the therapy.
  • the method comprises monitoring the change of insulin/IGFBP-1 ratio in the blood of the patient after the initiation of the IGF-1 R antagonist therapy in the patient, where an increase in the insulin/IGFBP-1 ratio after initiation of the therapy is indicative of effectiveness of the therapy.
  • Particular IGF-1 R antagonist therapies includes molecules that inhibit binding of IGF-1 to IGF-1 R, for examples, anti-IGF-1 R antibodies, such as figitumumab and antibodies disclosed in WO 02/053596, and small molecule inhibitors.
  • the change of the free IGF-1 concentration and insulin/IGFBP-1 ratio in the blood is determined in two or more samples taken at different time points, with a least one sample being taken after the initiation of the therapy. All of the samples may be taken after the initiation of the therapy; however, it is preferred that at least one sample is taken prior to initiation of the therapy (the "baseline sample") such that a baseline concentration of free IGF-1 or baseline insulin/IGFBP-1 ratio may be determined. Samples, other than the baseline samples, may be taken at any time points between the initiation and conclusion of the therapy such as 1 week, or 1 , 2, 3, 4, or more treatment cycles after the first dose of therapy.
  • the method comprises monitoring the change of the free IGF-1 concentration or insulin/IGFBP-1 ratio in the blood of the patient at 3 weeks after the initiation of the IGF-1 R antagonist therapy relative to the baseline free IGF-1 concentration or insulin/IGFBP-1 ratio, where an increase by at least 200%(i.e. the free IGF-1 concentration or insulin/IGFBP-1 ratio being at least 3 times the respective baseline value ) is indicative of effectiveness of the therapy.
  • the increase of the free IGF-1 concentration or insulin/IGFBP-1 ratio in the blood of the patient at 4 cycles after the initiation of the IGF-1 R antagonist therapy is at least 200% over the baseline free IGF-1 concentration.
  • the present invention provides a method of treating cancer in a patient with an IGF-1 R antagonist therapy (the "therapeutic method").
  • the method comprises (1 ) identifying a patient who has a concentration of free IGF-1 or insulin/IGFBP-1 ratio in the blood that is equal to, or greater than, a predetermined value, and (2) administering to the patient an therapeutically effective amount of an IGF-1 R antagonist.
  • the method comprises (1 ) identifying a patient who has an insulin/IGFBP-1 ratio in the blood that is equal to, or greater than, a predetermined value, and (2) administering to the patient an therapeutically effective amount of an IGF-1 R antagonist.
  • any cancer that is treatable by reducing the activity of IGF-IR may be treated by the therapeutic method of the invention.
  • specific cancers include epithelial squamous cell cancer, melanoma, leukemia, myeloma, stomach cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, renal cancer, prostate cancer, testicular cancer, thyroid cancer, and head and neck cancer.
  • IGF-1 R antagonist Any suitable IGF-1 R antagonist may be used to treat the cancer patient so identified.
  • suitable IGF-1 R antagonists include antibodies and antigen binding portions thereof, nucleic acid molecules, peptides, and non-peptide small organic molecules.
  • the IGF-1 R antagonist is an antibody that binds to IGF-1 R and inhibits the activity of IGF-1 R (IGF-1 R antagonist antibody).
  • IGF-1 R antagonist antibody particularly antibodies useful in practice of the invention include those described in WO 02/053596 (International Application Number: PCT/US01/51 1 13), which further describes antibodies 2.12.1 , 2.13.2., 2.14.3, 3.1.1 , 4.9.2, and 4.17.3. As disclosed in that published application, hybridomas producing these antibodies were deposited in the American Type Culture Collection (ATCC), 10801 University Boulevard, Manassas, VA 201 10-2209, on December 12, 2000 with the following deposit numbers:
  • ATCC American Type Culture Collection
  • amino acid sequences of each of the above antibodies are provided in the present application.
  • An index of SEQ ID NOs is provided in Table 3.
  • amino acids 20-470 with the signal sequence (amino acids 1 -19)
  • amino acids 20-470 with the signal sequence (amino acids 1 -19)
  • the IGF-1 antagonist antibody is selected from the group consisting of:
  • an antibody that comprises the amino acid sequences of the CDR1 , CDR2 and CDR3 of the heavy chain and the amino acid sequences of the CDR1 , CDR2 and CDR3 of the light chain of an antibody selected from the group consisting of antibody 2.12.1 , 2.13.2, 2.14.3, 4.9.2, 4.17.3, and 6.1 ;
  • an antibody that competes for binding to the IGF-1 R with an antibody selected from the group consisting of antibody 2.12.1 , 2.13.2, 2.14.3, 4.9.2, 4.17.3, and 6.1 ; and d) an antibody selected from the group consisting of antibody 2.12.1 , 2.13.2, 2.14.3, 4.9.2, 4.17.3, and 6.1.
  • the IGF-1 antagonist antibody is selected from the group consisting of;
  • SEQ ID NO.: 7 and a light chain that comprises the amino acid sequences of SEQ ID No.:
  • an antibody having a heavy chain that comprises the amino acid sequence of SEQ ID NO.: 13 and a light chain that comprises the amino acid sequences of SEQ ID NO.:
  • IGF-1 R antagonist antibodies examples include:
  • IGF-1 R antibodies that are disclosed in US 7,572,897 and WO 05005635, particularly the antibody produced by hybridoma cell line ⁇ IGF-1 R> HUMAB Clone 18 with accession number DSM ACC 2587, or antibody produced by hybridoma cell line ⁇ IGF-1 R> HUMAB Clone 22 with accession number DSM ACC 2594 ;
  • IGF-1 R antibodies or antigen biding portion thereof, that are disclosed in US 7,378,503 and WO 040087756, particularly an antibody that is obtainable from hybridoma cell line ⁇ IGF-1 R> HuMab Clone 1 a, ⁇ IGF-1 R> HuMab Clone 23, or ⁇ IGF-1 R> HuMab Clone 8;
  • IGF-1 R antibodies or antigen biding portion thereof, that are disclosed in US 7,241 ,444 and WO 03059951 ,
  • IGF-1 R antibodies or antigen biding portion thereof, that are disclosed in
  • IGF-1 R antibodies or antigen biding portion thereof, that are disclosed in US7217796 and WO 03100008, particularly (1 ) an antibody comprising a heavy chain encoded by a polynucleotide in plasmid 15H12/19D12 HCA ( gamma 4) which is deposited at the American Type Culture Collection (ATCC) under number PTA-5214; and a light chain encoded by a polynucleotide in plasmid 15H12/19D12 LCF ( kappa ) which is deposited at the American Type Culture Collection (ATCC) under number PTA-5220; and (2) an antibody comprising a heavy chain encoded by a polynucleotide in plasmid 15H12/19D12 HCA (gamma 1 ) which is deposited at the American Type culture Collection (ATCC) under number PTA-5216; and a light chain encoded by a polynucleotide in plasmid 15H12/19D12 LCF ( kappa 4)
  • IGF-1 R antibodies or antigen biding portion thereof, that are disclosed in US7,612,178 and WO 07126876, particularly (1 ) an antibody that is M13-C06.G4.P.agly which specifically binds to IGF-1 R produced by Chinese Hamster Ovary (CHO) cells deposited under American Type Culture Collection (ATCC) Deposit Number PTA-7444 or (2) An antibody that comprises an antigen binding domain identical to that of a monoclonal Fab antibody fragment of M13-C06.G4.P.agly produced by Chinese Hamster Ovary (CHO) cells deposited under American Type Culture Collection (ATCC) Deposit Number PTA- 7444.
  • Examples of specific anti-IGF-1 R antibodies include F-50035 and MK-0646 (Pierre
  • IGF-1 R inhibitors include OSI- 906 (OSI Pharmaceuticals); AEW-541 (Novartis); BMS-754807, BMS-536924 and BMS-554417 (Bristol- Myers Squibb); INSM-18 (Insmed); XL228 (Exelixis); and those disclosed in International Patent Application Nos. WO2002092599; WO2004/043962, WO2004/054996, WO2005097800; and WO2006074057; WO2008005956.
  • the IGF-1 R antagonist may be administered alone as monotherapy, or administered in combination with one or more additional therapeutic agents.
  • additional therapeutic agents that may be used in the combination therapy for treating cancer include (1 ) chemotherapeutic agents, (2) immunotherapeutic agents, and (3) hormone therapeutic agents.
  • chemotherapeutic agent refers to a chemical or biological substance that can cause death of cancer cells, or interfere with growth, division, repair, and/or function of cancer cells.
  • chemotherapeutic agents include those that are disclosed in WO 2006/088639, WO 2006/129163, and US 20060153808, the disclosures of which are incorporated herein by reference.
  • chemotherapeutic agents include: (1 ) alkylating agents, such as chlorambucil (Leukeran), mcyclophosphamide (CYTOXAN), ifosfamide (IFEX), mechlorethamine hydrochloride (MUSTARGEN), thiotepa (THIOPLEX), streptozotocin (ZANOSAR), carmustine (BICNU, GLIADEL WAFER), lomustine (CEENU), and dacarbazine (DTIC-DOME); (2) alkaloids or plant vinca alkaloids, including cytotoxic antibiotics, such as doxorubicin (Adriamycin), epirubicin (ELLENCE, PHARMORUBICIN), daunorubicin (CERUBIDINE, DAUNOXOME), nemorubicin, idarubicin (IDAMYCIN PFS, ZAVEDOS), mitoxantrone (DHAD, NOVANTRONE).
  • alkylating agents
  • dactinomycin actinomycin D, COSMEGEN
  • plicamycin plicamycin
  • mitomycin mitomycin
  • MUTAMYCIN mitomycin
  • BLENOXANE vinorelbine tartrate
  • VELBAN vinblastine
  • ONCOVIN vincristine
  • ELDISINE bleomycin
  • antimetabolites such as capecitabine (XELODA), cytarabine (CYTOSAR-U), fludarabine (FLUDARA), gemcitabine (GEMZAR), hydroxyurea (HYDRA), methotrexate (FOLEX, MEXATE, TREXALL), nelarabine (ARRANON), trimetrexate (NEUTREXIN), and pemetrexed (ALIMTA)
  • Pyrimidine antagonists such as 5-fluorouracil (5-FU); capecitabine (XELODA), raltitrexed (TOMUDEX), tegafur-uracil (UF
  • immunotherapeutic agents refers to a chemical or biological substance that can enhance an immune response of a mammal.
  • immunotherapeutic agents include: bacillus Calmette-Guerin (BCG); cytokines such as interferons; vaccines such as MyVax personalized immunotherapy, Onyvax-P, Oncophage, GRNVAC1 , Favld, Provenge, GVAX, Lovaxin C, BiovaxlD, GMXX, and NeuVax; and antibodies such as alemtuzumab (CAMPATH), bevacizumab (AVASTIN), cetuximab (ERBITUX), gemtuzunab ozogamicin (MYLOTARG), ibritumomab tiuxetan (ZEVALIN), panitumumab (VECTIBIX), rituximab (RITUXAN, MABTHERA), trastuzumab (HERCEPTIN), tos
  • BCG bac
  • hormone therapeutic agent refers to a chemical or biological substance that inhibits or eliminates the production of a hormone, or inhibits or counteracts the effect of a hormone on the growth and/or survival of cancerous cells.
  • agents suitable for the methods herein include those that are disclosed in US200701 17809.
  • hormone therapeutic agents include tamoxifen (NOLVADEX), toremifene (Fareston), fulvestrant (Faslodex), anastrozole (Arimidex), exemestane (Aromasin), letrozole (Femara), megestrol acetate (Megace), goserelin (Zoladex), and leuprolide (Lupron).
  • the combination therapy for treating cancer also encompasses a IGF-1 R antagonist in combination with surgery to remove a tumor or with radiation therapy, such as ionizing (electromagnetic) radiotherapy (e.g., X-rays or gamma rays) and particle beam radiation therapy (e.g., high linear energy radiation).
  • radiation therapy such as ionizing (electromagnetic) radiotherapy (e.g., X-rays or gamma rays) and particle beam radiation therapy (e.g., high linear energy radiation).
  • an IGF-1 R antagonist refers to any amount that is sufficient to cause any desirable or beneficial effect in the patient being treated, such as inhibition of further growth or spread of cancer cells, death of cancer cells, inhibition of reoccurrence of cancer, reduction of pain associated with the cancer, or improved survival of the patient.
  • the precise dosage level to be administered can be readily determined by a person skilled in the art and will depend on a number of factors, such as the type, and severity of the disorder to be treated, the particular IGF-1 R antagonist employed, the route of administration, the time of administration, the duration of the treatment, the particular additional therapy employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • IGF-1 , insulin and IGFBP-1 in whole blood, plasma or serum of a patient can be measured using various analytical assay methods that are known in the art, such as enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA),immunoradiometric assays, mass spectrometric immunoassay (such as the one disclosed in U.S. Patent No. 7,303,888), ultrafiltration, electrochemiluminescence immunoassay and biological assays. Additional information about immunoassays that may be used can be found in Immunoassays: A Practical Approach. James P. Gosling, editor.
  • ELISA enzyme linked immunosorbent assay
  • DSL-10-9400 ACTIVE Free IGF-I ELISA
  • the ELISA assay is an enzymatically amplified two-step "sandwich" immunoassay. In the assay, standards, controls and samples are incubated in microtitration wells which have been coated with an antibody against the protein of interest, i.e IGF-1 , insulin or IGFBP-1.
  • a detection antibody labeled with enzyme-horseradish peroxidase (HRP) is added to each well.
  • substrate tetramethylbenzidine (TMB) is added to the wells.
  • an acidic stopping solution is added. The degree of enzymatic turnover of the substrate is determined by dual wavelength absorbance measurement at 450 nm and between 600 and 630 nm. The absorbance measured is directly proportional to the concentration of the protein of interest in the samples. A set of standards with known concentrations of the protein of interest is used to plot a standard curve of absorbance versus free IGF-I, insulin or IGFBP-1 concentrations.
  • the concentrations of the protein of interest in the samples can then be calculated from this standard curve.
  • the samples of serum or plasma may be used, with plasma being preferred.
  • the immunoradiometric (IRMA) assay such as the DSL free IGF-1 kit (DSL-10- 9400) are assay in which the analyte to be measured is "sandwiched" between two antibodies. The first antibody is immobilised on the inside walls of the tubes. The other antibody is radiolabeled for detection. The analyte present in the unknowns, standards and controls are bound by both of the antibodies to form a "sandwich" complex.
  • the direct assay the unaltered sample is added directly to the assay tube.
  • the protein of interest is then captured by the antibody coating, the remaining sample is washed away, and the protein of interest bound to the tube is then detected using a radiolabeled antibody directed to a second epitope.
  • Ultrafiltration may also be used to determine the free concentrations of IGF-1 (Frystyk J et al Growth Horm IGF Res. 2001 ;1 1 :1 17-27).
  • This method requires that samples are applied to an ultrafiltration device comprising an ultrafiltration membrane placed in a supporting device (Amicon Division, Beverly,MA, USA). Prior to ultrafiltration, samples are equilibrated with a buffer and then patiented to centrifugation (300 x g). The presence of the proteins of interest in the ultrafiltrate can then be analyzed using ELISA, IRMA or other methods.
  • Clinical study, A4021002 was a multicenter, open-label, randomized, study investigating the combination of figitumumab with chemotherapy (paclitaxel and carboplatin) as first line treatment of chemotherapy na ' ive patients with advanced non-small cell lung cancer (NSCLC).
  • Patients were randomized 2:1 to receive paclitaxel, carboplatin, and figitumumab at in arm A (PCF), or paclitaxel and carboplatin alone in arm B (PC).
  • Paclitaxel was administered intravenously (IV) at 200 mg/m2 over 3 hours, carboplatin administered IV with area under the plasma concentration-time curve (AUC) 6 (IV) over 15-60 minutes, and figitumumab administered IV at 10 mg/kg (PCF10) or 20 mg/kg (PCF 20), every 3 weeks for up to 6 cycles.
  • Figitumumab is a fully human lgG2 monoclonal antibody against the insulin like growth factor receptor (IGF-IR).
  • IGF-IR insulin like growth factor receptor
  • Eligible patients had histologically or cytologically confirmed stage IV or 1MB NSCLC not amenable to curative treatment with surgery/radiation.
  • Eligible patients were at least 18 years of age and had at least one unidimensionally measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) and Eastern Cooperative Oncology Group performance status of 0/1.
  • RECIST Response Evaluation Criteria in Solid Tumors
  • Enrollment exclusions included women of childbearing potential who declined the use of contraception; active gastrointestinal abnormalities; symptomatic brain metastasis (patients with brain metastases could be enrolled if asymptomatic and stable); coexisting uncontrolled medical condition, including active cardiac disease, in the previous 6 months, infection, other active malignancy during the past 3 years, or dementia; neuropathy grade >1 ; known hypersensitivity to Cremophor®; and major surgical procedures or radiation therapy within 4 weeks or 1 week, respectively, prior to study drug administration.
  • the protocol was conducted in accordance with Good Clinical Practice guidelines and was approved by each participating institutional ethics review boards. All patients signed written informed consent before enrollment. Patients were eligible to receive up to a total of 6 cycles of chemotherapy unless disease progression or unacceptable toxicity developed. Tumor assessments were conducted at baseline and repeated every 6 weeks until disease progression. Disease status was assessed by investigator.
  • Table 1 shows the ROC area under the curve (AUC) and significance level (P) for the rate of PFS at 3 and 6 months in patients treated with PCF20.
  • ROC analyses were conducted to investigate the relationship between a patient's PFS while on figitumumab treatment and the ratio at baseline of the concentrations of IGF- 1 , IGF-2 and insulin, to the IGF-1 , -2 carrier proteins IGFBP-1 to 3.
  • the results of these analyses are shown in Table 2.
  • the specificity of the free IGF-1 and the insulin/IGFBP-1 ratio was investigated by assessing the ROC AUC in patients receiving only PC. Free IGF-1 and the insulin/IGFBP-1 ratio were not predictive of PFS at 3 months for PC patients. Due to the higher rate of progression of PC patients, there were insufficient data to analyze PFS at 6 months.
  • the treatment-biomarker interactions were further investigated using Cox proportional hazards models. This analysis relates the hazard ratios (risk of progression with or without a treatment) of patients above and below a biomarker criterion. Free IGF-1 cutoff criteria of 0.1 to 0.9 ng/mL were examined. Useful criteria were in the range of 0.5 - 0.9, with patients above the criterion having a substantial observed improvement in PFS on the PCF20 arm.
  • the estimated treatment-biomarker interaction terms from Cox proportional hazards models were between 2.5 and 3.5 for cuts 0.5-0.9, with one-sided P values of 0.1 1 (0.5 ng/mL criterion), 0.09 (0.6 ng/mL criterion), 0.030 (0.7 ng/mL criterion), 0.033 (0.8 ng/mL criterion), 0.026 (0.9 ng/mL criterion) adjusted for multiple testing.
  • FIG. 1 shows Kaplan and Meier estimates of PFS in patients enrolled in study A4021002 who had a baseline free IGF-1 level below 0.7 ng/mL. Median PFS for these patients were 4.30 (PC), 2.83 (PCF10) and 5.03 months (PCF20). These differences were not significant.
  • Figure 3 shows Kaplan and Meier estimates of PFS in patients enrolled in study A4021002 who received PCF20 and had a baseline free IGF-1 level either below 0.7 or equal or above 0.7 ng/mL.
  • Median PFS for these patients were 5.03 ( ⁇ 0.7 ng/mL) and 6.53 (>0.7 ng/mL).
  • Insulin/IGFBPI ratio cutoffs criteria of 0.5 to 1.1 were also examined using Cox proportional hazards model to test for treatment-biomarker interaction.. All cutoffs criteria appeared to be potentially useful, with one-sided P values for treatment-biomarker interaction of 0.07 (insulin/IGFBP-1 ratio of 0.5), 0.06 (ratio of 0.6), 0.02 (ratio of 0.7), 0.02 (ratio of 0.8), 0.03 (ratio of 0.9), 0.01 (ratio of 1 ) and .08 (ratio of 1.1 ) respectively, adjusted for multiple testing.
  • Figure 4 shows Kaplan and Meier estimates of PFS in patients enrolled in study A4021002 who had a baseline insulin/IGFBP-1 ratio below 0.8.
  • Figure 6 shows Kaplan and Meier estimates of PFS in patients enrolled in study A4021002 who received PCF20 and had an insulin/IGFBP-1 ratio either below 0.8 or equal or above 0.8.
  • Insulin 0.679 0.163 0.771 0.046
  • IGFBP-1 0.692 0.166 0.486 0.926
  • IGFBP-2 0.667 0.239 0.614 0.614
  • IGF-1/IGFBP1 0.750 0.043 0.558 0.736
  • IGF-1/IGFBP-2 0. ⁇ 91 0.170 0.513 0.946
  • IGF-1/IGFBP-3 0.538 0.806 0.696 0.163
  • IGF-2 IGFBP-1 0.662 0.245 0.646 0.343
  • IGF-2 IGFBP-2 0.752 0.071 0.677 0.242
  • IGF-2/IGFBP-3 0.754 0.071 0.523 0.881 lnsulln/IGFBP-1 0.756 0.024 0.786 0.032 lnsulin/IGFBP-2 0.679 0.163 0.700 0.115 lnsulin/IGFBP-3 0.538 0.789 0.643 0.350

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Abstract

La présente invention porte sur l'utilisation d'IGF-1 libre, et du rapport insuline/IGFBP dans le sang, en tant que biomarqueurs pour une thérapie du cancer par un antagoniste de l'IGF-1R, ainsi que sur un procédé pour le traitement du cancer par une thérapie du cancer utilisant l'IGF-1 R chez des patients choisis sur la base de ces biomarqueurs.
PCT/IB2010/056071 2010-01-05 2010-12-24 Biomarqueurs pour une thérapie du cancer par un anti-igf-1r WO2011083391A2 (fr)

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