WO2012103341A1 - Traitement de tumeurs solides à un stade avancé à l'aide d'anticorps anti-erbb3 - Google Patents

Traitement de tumeurs solides à un stade avancé à l'aide d'anticorps anti-erbb3 Download PDF

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Publication number
WO2012103341A1
WO2012103341A1 PCT/US2012/022733 US2012022733W WO2012103341A1 WO 2012103341 A1 WO2012103341 A1 WO 2012103341A1 US 2012022733 W US2012022733 W US 2012022733W WO 2012103341 A1 WO2012103341 A1 WO 2012103341A1
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seq
cdrl2
cdrh2
cycle
cdrl3
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Victor Moyo
Joseph Pearlberg
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Sanofi SA
Merrimack Pharmaceuticals Inc
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Sanofi SA
Merrimack Pharmaceuticals Inc
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Priority to AU2012211258A priority Critical patent/AU2012211258A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the ErbB3 receptor is 148 kD transmembrane receptor belonging to the
  • ErbB/EGFR receptor tyrosine kinase family although lacks intrinsic kinase activity.
  • the ErbB receptors form homo- and heterodimeric complexes that impact the physiology of cells and organs by mediating ligand-dependent (and in some cases ligand independent) activation of multiple signal transduction pathways.
  • ErbB3-containing heterodimers (such as ErbB2/ErbB3) in tumor cells have been shown to be the most mitogenic and oncogenic receptor complex within the ErbB family.
  • HRG heregulin
  • ErbB3 receptor ErbB3 dimerizes with other ErbB family members
  • ErbB3/ErbB2 dimerization results in transphosphorylation of ErbB3 on tyrosine residues contained within the cytoplasmic tail of the protein.
  • ErbB3-containing heterodimeric complexes are therefore potent activators of AKT, as ErbB3 possesses six tyrosine
  • PI3K phosphoinositol-3-kinase
  • HRG regulates growth, invasion and angiogenesis through either over expression or the activation of an autocrine or paracrine loop. Disruption of the heregulin autocrine loop by blocking HRG binding or disruption of the ErbB2/ErbB3 dimer is considered to provide an important therapeutic approach to controlling cancer cell growth.
  • compositions and methods for treating solid tumors comprising administering to the patient an anti-ErbB3 antibody according to a particular clinical dosage regimen (i.e., at a particular dose amount and according to a specific dosing schedule).
  • the human patient suffers from colorectal cancer, squamous cell head and neck cancer, non- small cell lung cancer, triple negative breast cancer or other solid tumors that have EGFR dependence.
  • an exemplary anti-ErbB3 antibody is antibody MM-121 or antigen binding fragments and variants thereof.
  • the antibody comprises variable heavy (VH) and/or variable light (VL) regions encoded by the nucleic acid sequences set forth in SEQ ID NOs: 1 and 3, respectively.
  • the antibody comprises VH and/or VL regions comprising the amino acid sequences set forth in SEQ ID NOs 2 and 4, respectively.
  • the MM-121 antibody comprises (in amino-to carboxy- terminal order) CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and/or (in amino-to carboxy- terminal order) CDRLl, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRLl) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3).
  • an antibody is used that competes for binding with and/or binds to the same epitope on human ErbB3 as the above- mentioned antibodies.
  • the epitope comprises residues 92- 104 of human ErbB3 (SEQ ID NO: 11).
  • the antibody competes with MM-121 for binding to human ErbB3 and has at least 90% variable region amino acid sequence identity with the above-mentioned anti-ErbB3 antibodies. See, e.g., US Patent No. 7,846,440 and US Patent Publication No. 20100266584.
  • methods of treating advanced solid tumors in a human patient comprising administering to the patient, an effective amount of (a) an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and
  • CDRLl, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRLl) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, and wherein for each cycle the anti-ErbB3 antibody is
  • the effective amount comprises administering the anti-ErbB3
  • methods for treatment e.g., effective treatment of an advanced solid stage tumors in a human patient are provided, the methods
  • CDRL1 CDRH2
  • SEQ ID NO: 7 CDRH3
  • CDRLl CDRL2
  • CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8
  • CDRLl SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3)
  • the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once per week at a dose of about 40 mg/kg.
  • methods for treating advanced solid stage tumors in a human patient comprising: administering to the patient an effective amount of (a) an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and
  • CDRLl, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRLl) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once every other week at a dose of about 40 mg/kg.
  • methods for treating advanced stage solid tumors in a human patient comprising administering to the patient an effective amount of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRLl, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRLl) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once every other week at a dose of about 60 mg/kg.
  • methods for treating advanced stage solid tumors in a human patient comprising administering to the patient an effective amount of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRLl, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRLl) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), wherein the effective amount comprises administering the anti-ErbB3 antibody once every three weeks at a dose of about 40 or 60 mg/kg.
  • methods of treating advanced stage solid tumors in a human patient comprising administering to the patient an effective amount of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRLl, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRLl) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once a week according to dose schedules -1, 1, 2, 3, 4, 5, or 6: Dose Level Dose (mg/kg)
  • the cancer is EGFR dependent.
  • the cancer is selected from the group consisting of: colorectal cancer, colon cancer, ocular melanoma, melanoma, ovarian cancer, prostate cancer, thymic carcinoma, esophageal cancer, squamous cell skin cancer, pancreatic cancer, peritoneal cancer, salivary gland carcinoma, squamous cell head and neck cancer, non-small cell lung cancer, breast cancer, and triple negative breast cancer.
  • the anti-ErbB3 antibody is MM-121.
  • the antibody is formulated for intravenous administration.
  • kits for treating advanced solid stage tumors in a human patient comprising: a dose of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth, respectively, in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth, respectively, in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), and instructions for using the anti-ErbB3 antibody in a method of the invention.
  • an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth, respectively, in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3)
  • a kit of the invention comprises at least 500 mg of the antibody.
  • an antiErbB3 antibody comprising: SEQ ID NO: 5 (CDRH1), SEQ ID NO: 6 (CDRH2), SEQ ID NO: 7 (CDRH3), SEQ ID NO: 8 (CDRL1), SEQ ID NO: 9 (CDRL2), and SEQ ID NO: 10 (CDRL3), for administration in at least one cycle, wherein the anti-ErbB3 antibody is administered at a weekly dose of about 20 mg/kg or 40 mg/kg.
  • an antiErbB3 antibody comprising: SEQ ID NO: 5 (CDRHl), SEQ ID NO: 6 (CDRH2), SEQ ID NO: 7 (CDRH3), SEQ ID NO: 8 (CDRL1), SEQ ID NO: 9 (CDRL2), and SEQ ID NO: 10 (CDRL3), for administration in at least one cycle, wherein the anti-ErbB3 antibody is administered once every other week at a dose of about 40 mg/kg or 60 mg/kg.
  • an antiErbB3 antibody comprising: SEQ ID NO: 5 (CDRHl), SEQ ID NO: 6 (CDRH2), SEQ ID NO: 7 (CDRH3), SEQ ID NO: 8 (CDRL1), SEQ ID NO: 9 (CDRL2), and SEQ ID NO: 10 (CDRL3), for administration in at least one cycle, wherein the anti-ErbB3 antibody is administered once every three weeks at a dose of about 40 or 60 mg/kg.
  • the patient does not have metastatic disease. In another embodiment, the patient has metastatic disease.
  • the treatment produces at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in number of metastatic lesions over time, complete response, partial response, stable disease, increase in overall response rate, or a pathologic complete response.
  • compositions comprising a clinically proven safe and effective amount of (a) an anti-ErbB3 antibody comprising CDRHl, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRHl) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3) and (b) a carrier.
  • an anti-ErbB3 antibody comprising CDRHl, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRHl) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3)
  • CDRL1, CDRL2 and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8
  • the anti-ErbB3 antibody is MM- 121.
  • the antibody is formulated for intravenous administration.
  • Figure 1 shows the patient enrollment and response summary for the phase I monotherapy expansion cohort.
  • the term "subject” or "patient” is a human cancer patient.
  • effective treatment refers to treatment producing a beneficial effect, e.g., amelioration of at least one symptom of a disease or disorder.
  • a beneficial effect can take the form of an improvement over baseline, i.e., an improvement over a measurement or observation made prior to initiation of therapy according to the method.
  • a beneficial effect can also take the form of arresting, slowing, retarding, or stabilizing of a deleterious progression of a marker of a solid tumor.
  • Effective treatment may refer to alleviation of at least one symptom of a solid tumor.
  • Such effective treatment may, e.g., reduce patient pain, reduce the size and/or number of lesions, may reduce or prevent metastasis of a tumor, and/or may slow tumor growth.
  • an effective amount refers to an amount of an agent that provides the desired biological, therapeutic, and/or prophylactic result. That result can be reduction, amelioration, palliation, lessening, delaying, and/or alleviation of one or more of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an effective amount comprises an amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation.
  • an effective amount is an amount sufficient to delay tumor development.
  • an effective amount is an amount sufficient to prevent or delay tumor recurrence.
  • An effective amount can be administered in one or more administrations.
  • the effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and may stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and may stop tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer.
  • an "effective amount" is the amount of MM- 121 clinically proven to effect a significant decrease in cancer or slowing of progression of cancer, such as an advanced solid tumor, e.g., that is EGFR dependent.
  • antibody describes polypeptides comprising at least one antibody derived antigen binding site (e.g., VH/VL region or Fv, or
  • Antibodies include known forms of antibodies.
  • the antibody can be a human antibody, a humanized antibody, a bispecific antibody, or a chimeric antibody.
  • the antibody also can be a Fab, Fab'2, ScFv, SMIP, Affibody®, nanobody, or a domain antibody.
  • the antibody also can be of any of the following isotypes: IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgAsec, IgD, and IgE.
  • the antibody may be a naturally occurring antibody or may be an antibody that has been altered (e.g., by mutation, deletion, substitution, conjugation to a non-antibody moiety).
  • an antibody may include one or more variant amino acids (compared to a naturally occurring antibody) which changes a property (e.g., a functional property) of the antibody.
  • a property e.g., a functional property
  • numerous such alterations are known in the art which affect, e.g., half-life, effector function, and/or immune responses to the antibody in a patient.
  • the term antibody also includes artificial polypeptide constructs which comprise at least one antibody- derived antigen binding site.
  • Useful anti-human-ErbB3 antibodies can be made using methods well known in the art.
  • art recognized anti-ErbB3 antibodies can be used.
  • Ab#3, Ab #14, Ab #17, Ab # 19, described in U.S. 7,846,440 can be used.
  • Antibodies that compete with any of these antibodies for binding to ErbB3 also can be used.
  • Additional art-recognized anti-ErbB3 antibodies which can be used include those disclosed in US 7,285,649; US20100310557; US20100255010, as well as antibodies IB4C3 and 2D ID 12 (U3 Pharma Ag), both of which are described in e.g.,
  • MM-121 also referred to in U.S. 7,846,440 as "Ab #6".
  • MM-121 binds to an extracellular domain of human ErbB3 and inhibits cellular activation by heregulin that results, e.g., in increased ErbB3 and AKT phosphorylation.
  • the MM-121 antibody comprises variable heavy (VH) and/or variable light (VL) regions encoded by the nucleic acid sequences set forth therein (and included here as SEQ ID NOs: l and 3), respectively.
  • the antibody comprises VH and/or VL regions comprising the amino acid sequences set forth therein and included here as SEQ ID NOs: 2 and 4, respectively.
  • the antibody comprises CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and/or CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3).
  • the antibody competes for binding with and/or binds to the same epitope on human ErbB3 as the above-mentioned antibodies.
  • the epitope comprises residues 92-104 of human ErbB3 (SEQ ID NO: 11).
  • the antibody binds to human ErbB3 and has at least 90% variable region sequence identity with the above-mentioned antibodies.
  • the antibody is a fully human monoclonal antibody, such as an IgG2, that binds to ErbB3 and prevents the HRG and EGF-like ligand- induced intracellular phosphorylation of ErbB3.
  • Anti-ErbB3 antibodies such as MM-121
  • MM-121 can be generated, e.g., in prokaryotic or eukaryotic cells, using methods well known in the art.
  • the antibody is produced in a cell line capable of glycosylating proteins, such as CHO cells.
  • compositions suitable for administration to a patient are typically in forms suitable for parenteral administration, e.g., in a in liquid carrier, or suitable for reconstitution into liquid solution or suspension, for intravenous administration.
  • compositions typically comprise a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable means approved by a government regulatory agency or listed in the U.S. Pharmacopeia or another generally recognized pharmacopeia for use in animals, particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, glycerol polyethylene glycol ricinoleate, and the like.
  • Water or aqueous solution saline and aqueous dextrose and glycerol solutions may be employed as carriers, particularly for injectable solutions (e.g., comprising an anti-ErbB3 antibody).
  • Liquid compositions for parenteral administration can be formulated for administration by injection or continuous infusion. Routes of administration by injection or infusion include intravenous, intraperitoneal, intramuscular, intrathecal and subcutaneous.
  • the anti-ErbB3 antibody is administered intravenously.
  • MM-121 for intravenous infusion (e.g., over the course of one hour) is supplied as a clear liquid solution in sterile, single-use vials containing 10.1 ml of MM-121 at a concentration of 25 mg/ml in an aqueous solution of 20mM histidine, 150mM sodium chloride, pH 6.5, which should be stored at 2-8°C.
  • a human patient for treatment using the subject methods and compositions has evidence of recurrent or persistent disease following primary chemotherapy.
  • the human patient suffers from colorectal cancer, colon cancer, ocular melanoma, melanoma, ovarian cancer, prostate cancer, thymic carcinoma, esophageal cancer, squamous cell skin cancer, pancreatic cancer, peritoneal cancer, salivary gland carcinoma, squamous cell head and neck cancer, non- small cell lung cancer, breast cancer, triple negative breast cancer, bladder cancer or leimyosarcoma.
  • Patients can be tested or selected for one or more of the above described clinical attributes prior to, during or after treatment.
  • anti-ErbB3 antibodies are administered to effect improvement in subjects having an advanced solid stage tumor.
  • anti-ErbB3 antibodies are administered to effect improvement in subjects having an advanced solid stage tumor.
  • the anti-ErbB3 antibody is MM- 121.
  • the anti-ErbB3 antibody is formulated for intravenous administration.
  • the anti-ErbB3 antibody is administered at a dose selected from: of 60 mg/kg, 40 mg/kg, 20 mg/kg, 15 mg/kg, 10 mg/kg, 6 mg/kg and/or 3.2 mg/kg.
  • the dose of antibody is varied over time.
  • the antibody may be initially
  • the antibody is initially administered at a low dose and increased over time.
  • Suitable treatment protocols include, for example, those wherein the anti- ErbB3 antibody is administered to a patient (i.e., human subject) once per week (at a dose of 3.2, 6, 10, 15, 20, or 40 mg/kg).
  • the anti-ErbB3 antibody is administered to a patient once per week at a dose of about 20 mg/kg or about 40 mg/kg.
  • the anti-ErbB3 antibody is
  • the anti-ErbB3 antibody is
  • a cycle of administration is four weeks. In one embodiment, the administration can be repeated, as necessary.
  • the amount of MM- 121 antibody administered is constant for each dose. In another embodiment, the amount of antibody administered varies with each dose. For example, the maintenance (or follow-on) dose of the antibody can be higher or the same as the loading dose which is first administered. In another embodiment, the maintenance dose of the antibody can be lower or the same as the loading dose.
  • responses to therapy may include:
  • patients treated according to the methods disclosed herein may experience improvement in at least one sign of cancer.
  • the patient so treated exhibits CR, PR, or SD.
  • the patient so treated experiences tumor shrinkage and/or decrease in growth rate, i.e., suppression of tumor growth.
  • unwanted cell proliferation is reduced or inhibited.
  • one or more of the following can occur: the number of cancer cells can be reduced; tumor size can be reduced; cancer cell infiltration into peripheral organs can be inhibited, retarded, slowed, or stopped; tumor metastasis can be slowed or inhibited; tumor growth can be inhibited; recurrence of tumor can be prevented or delayed; one or more of the symptoms associated with cancer can be relieved to some extent.
  • such improvement is measured by a reduction in the quantity and/or size of measurable tumor lesions.
  • Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter is to be recorded) as >10 mm by CT scan (CT scan slice thickness no greater than 5 mm), 10 mm caliper measurement by clinical exam or >20 mm by chest X-ray.
  • lesions can be measured on chest x-rays or CT or MRI films.
  • cytology or histology can be used to evaluate responsiveness to a therapy.
  • the cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease can be considered to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease.
  • administration of effective amounts of the anti- ErbB3 antibody according to any of the methods provided herein produce at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in number of metastatic lesions appearing over time, complete remission, partial remission, stable disease, increase in overall response rate, or a pathologic complete response.
  • kits that include a pharmaceutical composition containing an anti-ErbB3 antibody, such as MM-121, and a pharmaceutically-acceptable carrier, in a therapeutically effective amount adapted for use in the preceding methods.
  • the kits optionally can include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient having cancer.
  • the kit includes a syringe.
  • kits include multiple packages of the single-dose
  • composition(s) each containing an effective amount of the antibody (e.g., MM-121) for a single administration in accordance with the methods provided above.
  • an effective amount of the antibody e.g., MM-121
  • kits may provide one or more pre-filled syringes containing an amount of MM-121 that is about 100 times the dose in mg/kg indicated for administration in the above methods.
  • Example 1 Phase 1 Trial in Patients Having Solid Tumors
  • a phase 1 trial of MM-121 is conducted in patients having advanced solid tumors.
  • the study is a Phase 1 and pharmacologic open-label dose-escalation trial using a modified "3+3" design, where three or four patients are initially enrolled at a dose level and evaluated for safety. Successive cohorts of three or more patients will be treated at escalating doses until a maximum tolerated dose (or maximum target dose) is identified as described below. The study will initially explore a q 7-day dosing schedule, which may be modified to longer intervals under certain circumstances described below. An Expansion Cohort will be enrolled following demonstration of adequate MM-121 concentration levels in the dose escalation phase. The expansion cohort will further characterize safety, pharmacokinetics and explore pharmacodynamic endpoints.
  • the primary tolerability objective is to determine the Phase 2 dose based either on the maximum tolerated dose (MTD) or maximum target dose in patients with advanced solid malignancies.
  • the primary efficacy objective is to describe any objective response to MM-121 based on RECIST.
  • the secondary objectives of the study include the following:
  • the proposed dose levels for the study are shown in the table below.
  • the starting dose is 3.2 mg/kg.
  • Safety permitting, escalation will proceed in approximate half-log increments up to 10 mg/kg and then in lesser increments up to the target maximum doses.
  • additional intermediary cohorts may be explored.
  • Such cohorts may evaluate alternative dosing regimens (e.g. loading dose with different maintenance dose schedule) or weekly dosing at doses ⁇ 40 mg/kg. Additional cohorts will utilize the same 3 + 3 design and only doses ⁇ 40 mg/kg will be explored.
  • the dose will escalate to the next level only if three or more patients have been evaluated at the current dose level and the criteria for MTD have not been met.
  • a patient who experiences a dose-limiting toxicity may not receive additional doses of MM-121 and will be removed from the study. If there is evidence that a patient who experiences a DLT has also derived clinical benefit from treatment with MM-121, then the specifics of the case will be reviewed. Such a patient may continue on study at the next lower dose level if the consensus judgment, with FDA concurrence, is that continued treatment is in the patient' s best interest. Patients should have recovered from toxicity to baseline or grade 1 (except alopecia) prior to re-treatment. For hemoglobin DLTs, patients should recover to their baseline grade before re-treatment.
  • the MTD is defined as the highest dose level in which a DLT is experienced by fewer than two patients in a cohort of 3-6 patients.
  • MTD Maximum Tolerated Dose
  • Histological or cytological confirmed advanced solid tumors that have recurred or progressed following standard therapy, or that have not responded to standard therapy, or for which there is no standard therapy, or who are not candidates for standard therapy;
  • PS ECOG Performance Score
  • an effective form of contraception is an oral contraceptive or a double barrier method. This applies to women of childbearing potential as well as fertile men and their partners;
  • o Advanced/metastatic breast cancer with histologically or cytologically confirmed ER+ and/or PR+, Her2/neu non- overexpressing; OR, o Advanced/metastatic histological confirmation of epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer; OR, o Additional tumor types such as metastatic colorectal, advanced non small cell lung cancer, or others may be considered on a per-patient basis;
  • radiotherapy whose disease is stable, and who have been on a stable dose of corticosteroids for at least 2 weeks prior to the first scheduled day of dosing will be eligible for the trial;
  • MM-121 will be administered weekly (or in some circumstances, on other schedules, as described above).
  • MM-121 should be brought to room temperature prior to administration. Vials of MM-121 should not be shaken. The appropriate quantity of MM-121 will be removed from the vial, diluted in 250 mis of 0.9% normal saline and administered over 90 minutes for the first administration. MM-121 should be administered using a low protein binding 0.22 micrometer in-line filter. In the absence of an infusion reaction, subsequent doses may be administered over 60 minutes.
  • a patient' s body weight at the start of a cycle is to be used to calculate the dose used throughout the cycle. Should a patient's body weight change by 10%, a new total dose should be calculated to reflect this change.
  • the primary efficacy endpoint for this study is the objective response defined using RECIST.
  • Treatment emergent adverse events will be presented by treatment cohort, by patient, by NCI CTCAE grade and by MedDRA system organ class. Separate listings will be presented for total adverse events, serious adverse events, adverse events related to MM- 121 and Grade 3/4 adverse events will be presented.
  • Pharmacokinetic parameters will be derived from the blood PK samples and will be analyzed using descriptive statistics, including the median, mean and 95% confidence intervals around parameter estimates by dose level.
  • PK parameters will include C max , T max , AUC (area under the concentration curve), clearance, volume of distribution at steady state (Vdss), and the terminal elimination half-life. Estimation of the pharmacokinetic parameters will be performed using standard non-compartmental methods.
  • Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques (CT, MRI, x-ray) or as >10 mm with spiral CT scan. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).
  • Target lesions All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at screening. Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference by which to characterize the objective tumor response.
  • LD longest diameter
  • Non-target lesions include measurable lesions that exceed the maximum number per organ or total of all involved organs as well as non-measurable lesions. Measurements of these lesions are not required, but the presence or absence of each should be noted throughout follow-up.
  • Tumor lesions that are situated in a previously irradiated area will not be considered measurable. The following are not considered measurable lesions; bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, abdominal masses that are not confirmed and followed by imaging techniques and cystic lesions.
  • the best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
  • the patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.
  • the duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
  • the duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.
  • Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started.
  • Time-to-Progression is measured from the start of the treatment until the criteria for progression are met, taking as reference the screening measurements.
  • Survival Time is measured from the start of the treatment until death of the patient. When the last patient reaches the End of Treatment visit, all patients in the survival/follow-up period will be removed from this protocol and survival status will be monitored outside of this protocol.
  • a dose escalation study had been performed in 25 patients having advanced solid stage tumors and 6 dose levels (3.2, 6, 10, 15, 20, or 40 mg/kg). MM-121 was well tolerated with a favorable safety profile. Six patients displayed a clinical benefit, as demonstrated by stable disease.

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Abstract

La présente invention concerne des procédés et des compositions de traitement clinique de tumeurs solides à un stade avancé à l'aide d'anticorps anti-ErbB3.
PCT/US2012/022733 2011-01-27 2012-01-26 Traitement de tumeurs solides à un stade avancé à l'aide d'anticorps anti-erbb3 Ceased WO2012103341A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9085622B2 (en) 2010-09-03 2015-07-21 Glaxosmithkline Intellectual Property Development Limited Antigen binding proteins
WO2015100459A3 (fr) * 2013-12-27 2015-08-20 Merrimack Pharmaceuticals, Inc. Profils de biomarqueur pour prédire les résultats d'une thérapie cancéreuse utilisant des inhibiteurs d'erbb3 et/ou des chimiothérapies
WO2016168730A1 (fr) 2015-04-17 2016-10-20 Merrimack Pharmaceuticals, Inc. Traitements combinés avec seribantumab
WO2017160990A1 (fr) 2016-03-15 2017-09-21 Merrimack Pharmaceuticals, Inc. Méthodes de traitement du cancer du sein er+, her2-hrg+ à l'aide de traitements d'association comportant un anticorps anti-erbb3
US10184006B2 (en) 2015-06-04 2019-01-22 Merrimack Pharmaceuticals, Inc. Biomarkers for predicting outcomes of cancer therapy with ErbB3 inhibitors

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* Cited by examiner, † Cited by third party
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US20100226919A1 (en) * 2007-10-19 2010-09-09 Pharma Mar, S.A. Antitumoral Treatments
US20100266584A1 (en) * 2007-02-16 2010-10-21 Merrimack Pharmaceuticals, Inc. Antibodies against the ectodomain of erbb3 and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100266584A1 (en) * 2007-02-16 2010-10-21 Merrimack Pharmaceuticals, Inc. Antibodies against the ectodomain of erbb3 and uses thereof
US7846440B2 (en) * 2007-02-16 2010-12-07 Merrimack Pharmaceuticals, Inc. Antibodies against ErbB3 and uses thereof
US20100226919A1 (en) * 2007-10-19 2010-09-09 Pharma Mar, S.A. Antitumoral Treatments

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9085622B2 (en) 2010-09-03 2015-07-21 Glaxosmithkline Intellectual Property Development Limited Antigen binding proteins
WO2015100459A3 (fr) * 2013-12-27 2015-08-20 Merrimack Pharmaceuticals, Inc. Profils de biomarqueur pour prédire les résultats d'une thérapie cancéreuse utilisant des inhibiteurs d'erbb3 et/ou des chimiothérapies
US10273304B2 (en) 2013-12-27 2019-04-30 Merrimack Pharmaceuticals, Inc. Biomarker profiles for predicting outcomes of cancer therapy with ERBB3 inhibitors and/or chemotherapies
WO2016168730A1 (fr) 2015-04-17 2016-10-20 Merrimack Pharmaceuticals, Inc. Traitements combinés avec seribantumab
US20160303232A1 (en) * 2015-04-17 2016-10-20 Merrimack Pharmaceuticals, Inc. Combination treatments with seribantumab
US10184006B2 (en) 2015-06-04 2019-01-22 Merrimack Pharmaceuticals, Inc. Biomarkers for predicting outcomes of cancer therapy with ErbB3 inhibitors
WO2017160990A1 (fr) 2016-03-15 2017-09-21 Merrimack Pharmaceuticals, Inc. Méthodes de traitement du cancer du sein er+, her2-hrg+ à l'aide de traitements d'association comportant un anticorps anti-erbb3

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