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WO2017035482A1 - Polythérapies pour le traitement de cancers positifs à l'héréguline - Google Patents

Polythérapies pour le traitement de cancers positifs à l'héréguline Download PDF

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Publication number
WO2017035482A1
WO2017035482A1 PCT/US2016/049027 US2016049027W WO2017035482A1 WO 2017035482 A1 WO2017035482 A1 WO 2017035482A1 US 2016049027 W US2016049027 W US 2016049027W WO 2017035482 A1 WO2017035482 A1 WO 2017035482A1
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WIPO (PCT)
Prior art keywords
dose
administered
seq
composition
egfr antibodies
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PCT/US2016/049027
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English (en)
Inventor
Akos CZIBERE
Gavin Macbeath
James Murray
Rachel C. NERING
Beni B. WOLF
Olga BURENKOVA
William Kubasek
Marisa WAINSZELBAUM
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Merrimack Pharmaceuticals, Inc
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Publication of WO2017035482A1 publication Critical patent/WO2017035482A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591—Stabilisation, fragmentation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • 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

Definitions

  • the ErbB network consists of four receptor tyrosine kinases (RTKs): epidermal growth factor receptor (EGFR or ErbB 1), ErbB2 (HER2), ErbB3 (HER3) and ErbB4
  • RTKs receptor tyrosine kinases
  • HER4 multiple ErbB ligands, and downstream signaling molecules that mediate cell proliferation, survival and anti-apoptosis
  • the ErbB network is essential for growth and development of normal epithelial tissues. Deregulated ErbB signaling, however, occurs frequently in solid tumors and this enhances both aberrant tumor growth and drug resistance.
  • EGFR and ErbB2 are valid therapeutic targets with antagonists having well proven clinical activity, particularly in biomarker-defined patient populations. These include KRAS wild-type colorectal cancer (CRC), EGFR-mutant non-small cell lung cancer
  • NSCLC ErbB 3- amplified breast and gastric cancer. Less is known about ErbB3 and ErbB4. Emerging data, however, indicate that ErbB3 and its ligand, heregulin (HRG), promote clinically significant resistance to both targeted agents and chemotherapy. Despite the clinical success with EGFR and ErbB2 inhibition, de novo and acquired resistance limit clinical benefit for many patients. Accordingly, it is an object of the present invention to provide improved methods for treating patients with heregulin positive cancers.
  • HRG heregulin
  • compositions and methods for treating heregulin positive cancers ⁇ e.g., non- small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), or colorectal cancer (CRC)) in a human patient, comprising administering to the patient an anti-ErbB3 antibody and a composition of anti-EGFR antibodies according to a particular clinical dosage regimen ⁇ i.e., at a particular dose amount and according to a specific dosing schedule).
  • An exemplary anti-ErbB3 antibody is seribantumab (also known as "MM- 121 " or "Ab #6”) or antigen binding fragments and variants thereof.
  • the anti-ErbB3 antibody comprises the heavy and light chain CDRs or variable regions of seribantumab.
  • the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of seribantumab having the sequence set forth in SEQ ID NO: 10 and the CDR1,
  • the antibody comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively.
  • the antibody comprises VH and/or VL regions having the amino acid sequences set forth in SEQ ID NO: 10 and SEQ ID NO: 12, respectively.
  • the anti-ErbB3 antibody comprises VH and/or VL regions encoded by the nucleic acid sequences set forth in SEQ ID NOs: 9 and 11, respectively.
  • the anti-ErbB3 antibody comprises heavy and/or light chains having the amino acid sequences set forth in SEQ ID NO: 7 and SEQ ID NO: 8, respectively.
  • 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: 13).
  • the antibody binds all or a portion of residues 92-104 of human ErbB3 (SEQ ID NO: 13).
  • the epitope is a discontinuous epitope.
  • the antibody binds all or a portion of a discontinuous epitope comprising residues 92- 104 and 129 of human ErbB3 (SEQ ID: 13).
  • the antibody competes with seribantumab for binding to human ErbB3 and has at least 90% variable region amino acid sequence identity with the above-mentioned anti- ErbB3 antibodies (e.g., at least about 90%, 95% or 99% variable region identity with SEQ ID NO: 10 and SEQ ID NO: 12).
  • composition of anti-EGFR antibodies is MM- 151.
  • the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 14, 15, and 16 , respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 17, 18, and 19, respectively; (2) a monoclonal antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 20, 21, and 22, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 23, 24, and 25, respectively; and (3) a monoclonal antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 26, 27, and 28, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 29, 30, and 31, respectively.
  • composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising the CDRl, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 32, and the CDRl, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 33; (2) a monoclonal antibody
  • composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 32; (2) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 34 and (3) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 36.
  • composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a light chain variable region comprising SEQ ID NO: 33; (2) a monoclonal antibody comprising a light chain variable region comprising SEQ ID NO: 35; and (3) a monoclonal antibody comprising a light chain variable region comprising SEQ ID NO: 37.
  • composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 32 and a light chain variable region comprising SEQ ID NO: 33; (2) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 34 and a light chain variable region comprising SEQ ID NO: 35; and (3) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 36 and a light chain variable region comprising SEQ ID NO: 37.
  • composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 39; (2) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 41 and (3) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 43.
  • composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a light chain variable region comprising SEQ ID NO: 40; (2) a monoclonal antibody comprising a light chain variable region comprising SEQ ID NO: 42; and (3) a monoclonal antibody comprising a light chain variable region comprising SEQ ID NO: 44.
  • composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 39 and a light chain variable region comprising SEQ ID NO: 40; (2) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 41 and a light chain variable region comprising SEQ ID NO: 42; and (3) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 43 and a light chain variable region comprising SEQ ID NO: 44.
  • composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a heavy chain comprising SEG ID NO: 45 and a light chain comprising SEQ ID NO: 46; (2) a monoclonal antibody comprising a heavy chain comprising SEG ID NO: 47 and a light chain comprising SEQ ID NO: 48; and (3) a monoclonal antibody comprising a heavy chain comprising SEG ID NO: 49 and a light chain comprising SEQ ID NO: 50.
  • the anti-EGFR antibodies (1), (2), and (3) are in the composition at a molar ratio of 2:2: 1 to each other.
  • each of the anti-EGFR antibodies in the composition is a human antibody.
  • the composition of anti-EGFR antibodies comprises a pharmaceutically acceptable carrier.
  • the composition is a sterile composition. Accordingly, in one aspect, methods of treating a human patient with a heregulin positive cancer (e.g., NSCLC, SCCHN, or CRC) are provided, the methods comprising administering to the patient an anti-ErbB3 antibody and a composition of anti-EGFR antibodies.
  • the dose of the anti-ErbB3 antibody, or antigen binding fragment thereof is a flat- fixed dose that is fixed irrespective of the weight of the patient.
  • the anti-ErbB3 antibody, or antigen binding fragment thereof may be administered at a fixed dose of 0.75 g, 1.0 g, 1.5 g, or 2.0 g without regard to the patient's weight.
  • dosage regimens are adjusted to provide the optimum desired response (e.g., an effective response).
  • the dose of the composition of anti-EGFR antibodies is adjusted to the body-surface area (BSA) of the individual patient.
  • BSA body-surface area
  • the dose of the composition of anti-EGFR antibodies may be administered at a dose of 9 mg/kg or 10.5 mg/kg.
  • the composition of anti-EGFR antibodies is administered during the priming phase, prior to the start of the cycle.
  • the priming phase is a period of two weeks and the composition of anti-EGFR antibodies is administered on week one of the priming phase at a fixed dose of 225 mg.
  • the priming phase is a period of two weeks and the composition of anti-EGFR antibodies is administered on week two of the priming phase at a fixed dose of 450 mg.
  • methods of treating a human patient with a heregulin positive cancer e.g., NSCLC, SCCHN, or CRC
  • the methods comprise administering to the patient:
  • CDRL1 SEQ ID NO: 1
  • CDRL2 CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 4
  • CDRL3 CDRL1 SEQ ID NO: 5
  • CDRL3 CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 4
  • composition of anti-EGFR antibodies comprising:
  • a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3
  • the priming phase is a period of two weeks and the composition is administered on week one of the priming phase at a fixed dose of 225 mg and on week two of the priming phase at a fixed dose of 450 mg, and
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 0.75 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg;
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 0.75 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg;
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg;
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg;
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.5 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg;
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.5 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg;
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 2.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg; or
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 2.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg.
  • the composition of anti-EGFR antibodies is administered during the priming phase, prior to the start of the cycle.
  • the priming phase is a period of two weeks and the composition of anti-EGFR antibodies is administered on week one of the priming phase at a fixed dose of 225 mg.
  • the priming phase is a period of two weeks and the composition of anti-EGFR antibodies is administered on week two of the priming phase at a fixed dose of 450 mg.
  • methods of treating a human patient with a heregulin positive cancer e.g., NSCLC, SCCHN, or CRC
  • the methods comprise administering to the patient:
  • CDRL1 SEQ ID NO: 1
  • CDRL2 CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 4
  • CDRL3 CDRL1 SEQ ID NO: 5
  • CDRL3 CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 4
  • composition of anti-EGFR antibodies comprising:
  • a monoclonal antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 32, and the CDR1, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 33;
  • a monoclonal antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 34, and the CDR1, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 35;
  • a monoclonal antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 36, and the CDR1, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 37,
  • the method comprises a priming phase and a cycle
  • the priming phase is a period of two weeks and the composition is administered on week one of the priming phase at a fixed dose of 225 mg and on week two of the priming phase at a fixed dose of 450 mg, and wherein the cycle is a period of four weeks, wherein:
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 0.75 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg;
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 0.75 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg;
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg;
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg;
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.5 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg;
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.5 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg;
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 2.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg; or
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 2.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg.
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 0.75 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg.
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 0.75 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg. In another embodiment, during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg. In another embodiment, the anti-ErbB3 antibody is administered on week one of the priming phase at a fixed dose selected from the group consisting of 0.75 g, 1.0 g, 1.5 g, and 2.0 g.
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg.
  • the anti-ErbB3 antibody is administered
  • composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg.
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.5 g and the composition is administered every two weeks at a dose of 10.5 mg/kg.
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 2.0 g and the composition is administered every two weeks at a dose of 9 mg/kg.
  • the anti-ErbB3 antibody is administered once weekly at a fixed dose of 2.0 g and the composition is administered every two weeks at a dose of 10.5 mg/kg.
  • the anti-ErbB3 antibody is administered prior to the composition of anti-EGFR antibodies.
  • acetaminophen, diphenhydramine, or methylprednisone is administered prior to administration of the anti-ErbB3 antibody.
  • acetaminophen is administered at a dose of 650 mg by mouth or intravenously
  • diphenhydramine is administered at a dose of 25-50 mg by mouth or intravenously
  • methylprednisone SOLUMEDROL
  • SOLUMEDROL methylprednisone
  • acetaminophen, diphenhydramine, or methylprednisone is administered 30 - 90 minutes prior to administration of the anti-ErbB3 antibody.
  • acetaminophen, diphenhydramine, or methylprednisone is administered prior to administration of the composition of anti-EGFR antibodies (e.g., 30-90 minutes prior to the administration of the composition of anti-EGFR antibodies) in a dose described above.
  • an H2 antagonist e.g., cimetidine, ranitidine, famotidine, or nizatidine
  • an H2 antagonist is administered prior to the anti-ErbB3 antibody or the composition of anti-EGFR antibodies (on weeks when the anti-ErbB3 antibody is not administered).
  • the antibodies, or antigen binding fragments thereof, and compositions described herein can be administered to a patient by any suitable means.
  • the anti- Erb3 antibody and composition of anti-EGFR antibodies are formulated for intravenous administration.
  • the anti-ErbB3 antibody is intravenously infused over 60 minutes.
  • a first intravenous administration of the composition of anti- EGFR antibodies is infused at a rate of 25 mg/hr over 30 minutes, 50 mg/hr over 30 minutes, or 100 mg/hr until completion.
  • a second intravenous administration of the composition of anti-EGFR antibodies is infused at a rate of 25 mg/hr over 30 minutes, 50 mg/hr over 30 minutes, 100 mg/hr over 30 minutes, or 200 mg/hr until completion.
  • a third intravenous administration of the composition of anti-EGFR antibodies is infused at a rate of 50 mg/hr over 30 minutes, 100 mg/hr over 30 minutes, or 200 mg/hr over 30 minutes, or 400 mg/hr until completion.
  • fourth and subsequent intravenous administrations of the composition of anti-EGFR antibodies are infused at a rate of 100 mg/hr and advanced as tolerated.
  • seribantumab for the treatment of a heregulin-positive cancer, characterized in that the seribantumab is co-administered with MM- 151 are also contemplated.
  • the treatment produces at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in metastasis, complete remission, partial remission, stable disease, increase in overall response rate, or a pathologic complete response.
  • kits that include an anti-ErbB3 antibody, or antigen binding fragment thereof, such as seribantumab, and a pharmaceutically-acceptable carrier, and a composition of anti-EGFR antibodies, such as MM- 151, in a therapeutically effective amount adapted for use in the methods described herein.
  • the kit comprises:
  • CDRL1 amino acid sequences set forth in SEQ ID NO: 1 (CDRH1) SEQ ID NO: 2 (CDRH2) and SEQ ID NO: 37 (CDRH3)
  • CDRL1 CDRL2
  • CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 4 (CDRL1) SEQ ID NO: 5 (CDRL2) and SEQ ID NO: 6 (CDRL3);
  • composition of anti-EGFR antibodies comprising: (1) a monoclonal
  • the kit comprises:
  • CDRL1 amino acid sequences set forth in SEQ ID NO: 1 (CDRH1) SEQ ID NO: 2 (CDRH2) and SEQ ID NO: 37 (CDRH3)
  • CDRL1 CDRL2
  • CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 4 (CDRL1) SEQ ID NO: 5 (CDRL2) and SEQ ID NO: 6 (CDRL3);
  • composition of anti-EGFR antibodies comprising: (1) a monoclonal
  • Figures 1A and IB depict the effect of MM- 121 in combination with cetuximab in two head and neck cell lines in xenograft models.
  • Figure 2 depicts the results of treatment of Liml215 CRC xenograft tumors with 25Etrio (MM- 151), MM- 121, and 25Etrio plus MM- 121.
  • Figure 3 is a schematic depicting the design of the study.
  • Figure 4 is a schematic depicting the dose adjustment for skin reactions related to MM- 151 treatment.
  • Figure 5 is the schedule of assessments.
  • Figure 6 is a timeline for completing all procedures during normal business hours.
  • the term "subject” or “patient” is a human patient (e.g., a patient having a heregulin positive cancer).
  • 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.
  • Effective treatment may refer to alleviation of at least one symptom of cancer.
  • 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 can be administered in one or more administrations.
  • the term “priming phase” refers to the phase preceding the first cycle of the clinical trial (e.g., wherein the composition of anti-EGFR antibodies is administered).
  • cycle refers to the treatment phase of the clinical trial. In certain embodiments, treatment is continued as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs.
  • the terms “fixed dose”, “flat dose” and “flat-fixed dose” are used interchangeably and refer to a dose that is administered to a patient without regard for the weight or body surface area (BSA) of the patient.
  • the fixed or flat dose is therefore not provided as a mg/kg dose, but rather as an absolute amount of the agent.
  • a "body surface area (BSA)-based dose” refers to a dose of the agent that is adjusted to the body-surface area (BSA) of the individual patient.
  • a BSA-based dose may be provided as mg/kg body weight.
  • Du Bois formula see Du Bois D, Du Bois EF (Jun 1916) Archives of Internal Medicine 17 (6): 863- 71; and Verbraecken, J. et al. (Apr 2006). Metabolism— Clinical and Experimental 55 (4): 515-24).
  • Other exemplary BSA formulas include the Mosteller formula (Mosteller RD.
  • inhibitor refers to any statistically significant decrease in biological activity, including full blocking of the activity.
  • inhibitor can refer to a statistically significant decrease of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 100% in biological activity.
  • the phrase "inhibition of cell growth,” as used herein, refers to the ability of an antibody or antibody mixture to statistically significantly decrease the growth of a cell relative to the growth of the cell or cells in the absence of the antibody (control) either in vivo or in vitro.
  • the growth of a cell e.g., a cancer cell
  • the growth of a cell may be decreased by at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or about 100% when the cells are contacted with the combination disclosed herein, relative to the growth measured in the absence of the combination (control) or when the cells are contacted with a single species of monoclonal antibody.
  • Cellular growth can be assayed using art recognized techniques which measure the rate of cell division, the fraction of cells within a cell population undergoing cell division, and/or the rate of cell loss from a cell population due to terminal differentiation or cell death (e.g., using a CELLTITER-GLO or similar assay).
  • treat refers to therapeutic or preventative measures described herein.
  • the methods of “treatment” employ administration to a subject, the combination disclosed herein in order to prevent, cure, delay, reduce the severity of, or ameliorate one or more symptoms of the disease or disorder or recurring disease or disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • sample refers to tissue, body fluid, or a cell (or a fraction of any of the foregoing) taken from a patient. Normally, the tissue or cell will be removed from the patient, but in vivo diagnosis is also contemplated. In the case of a solid tumor, a tissue sample can be taken from a surgically removed tumor and prepared for testing by
  • lymphomas and leukemias lymphocytes, leukemic cells, or lymph tissues can be obtained (e.g. , leukemic cells from blood) and appropriately prepared.
  • Other samples including urine, tears, serum, plasma, cerebrospinal fluid, feces, sputum, cell extracts etc. can also be useful for particular cancers.
  • antibody describes polypeptides comprising at least one antibody derived antigen binding site (e.g., VH/VL region or Fv, or CDR).
  • 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 by a protein engineering technique (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 or engineered polypeptide constructs which comprise at least one antibody-derived antigen binding site.
  • an antibody binds to a protein antigen and/or the affinity for an antibody to a protein antigen are known in the art.
  • the binding of an antibody to a protein antigen can be detected and/or quantified using a variety of techniques such as, but not limited to, Western blot, dot blot, surface plasmon resonance (SPR) method (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.), or enzyme-linked immunosorbent assay (ELISA).
  • SPR surface plasmon resonance
  • ELISA enzyme-linked immunosorbent assay
  • k a refers to the rate constant for association of an antibody to an antigen.
  • the term refers to the rate constant for dissociation of an antibody from the antibody/antigen complex.
  • the antibody competes for binding with, and/or binds to the same epitope on a target antigen as, the antibodies described herein.
  • the term "binds to the same epitope" with reference to two or more antibodies means that the antibodies bind to the same segment of amino acid residues, as determined by a given method.
  • Techniques for determining whether antibodies bind to the "same epitope" with the antibodies described herein include, for example, epitope mapping methods, such as, x-ray analyses of crystals of antigen: antibody complexes which provides atomic resolution of the epitope and
  • HDX-MS hydrogen/deuterium exchange mass spectrometry
  • Antibodies that "compete with another antibody for binding to a target” refer to antibodies that inhibit (partially or completely) the binding of the other antibody to the target. Whether two antibodies compete with each other for binding to a target, i.e., whether and to what extent one antibody inhibits the binding of the other antibody to a target, may be determined using known competition experiments. In certain embodiments, an antibody competes with, and inhibits binding of another antibody to a target by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%. The level of inhibition or competition may be different depending on which antibody is the "blocking antibody” (i.e., the cold antibody that is incubated first with the target). Competing antibodies bind to the same epitope, an overlapping epitope or to adjacent epitopes (e.g., as evidenced by steric hindrance).
  • Antibodies, or antigen-binding fragments thereof described herein, used in the methods described herein can be generated using a variety of art-recognized techniques. Monoclonal antibodies may be obtained by various techniques familiar to those skilled in the art. Briefly, spleen cells from an animal immunized with a desired antigen are immortalized, commonly by fusion with a myeloma cell (see, Kohler & Milstein, Eur. J. Immunol. 6: 511- 519 (1976)). Alternative methods of immortalization include transformation with Epstein Barr Virus, oncogenes, or retroviruses, or other methods well known in the art.
  • Colonies arising from single immortalized cells are screened for production of antibodies of the desired specificity and affinity for the antigen, and yield of the monoclonal antibodies produced by such cells may be enhanced by various techniques, including injection into the peritoneal cavity of a vertebrate host.
  • ErbB3 refers human ErbB3 protein, as described in U.S. Pat. No. 5,480,968 and Plowman et al, Proc. Natl. Acad. Sci. USA, 87:4905-4909 (1990); see, also, Kani et al, Biochemistry 44: 15842-857 (2005), Cho and Leahy, Science 297: 1330-1333 (2002)).
  • the protein sequence of human ErbB3 is set forth in SEQ ID NO: 13.
  • the term “heregulin” (HRG) refers to an ErbB3 ligand that activates ErbB3, thereby initiating intracellular signaling in tumor cells.
  • a "heregulin positive cancer” is a cancer which expresses heregulin.
  • Heregulin can be detected, for example, using a chromogenic RNA-In Situ Hybridization Assay (RNA- ISH), e.g., as described in WO 2015/100459, the teachings of which are expressly incorporated herein by reference.
  • RNA- ISH chromogenic RNA-In Situ Hybridization Assay
  • EGFR human EGFR protein
  • HER1 also referred to as ErbB l or HER1
  • EGFR-ECD The EGFR extracellular domain, or EGFR-ECD, is the portion of the EGFR protein that extends beyond the cell surface in vivo, and is thus accessible to antibodies on the exterior of the cell.
  • the wild-type EGFR-ECD protein sequence is SEQ ID NO:38.
  • an "EGFR-ECD mutation” or a “mutation in the extracellular domain of EGFR” may refer to an EGFR-ECD protein sequence with a difference in at least one amino acid residue as compared to the wild type sequence; an "EGFR-ECD mutation” may also refer to a change in that portion of the DNA or RNA coding sequence that corresponds to a change in the protein sequence of the extracellular domain of EGFR. In some embodiments, the change in the DNA or RNA coding sequence occurs in exon 12 of the EGFR gene or transcript. In other embodiments, the EGFR-ECD mutation is a change in the protein sequence
  • Anti-ErB3 antibodies (or VH/VL domains derived therefrom) suitable for use in the invention can be generated using methods well known in the art. Alternatively, art recognized anti-ErbB3 antibodies can be used. Antibodies that compete with any of these art-recognized antibodies for binding to ErbB3 also can be used.
  • An exemplary anti-ErbB3 antibody is seribantumab (also known as “MM- 121 " or "Ab
  • Seribantumab is a human
  • the anti-ErbB3 antibody comprises the heavy and light chain CDRs or variable regions of seribantumab. Accordingly, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of seribantumab having the sequence set forth in SEQ ID NO: 10 and the CDR1, CDR2 and CDR3 domains of the VL region of seribantumab having the sequence set forth in SEQ ID NO: 12. In another embodiment, the antibody comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively.
  • the antibody comprises VH and/or VL regions having the amino acid sequences set forth in SEQ ID NO: 10 and SEQ ID NO: 12, respectively.
  • the anti-ErbB3 antibody comprises VH and/or VL regions encoded by the nucleic acid sequences set forth in SEQ ID NOs: 9 and 11, respectively.
  • the anti-ErbB3 antibody comprises heavy and/or light chains having the amino acid sequences set forth in SEQ ID NO: 7 and SEQ ID NO: 8, respectively.
  • 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: 13).
  • the antibody competes with seribantumab 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.
  • compositions of anti-EGFR antibodies (or VH/VL domains derived therefrom) suitable for use in the invention can be generated using methods well known in the art.
  • compositions comprising art recognized anti-EGFR antibodies, such as Syi 004 (Symphogen), can be used.
  • Antibodies that compete with any of these art-recognized antibodies for binding to EGFR also can be used.
  • MM-151 is an oligoclonal therapeutic consisting of a mixture of three fully human monoclonal antibodies designed to bind and inhibit signaling of the Epidermal Growth Factor Receptor (EGFR).
  • MM- 151 is a mixture of three independent antibodies (PIX + P2X + P3X), which to three non-overlapping sites on EGFR to maximize inhibition of ligand-dependent and independent signaling (see, e.g., WO 2013/006547 and Kearns et al., 2015, Mol. Cancer Ther., 14: 1625-36, the teachings of both of which are expressly incorporated herein by reference).
  • PIX, P2X, and P3X correspond to CAS Registry Numbers 1509928-01- 1, 1509928-02-2, and 1509928-03-3, respectively.
  • the PIX, P2X and P3X monoclonal antibodies are affinity matured antibodies of parental antibodies referred to as ca, cd and ch, respectively, disclosed in WO 2011/140254, the teachings of which are expressly incorporated herein by reference.
  • the CDR amino acid sequences of PIX, P2X and P3X are shown below:
  • V H and V L amino acid sequences (including leader sequences) for PIX are shown in SEQ ID NO: 32 and SEQ ID NO: 33, respectively.
  • the full-length V H and VL amino acid sequences (including leader sequences) for P2X are shown in SEQ ID NO: 34 and SEQ ID NO:35, respectively.
  • VH and VL CDR segments as presented herein are arranged, e.g., in the amino to carboxy terminal order of CDR1 , CDR2 and CDR3.
  • the mature full-length V H and V L amino acid sequences for P1X are shown in SEQ ID NO: 39 and SEQ ID NO: 40, respectively.
  • the mature full-length V H and V L amino acid sequences for P2X are shown in SEQ ID NO: 41 and SEQ ID NO: 42, respectively.
  • the mature full-length V H and V L amino acid sequences for P3X are shown in SEQ ID NO: 43 and SEQ ID NO: 44, respectively.
  • mature heavy and light chain variable region sequences do not include leader sequences, since the leader sequences are ultimately cleaved from the mature variable regions sequences.
  • the mature heavy and light chain variable regions sequences are inherent regions within the precursor sequences that can readily be identified using well established rules and art-recognized techniques. Based on known CDR and consensus sequences, one of ordinary skill in the art can identify the residues corresponding to the beginning and end of the variable regions (and thus, also the mature portion), as taught, for example, by Roguska et al. (Proc. Nati. Acad. Sci. USA, Vol. 91, pp. 969-973, February 1994).
  • the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 14, 15, and 16, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 17, 18, and 19, respectively; (2) a monoclonal antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 20, 21, and 22, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 23, 24, and 25, respectively; and (3) a monoclonal antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 26, 27, and 28, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 29, 30, and 31, respectively.
  • CDRs can be defined differently according to different methods.
  • the positions of the CDRs or framework regions within a light or heavy chain variable domain can be as defined by Kabat et al. [(1991) "Sequences of Proteins of Immunological Interest.” NIH Publication No. 91-3242, U.S.
  • the CDRs can be referred to as “Kabat CDRs” (e.g., “Kabat LCDR2” or “Kabat HCDR1").
  • the positions of the CDRs of a light or heavy chain variable region can be as defined by Chothia et al. (1989) Nature 342:877-883. Accordingly, these regions can be referred to as “Chothia CDRs” (e.g., “Chothia LCDR2” or “Chothia HCDR3").
  • the positions of the CDRs of the light and heavy chain variable regions can be as defined by a Kabat-Chothia combined definition.
  • these regions can be referred to as “combined Kabat-Chothia CDRs".
  • Thomas et al. [(1996) Mol Immunol 33(17/18): 1389-14011 exemplifies the identification of CDR boundaries according to Kabat and Chothia definitions.
  • the positions of the CDRs or framework regions within a light or heavy chain variable domain can be as defined by the international ImMunoGeneTics database (IMGT) standard. Marie-Paule Lefranc et al. [(2003)
  • IMGT CDRs ⁇ e.g., "IMGT-LCDR2" or “IMGT-HCDR3"
  • the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising the CDRl, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 32, and the CDRl, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 33; (2) a monoclonal antibody comprising the CDRl, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 34, and the CDRl, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 35; and (3) a monoclonal antibody comprising the CDRl, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 36, and the CDRl, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 37.
  • composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 32; (2) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 34 and (3) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 36.
  • composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a light chain variable region comprising SEQ ID NO: 33; (2) a monoclonal antibody comprising a light chain variable region comprising SEQ ID NO: 35; and (3) a monoclonal antibody comprising a light chain variable region comprising SEQ ID NO: 37.
  • composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 32 and a light chain variable region comprising SEQ ID NO: 33; (2) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 34 and a light chain variable region comprising SEQ ID NO: 35; and (3) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 36 and a light chain variable region comprising SEQ ID NO: 37.
  • composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising the mature portion of the heavy chain variable region comprising SEQ ID NO: 32 and the mature portion of the light chain variable region comprising SEQ ID NO: 33; (2) a monoclonal antibody comprising the mature portion of the heavy chain variable region comprising SEQ ID NO: 34 and the mature portion of the light chain variable region comprising SEQ ID NO: 35; and (3) a monoclonal antibody comprising the mature portion of the heavy chain variable region comprising SEQ ID NO: 36 and the mature portion of the light chain variable region comprising SEQ ID NO: 37.
  • composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising residues 20-140 of the heavy chain variable region SEQ ID NO: 32 and residues 21-127 of the light chain variable region comprising SEQ ID NO: 33; (2) a monoclonal antibody comprising residues 20-138 of the heavy chain variable region comprising SEQ ID NO: 34 and residues 21-133 of the light chain variable region comprising SEQ ID NO: 35; and (3) a monoclonal antibody comprising residues 20-142 of the heavy chain variable region comprising SEQ ID NO: 36 and residues 21-128 of the light chain variable region comprising SEQ ID NO: 37.
  • composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 39 and a light chain variable region comprising SEQ ID NO: 40; (2) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 41 and a light chain variable region comprising SEQ ID NO: 42; and (3) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 43 and a light chain variable region comprising SEQ ID NO: 44.
  • composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a heavy chain comprising SEQ ID NO: 45 and a light chain comprising SEQ ID NO: 46; (2) a monoclonal antibody comprising a heavy chain comprising SEQ ID NO: 47 and a light chain comprising SEQ ID NO: 48; and (3) a monoclonal antibody comprising a heavy chain comprising SEQ ID NO: 49 and a light chain comprising SEQ ID NO: 50.
  • the anti-EGFR antibodies (1), (2), and (3) are in the composition at a molar ratio of 2:2: 1 to each other.
  • the anti-ErbB3 antibodies and/or anti-EGFR antibodies can be formulated as pharmaceutical solutions, e.g., for administration to a subject for the treatment of cancer.
  • the pharmaceutical compositions will generally include a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier refers to, and includes, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • compositions can include a pharmaceutically acceptable salt, e.g., an acid addition salt or a base addition salt, sugars, carbohydrates, polyols and/or tonicity modifiers.
  • compositions can be formulated according to standard methods.
  • Pharmaceutical formulation is a well-established art, and is further described in, e.g., Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20 th Edition, Lippincott, Williams & Wilkins (ISBN: 0683306472); Ansel et al. (1999) "Pharmaceutical Dosage Forms and Drug Delivery Systems," 7 th Edition, Lippincott Williams & Wilkins Publishers (ISBN:
  • compositions can be in a variety of forms. These forms include, e.g., liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
  • liquid solutions e.g., injectable and infusible solutions
  • dispersions or suspensions tablets, pills, powders, liposomes and suppositories.
  • the preferred form depends, in part, on the intended mode of administration and therapeutic application.
  • compositions containing a composition intended for systemic or local delivery can be in the form of injectable or infusible solutions.
  • compositions can be formulated for administration by a parenteral mode (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection).
  • parenteral mode e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection.
  • parenteral administration e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection.
  • parenteral administration e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection.
  • parenteral mode e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection.
  • Treatment outcomes can be evaluated using standard measures for tumor response.
  • Target lesion (tumor) responses to therapy are classified as:
  • CR Complete Response
  • PR Partial Response
  • PD Progressive Disease
  • Stable Disease Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. (Note: a change of 20% or less that does not increase the sum of the diameters by 5 mm or more is coded as stable disease). To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once after study entry at a minimum interval of 6 weeks.
  • Non-target lesion responses to therapy are classified as:
  • CR Complete Response
  • Non-CR/Non-PD Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits
  • Progressive Disease (PD) Either or both of appearance of one or more new lesions and unequivocal progression of existing non-target lesions.
  • unequivocal progression must be representative of overall disease status change, not a single lesion increase.
  • the treatment may produce at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in metastasis, complete remission, partial remission, stable disease, increase in overall response rate, or a pathologic complete response.
  • Response may also be 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.
  • non-target lesions e.g., pathological lymph nodes
  • Lesions can be measured using, e.g., x-ray, CT, or MRI images.
  • Microscopy, cytology or histology can be also used to evaluate responsiveness to a therapy. An effusion that appears or worsens during treatment when a measurable tumor has otherwise met criteria for response or stable disease can be considered to indicate tumor progression, but only if there is cytological confirmation of the neoplastic origin of the effusion.
  • the patient so treated experiences tumor shrinkage and/or decrease in growth rate, i.e., suppression of tumor growth.
  • tumor cell proliferation is reduced or inhibited.
  • 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.
  • Other indications of a favorable response include reduction in the quantity and/or size of measurable tumor lesions or of non-target lesions.
  • kits which include a dose of an anti-ErbB3 antibody (such as seribantumab), or an antigen binding fragment thereof, and a dose of a composition of anti-EGFR antibodies (such as MM- 151), in a therapeutically effective amount adapted for use in the preceding methods.
  • the kits optionally also 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 also can include a syringe. Instruments or devices necessary for administering the
  • composition(s) also may be included in the kits.
  • the present invention provides a kit comprising:
  • CDRL1 amino acid sequences set forth in SEQ ID NO: 1 (CDRH1) SEQ ID NO: 2 (CDRH2) and SEQ ID NO: 37 (CDRH3)
  • CDRL1 CDRL2
  • CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 4 (CDRL1) SEQ ID NO: 5 (CDRL2) and SEQ ID NO: 6 (CDRL3);
  • composition of anti-EGFR antibodies comprising: (1) a monoclonal
  • antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NO:
  • the present invention provides a kit comprising:
  • CDRL1 sequences comprising the amino acid sequences set forth in SEQ ID NO: 1 (CDRH1) SEQ ID NO: 2 (CDRH2) and SEQ ID NO: 37 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 4 (CDRL1) SEQ ID NO: 5 (CDRL2) and SEQ ID NO: 6 (CDRL3); B.
  • a dose of a composition of anti-EGFR antibodies comprising: (1) a monoclonal antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 32, and the CDR1, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 33; (2) a monoclonal antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 34, and the CDR1, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 35; and (3) a monoclonal antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 36, and the CDR1, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 37; and
  • MM-121 in combination with cetuximab was explored in two head and neck cell lines in xenograft models.
  • Mice were treated with PBS control, cetuximab, MM-121 at low (LD) and high (HD) doses, or the combinations.
  • Tumor volumes were measured three times a week (Figure 1A) and tumors were harvested and weighed after treatment ( Figure IB).
  • Figure 1A For the Tu212 xenograft model, a similar result was found with both cetuximab and MM-121 monotherapies showing intermediate effects and the combination having great potency.
  • the SCC47 xenograft model was found to be highly sensitivity to MM-121 and this drug alone was enough to halt tumor growth.
  • MM-151 has poor pharmacokinetics in mice due to cross-reactivity with mouse EGFR.
  • the equivalent tri-clonal mixture used in place of MM- 151 is referred to as "25Etrio".
  • Figure 2 shows the steady growth of untreated Liml215 tumors (PBS) and slowed tumor growth with 25Etrio or MM- 121 monotherapies. The 25Etrio plus MM-121 appeared to halt tumor growth and cause some tumor regression.
  • the primary aim of the dose escalation is to define the safety, tolerability, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), pharmacokinetic (PK), potential immunogenicity, and ErbB biomarker levels for the MM-151 plus MM-121 combination in advanced colorectal cancer (CRC), squamous cell carcinoma of the head and neck (SCCHN) and non-small cell lung cancer (NSCLC).
  • MTD maximum tolerated dose
  • R2D recommended Phase 2 dose
  • PK pharmacokinetic
  • potential immunogenicity potential immunogenicity
  • ErbB biomarker levels for the MM-151 plus MM-121 combination in advanced colorectal cancer (CRC), squamous cell carcinoma of the head and neck (SCCHN) and non-small cell lung cancer (NSCLC).
  • the primary aim of the dose expansion is to further characterize safety, biomarker levels and to assess the preliminary clinical activity of the MM-151 plus MM-121 combination when administered at the maximum tolerated dose in CRC patients that are KRAS wild-type.
  • CRC treated with MM-151 plus MM-121 include: describing the dose limiting toxicities (DLTs), characterizing the adverse event profile, determining the pharmacokinetic parameters, determining the immunogenicity parameters, assessing the 8, 16 and 24 week disease control rates (RECIST stable disease (SD), RECIST partial response (PR), or RECIST complete remission (CR)), assessing Progression Free Survival (PFS) based on RECIST 1.1, describing any objective response based on RECIST vl.l, assessing ErbB pathway biomarkers in pre-treatment tumor biopsies and archived tissue samples, assessing the pharmacodynamic effects of treatment on heregulin mRNA and on ErbB pathway activation via pre- and on-treatment tumor biopsies, and exploring the relationship between clinical activity (and/or toxicity) and changes in blood and additional tissue biomarkers.
  • DLTs dose limiting toxicities
  • SD 8, 16 and 24 week disease control rates
  • PR RECIST partial response
  • CR RECIST complete remission
  • the overall study design is depicted in Figure 3.
  • the study is a two-part Phase 1, non-randomized, open-label study of MM- 151 plus MM- 121 in patients with advanced, heregulin -positive cancers.
  • patients Following signing informed consent and evaluation of initial eligibility criteria, patients provide a tissue sample to a central lab facility for heregulin testing. Recent tumor tissue can be used for the heregulin assessment if it was collected in the last 6 months, otherwise, a fresh biopsy should be collected. If a fresh biopsy is collected, investigators should choose an easily accessible tumor lesion to minimize any possible risk associated with the collection of the tissue. As a general guideline, if the selected procedural location has an established serious complication rate of >2% at the institution completing the procedure, this is considered a high-risk procedure and should be avoided.
  • the central lab analyzes the tumor sample for heregulin levels utilizing in-situ hybridization (ISH).
  • ISH in-situ hybridization
  • Part 1 is a dose escalation to determine the safety, tolerability and maximum tolerated dose/recommended Phase 2 dose of MM-151 plus MM-121 in heregulin -positive SCCHN, NSCLC or CRC cancers.
  • cohorts of 3 or 4 patients are enrolled in a 3 + 3 design to assess the safety and pharmacokinetic properties and to establish the maximum tolerated dose or recommended Phase 2 dose of the MM-121 plus MM-151 combination.
  • Pretreatment biopsies, recent tumor tissue, and archived samples are evaluated for heregulin mRNA levels and other pathway biomarkers.
  • the MM-121 program has demonstrated in multiple indications (breast, ovarian, lung), that elevated heregulin expression in tumor tissue may predict response to MM-121 (see, e.g., Liu, Joyce, et al, J. Clin. Oncol. 32:5s, 2014 (suppl; abstr 5519) (2014), Cleary, JM, et al, J. Clin. Oncol 32:5s, 2014 (suppl; abstr 3076) (2014), Higgins, M, et al, J. Clin. Oncol.
  • Blood samples are taken at various time points during the study to determine the PK of MM-151 and MM-121 when administered in combination, as well as related pathway biomarkers.
  • Cycles are repeated every 4 weeks until disease progression, intolerable toxicity or other reason for study termination.
  • Three or four patients are enrolled initially into each dose escalation cohort of the study. After the third patient enrolled in a cohort has completed the 6 week dose limiting toxicity window, the data is evaluated. If the safety profile is acceptable, enrollment proceeds to the next cohort.
  • MM-151 is dosed once weekly (QW) and MM-121 is dosed every two weeks (Q2W).
  • MM-121 is administered first. It is intended that patients are treated until disease progression or intolerable toxicity.
  • the safety profile in the 6 week dose limiting toxicity window which begins from the date of first dose of study drug, is used to inform decisions about dose escalations for the next cohort. A patient must receive at least three of his/her planned doses of the combination to be considered evaluable for a dose escalation decision.
  • each dose level includes at least one patient enrolled from each site. However, the goal is to enroll all patients in a cohort within a two-week period. If a site does not anticipate identifying a patient within these two weeks, one or more additional patient may come from any site.
  • MM-121 is administered prior to MM-151 administration on weeks when they are administered together.
  • the first two doses of MM-151 are priming doses of 225 mg and 450 mg.
  • the third dose starts Cycle 1 Week 1 at the dose levels listed.
  • Dosing begins at Dose Level 1A.
  • a 6-week dose limiting toxicity evaluation window that includes a 2 week priming phase for MM-151 and a four week cycle 1 is used for dose escalation decisions. If no dose limiting toxicity is observed in a cohort of 3 patients, escalation proceeds to Level 2A and then Level 3A. If a dose limiting toxicity is observed in the first 3 patients enrolled into an "A" cohort, a total of 6 patients are enrolled in the current cohort and assessed for safety and tolerability. If there is no more than 1 patient with a dose limiting toxicity in a cohort of 6 patients in a given dose level, enrollment commences to the next "A" dose level.
  • Dose levels -1A or - IB are only be enrolled in the event that dose levels 1A and IB result in observed toxicity which limits further dosing. Dose levels 1B-3B are only be enrolled if observed toxicity limits further dosing in dose levels 1A-3A. For example, if a dose limiting toxicity is observed in dose level 2A, the next cohort enrolled is dose level 2B. Intermediate MM- 151 and MM-121 doses or alternate dosing schedules can be explored.
  • a 6 week dose limiting toxicity evaluation window that includes a two week priming phase for MM- 151 plus a four week cycle 1, is employed for dose escalation decisions in Part 1 of the study.
  • MM- 151 and MM- 121 administered in combination the following adverse events are considered dose limiting if they occur within six weeks of the date of first dose of study drug, and the relatedness is possible, probable or definite with regards to the combination:
  • a patient who experiences a dose-limiting toxicity does not receive additional doses of MM-151 or MM-121 and is removed from the study. If there is evidence that a patient who experiences a dose limiting toxicity has also derived clinical benefit from treatment with the MM-151 and MM-121, then the specifics of the case are reviewed. Such a patient may continue on study at a lower dose level if the consensus judgment is that continued treatment is in the patient' s best interest. Patients should have recovered from toxicity to baseline (except alopecia) prior to re-treatment.
  • the maximum tolerated dose is defined as the highest dose level at which a dose limiting toxicity is experienced by fewer than 2 patients in a cohort of 3 to 6 patients. If a patient experiences a treatment-related toxicity that qualifies as a dose limiting toxicity, up to 3 additional patients are enrolled at that dose level, for no more than 6 total patients. If no additional dose limiting toxicities are observed, the dose escalation resumes. If a second patient experiences a treatment-related toxicity that qualifies as a dose limiting toxicity at that dose, that dose is considered the toxic dose.
  • the maximum tolerated dose is then defined as the next lower dose level and an additional 3 patients are enrolled (for a total of 6) to ensure that ⁇ 1 patient out of 6 experienced a treatment-related toxicity that qualifies as a dose limiting toxicity. If a maximum tolerated dose is not declared, a recommended Phase 2 dose is determined by assessing the overall safety and tolerability, pharmacokinetic,
  • AST Aspartate aminotransferase
  • ALT Alanine aminotransferase
  • Alkaline Phosphatase ⁇ 2.5 x ULN ⁇ 5 x ULN is acceptable if bone or liver metastases are present
  • Serum electrolytes (potassium, magnesium, calcium and phosphate) within
  • NSCLC Non-Small Cell Lung Cancer
  • Untreated (primary) or symptomatic CNS (primary or metastatic) malignancies patients with CNS metastases who have undergone surgery or radiotherapy or who have been on a stable dose of corticosteroids (e.g. 8 mg dexamethasone) for at least 2 weeks and whose disease is stable prior to the first scheduled day of dosing is eligible for the trial.
  • corticosteroids e.g. 8 mg dexamethasone
  • RNA-ISH RNA in situ hybridization
  • RNA-ISH is a test in which oligonucleotide target probes are hybridized to the RNA in formalin-fixed, paraffin-embedded (FFPE) tissue samples. The signal on the target RNA molecule is detected by using a chromogenic substrate reaction. This approach enables mRNA molecules to be visualized and scored by pathologists in a manner similar to a standard immunohistochemistry assay.
  • FFPE paraffin-embedded
  • the heregulin RNA-ISH assay can measure mRNA expression on tissue slides obtained from recent tumor tissue blocks, core biopsies or fine needle aspirates. Any of these methods of collection are therefore acceptable for testing, as long as the patient did not receive intervening systemic therapy between the time of tissue collection and screening for this study. Clinical trial specimens are submitted directly by clinical sites to a certified facility, in 70% ethanol.
  • the facility processes the samples and provides the stained slides to a trained pathologist to assess tumor content and percentage of tumor cells expressing heregulin mRNA.
  • the pathologist assigns scores of 0, 1+, 2+ or 3+ based on heregulin mRNA staining. Samples scored at > 1+ are considered heregulin positive, and samples scored at 0 are considered heregulin negative. The results are communicated back to the investigative site within 7 days of site shipment date.
  • the Investigator removes the patient from the trial in the best interests of the patient;
  • MM-121 is supplied in sterile, single-use vials containing 10.1 mL of MM-121 at a concentration of 25 mg/ml in 20 mM histidine, 150 mM sodium chloride, and pH 6.5. MM- 121 appears as a colorless liquid solution and may contain a small amount of visible, white, amorphous, MM-121 particulates.
  • MM-121 is stored refrigerated (2 to 8°C, 35.6 to 46.4°F) with protection from light. Light protection is not required during infusion. MM-121 is not frozen. The pharmacy is provided with expiration dates for stored MM-121. Stability data are generated on a continual basis and the expiration date is continually updated by notification to the pharmacy.
  • MM-121 Twenty vials of MM-121 are packaged in a cardboard container. The individual vials, as well as the outside of the cardboard container, are labeled in accordance with local regulatory requirements.
  • MM-121 is administered as an intravenous infusion once every 2 weeks as a fixed dose. Administration of MM-121 requires multiple vials, all of which come from the same lot number.
  • MM-121 is brought to room temperature prior to mixing with saline. Vials of MM- 121 are not shaken.
  • the appropriate quantity of study drug is removed from the vial, diluted in 250 mL of 0.9% normal saline and administered over 60 minutes (+15 minutes) for all infusions, in the absence of infusion reactions, using a low protein binding 0.22 micrometer in-line filter. The line is flushed before and after the study drug infusion. Study drug is not administered as a bolus or a push.
  • MM-121 is dosed first, followed by MM-151.
  • MM-151 is stored refrigerated (2 to 8°C, 35.6 to 46.4°F) and protected from light. MM-151 diluted in saline can be held at room temperature for up to 4 hours before infusion. MM-151 is not frozen. The pharmacy is provided with expiration dates for stored MM-151. Stability data are generated on a continual basis and the expiration date is continually updated by notification to the pharmacy. Vials of MM-151 are not used beyond their date of stability.
  • MM-121 is dosed first, followed by MM-151.
  • MM-151 premedication On days when MM-121 is not administered, MM-151 premedication is administered 30-90 minutes prior to MM-151 infusion) with one of the following:
  • the first two doses of MM-151 are administered during a two week priming phase.
  • the first priming dose is given as a fixed dose of 225 mg in week 1 and the second priming dose is given as a fixed dose of 450 mg in week 2 (Table 2). Subsequent dose levels are given as per the dose level defined for Cycle 1.
  • mpk Note cycle 1 and subsequent weekly doses of MM-151 are the mg/kg dose level of the current cohort.
  • the MM-151 infusion rate are increased over time as outlined in Table 3 below.
  • MM-151 is brought to room temperature prior to administration. Vials of MM-151 are not shaken. The appropriate quantity of MM-151 is removed from the vial, diluted to a final concentration of 2 mg/ml in 0.9% normal saline and administered according to the infusion rate in Table 4. MM-151 is administered using a low protein binding 0.22 micrometer in-line filter. The line is flushed before and after MM- 151 infusion. MM- 151 is not administered as a bolus or a push.
  • a patient' s body weight at the start of a cycle (or Priming Phase), at a minimum, is used to calculate the dose used throughout the cycle. If site-specific policies advise more frequent measurement of a patient's body weight to calculate dose, that is acceptable. Should a patient' s body weight change by 10%, as compared to Day 1 of the current cycle, a new total dose is calculated to reflect this change.
  • Patients are monitored for 1 hour following MM- 151 infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., Epinephrine, corticosteroids, intravenous antihistamines, bronchodilators and oxygen). Longer monitoring is required to confirm resolution of the event in patients requiring treatment for infusion reactions.
  • agents necessary to treat anaphylaxis e.g., Epinephrine, corticosteroids, intravenous antihistamines, bronchodilators and oxygen.
  • the patient may be rechallenged with MM- 151 and MM- 121
  • anti-MM-151 and anti-MM-121 antibody assays are obtained within 24 hours following the event. Patients experiencing severe Grade 4 hypersensitivity reactions to MM-151 or MM-121, despite the use of premedication, are not re-challenged. Such reactions, including hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema or generalized urticaria, require immediate discontinuation of MM-151/MM-121 and aggressive symptomatic therapy, in accordance with institutional practice and investigator discretion.
  • Serum electrolytes from a recent pre-study collection including magnesium, potassium and calcium, are checked on the day of infusion and repleted as necessary.
  • Electrolyte monitoring is continued per the Schedule of Assessments. Electrolytes are replaced as necessary. Isolated, clinically non- significant electrolyte abnormalities do not require dose reduction.
  • Grade 1 Monitor electrolytes per schedule of assessments and if hypomagnesemia worsens, follow guidelines below.
  • Acneiform rash and other dermatologic toxicities are common toxicities of EGFR-targeted treatment. Patients are monitored throughout the course of therapy for skin and soft tissue toxicities and
  • Tables 5 - 8 summarize treatment guidances for dermatologic toxicities related to anti-EGFR therapies
  • ADL Body emollient or emollient with urea
  • Mucositis/Stomatitis Mouth ulcers, stomatitis and oral mucositis have been seen with the treatment of MM- 151 and can occur with the combination of MM-151 and MM- 121.
  • Treatments with or without topical corticosteroids Treatment with or without topical corticosteroids.
  • Agents containing hydrogen peroxide, iodine, and thyme derivatives tend to worsen mouth ulcers and are avoided.
  • Anti-fungal agents are avoided unless a fungal infection is diagnosed, in which case topical antifungal agents are preferred.
  • MM-151 and MM-121 therapy is held for up to 28 days to allow for recovery from toxicity. If a patient does not recover from toxicity within 28 days, the patient's continuation on study is discussed regarding risks and benefits of continuation.
  • the dose limiting toxicity evaluation window if a patient experiences a toxicity requiring more than one held doses (e.g. one week off treatment), the patient's continuation is discussed and the event is evaluated for dose limiting toxicity criteria.
  • MM-121 a typical dose reduction schedule is from 2 to 1.5 to 1 to 0.75 to 0.5 g.
  • MM-151 a typical dose reduction schedule is from 10.5 to 9 to 7.5 to 6 to 3 mg/kg.
  • Radiotherapy patients who require a short course of palliative radiotherapy can
  • Steroids are only be permitted as required per premedication regimens and on a case by case basis requiring approval by the Sponsor prior to initiation of treatment (examples include asthma, COPD), and as part of a premedication regimen for study treatment.
  • Stable doses of corticosteroids e.g. 5 mg of prednisone or equivalent are permitted for the management of CNS metastasis and do not require sponsor approval.
  • Other permitted uses of corticosteroids include topical cutaneous, ophthalmic, nasal and inhalational steroids.
  • a medical history includes all pertinent prior medical conditions, surgeries or other medical procedures.
  • Vital signs include weight, resting blood pressure, pulse, respiratory rate and temperature.
  • the ECOG Performance Score is by questioning the patient about their functional capabilities.
  • the ECOG scale is described in Table 9.
  • a 12 lead ECG includes a description of the cardiac rate, rhythm, interval durations and an overall impression.
  • Fridericia Formula is used to calculate the QTc interval.
  • Fridericia's formula is a clinical correction formula for determining the heart-rate corrected QT interval, where QTF is the QT interval corrected for heart rate, the RR is the interval (in seconds) between QRS complexes, and QT is measured in milliseconds. Fridericia's formula takes the cube root of RR.
  • the Fridericia Formula is as follows:
  • V "/RR A multiple gated acquisition scan or echocardiogram is performed to determine ejection fraction.
  • the same procedure (MUGA or Echo) is performed during Screening to determine the ejection fraction should be employed at subsequent visits.
  • MUGA or Echo The same procedure (MUGA or Echo) is performed during Screening to determine the ejection fraction should be employed at subsequent visits.
  • Echocardiogram is performed post-screening for any study subject who develops symptoms consistent with new onset of congestive heart failure.
  • Tumor response is evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Eisenhauer, E. et al. (2009). New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European Journal of Cancer (Oxford, England : 1990), 45(2), 228-47. doi: 10.1016/j.ejca.2008.10.026) to establish disease progression by computerized tomography or magnetic resonance imaging (MRI).
  • MRI magnetic resonance imaging
  • other radiographic or scintigraphic procedures such as radionuclide bone scans
  • the extent of disease assessment is completed until it has been determined the patient has progressive disease (in accordance with RECIST vl. l). In the event the patient discontinues study treatment for reasons other than disease progression, an extent of disease assessment is completed as soon as possible relative to the date of study termination to ensure disease progression is not present and to assess overall disease status. In such patients, this assessment occurs no later than the date of the 30 day follow up visit.
  • a complete blood count includes a white blood count (WBC) and differential, hemoglobin, hematocrit and platelet count.
  • a coagulation profile includes a partial thromboplastin time (PTT) and an
  • Serum chemistry includes BUN, serum creatinine, glucose, bilirubin, AST, ALT, alkaline phosphatase, LDH, uric acid, total protein, albumin, calcium, magnesium, phosphate and electrolytes.
  • the required screening electrolytes are potassium, magnesium, calcium, and phosphate.
  • the required electrolytes are potassium, calcium, and magnesium.
  • Carcinoembryonic antigen (CEA) is a protein biomarker tested for in blood serum. This protein is typically produced in fetal development and production ends before birth. This biomarker in adults has been associated with some forms of cancer, including CRC, where it is a routine measure of disease burden.
  • a urinalysis include descriptions of color and clarity; pH; specific gravity; and analyses of hemoglobin, glucose, ketones and total protein.
  • a microscopic examination of the urine, to include WBC, RBC, bacteria and casts is performed if the urinalysis is abnormal.
  • a urine or serum pregnancy test is obtained for all females of childbearing potential. Exempt female patients include those who have undergone a bilateral oophorectomy or hysterectomy or who are menopausal (defined as absence of a menstrual cycle for at least 12 consecutive months).
  • Serum samples are collected to assess to determine the presence of an immunologic reaction to MM-151 or MM-121 (i.e. human anti-human antibodies; HAHA).
  • MM-151 or MM-121 i.e. human anti-human antibodies; HAHA.
  • Serum samples are collected to determine the levels of each of the monoclonal antibodies that comprise MM-151 and MM-121 according to Table 10 below. Additional analytes which may impact the pharmacokinetics of MM-151 and MM-121 are also measured from this sample.
  • Blood samples are collected to conduct exploratory studies to further characterize and correlate possible biomarkers that may help to predict or evaluate efficacy and/or toxicity. Samples are used to conduct specific biomarker analysis, or, in the event that there is remaining sample available after conducting these analyses, it is stored for future biomarker analysis related to this combination. At the time of informed consent, patients are able to refuse storage of these remaining samples.
  • IRR infusion-related reaction
  • FFPE formalin fixed paraffin embedded
  • the pre-dosing assessments i.e., labs, ECOG, AEs, etc
  • Figure 6 is a timeline of a typical day that would allow for all assessments to be completed during normal business hours.
  • An adverse event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
  • An adverse event can therefore be any unfavorable and unintended sign, including abnormal laboratory findings, symptoms, or diseases temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Worsening of a medical condition for which the efficacy of the study drug is being evaluated will not be considered an adverse event.
  • An unexpected adverse event is one for which the nature or severity of the event is not consistent with the applicable product information, e.g., the Investigator's brochure or Package Insert.
  • SAE serious adverse event
  • severe is often used to describe the intensity (severity) of an event; the event itself may be of relatively minor medical significance (such as a severe headache). This is not the same as “serious”, which is based on patient/event outcome or action criteria usually associated with events that pose a threat to a patient's life or functioning,
  • SAE reporting begins on the date the patient provides informed consent to participate in the study.
  • Treatment-emergent adverse event reporting begins as of the first dose of MM- 121 and MM-151 in the priming phase.
  • Overdose of MM-151 or MM-121 is defined as > 133% of planned dose of MM-151 or MM-121.
  • the medical monitor is contacted as deemed necessary by the site. Current contact information is maintained at the site within the regulatory binder. All SAEs are evaluated by the Sponsor's medical monitor. If meeting the
  • the Sponsor will report the adverse event to all regulatory authorities with jurisdiction over ongoing trials with the study drug and to all other Investigators involved in clinical trials with the study drug.
  • the Investigator is responsible for reporting all SAEs to the appropriate IRB/EC.
  • Fatal an event that results in the death of the patient.
  • Unrelated This category is applicable to those AEs that are clearly due to extraneous causes (concurrent drugs, environment, etc.) and/or the clinically plausible temporal sequence is inconsistent with the onset of the event and the administration of the study drug and do not meet the criteria for drug relationship listed under UNLIKELY, POSSIBLY, PROBABLY, DEFINITELY RELATED or UNKNOWN.
  • Probable The event follows a reasonable temporal sequence from administration of the study drug and the event follows a known response pattern to the study drug AND the event cannot have been reasonably explained by an intercurrent medical condition which or the event cannot be the effect of a concomitant medication
  • the pregnant partner In the event of a pregnancy occurring in the partner of a male patient participating in the study, the pregnant partner is requested to report the pregnancy to the Sponsor. The partner is informed of the risks of continuing with the pregnancy, the possible effects on the fetus, and is followed until conclusion of the pregnancy.
  • the total number of patients enrolled in the Dose Escalation Phase depends on the number of dose cohorts required to identify the maximum tolerated dose or recommended Phase 2 dose. Escalation to the next dose cohort depends on the background toxicity rate (i.e., probability of dose limiting toxicity at a given dose).
  • the proposed plan for dose escalation provides a 91% probability that dose escalation proceeds at doses associated with dose limiting toxicity probability of ⁇ 10%.
  • Table 12 below shows the probability of escalation from cohort to cohort with various toxicity rates.
  • the true dose limiting toxicity rate at the maximum tolerated dose is 10-20%, there is a 77-96% probability of observing at least 1 dose limiting toxicity in the 14 patient expansion cohort (Table 13). If more than 1 dose limiting toxicity is observed and the dose limiting toxicity rate is greater than 33% in the expansion cohort, further enrollment to the cohort is stopped and the safety and PK data is reviewed to determine how further dosing will proceed. If it is decided that a new dose should be investigated, 14 additional patients are enrolled at that dose.
  • Categorical variables are summarized by frequency distributions (number and percentages of patients) and continuous variables are summarized by descriptive statistics (mean, standard deviation, median, minimum, maximum). Both efficacy and safety analyses re performed using all the patients who received at least one infusion of both MM-151 and MM-121.
  • the demographic and baseline data is summarized by dose level. No formal statistical analysis is performed on these data.
  • DCR Disease control rate
  • PR + CR + SD Progression free survival
  • Treatment emergent adverse events are presented by treatment cohort, by patient, by NCI CTCAE version 4.0 grade and by MedDRA system organ class. Separate listings are presented for total adverse events, serious adverse events, adverse events related to MM-151 plus MM-121 and Grade 3/4 adverse events are presented.
  • RNA expression of resistance-related ligands is assessed, and may include EGFR ligands, heregulin (the ligand for ErbB3), IGF-1, IGF-2, HGF, and other resistance-related ligands. Additionally, quantitative measurements of staining by immunohistochemistry is obtained and includes an assessment of the following: EGFR (ErbB l), ErbB2 (HER2), ErbB3 (HER3), ErbB4, IGF- 1R, c-Met, and other receptors that mediate resistance. Blood samples are assessed for quantitative measurements of cytokines and other biomarkers related to ErbB and resistance signaling.
  • markers indicative of pathway activation, are assessed in patient-matched pairs of pre- and on-treatment biopsies. These markers are measured by IHC and include p-Erk, p-Akt, p-S6, and other pathway-related proteins.
  • EXAMPLE 3 Leading-edge Biomarker-Selected, Multi-Arm Basket Trial that Matches Patients with Most Appropriate Combination Regimens; A Phase 1 Biomarker-directed Study Evaluating the Co-Administration of MM-151 with MM-121, MM-141, or Trametinib in EGFR-Driven Cancers;
  • EGFR Epidermal Growth Factor Receptor
  • CRC colorectal cancer
  • SCCHN squamous cell carcinoma of the head and neck
  • NSCLC non- small cell lung cancer
  • EGFR inhibitors prolong overall survival in many patients, resistance inevitably develops. Resistance usually arises through alterations in the EGFR pathway itself or through upregulation of alternative signaling pathways.
  • mutations in KRAS and NRAS are strong predictors of resistance to EGFR inhibitors. Such resistance may potentially be overcome by combining MM-151, a potent EGFR inhibitor, with trametinib, a MEK inhibitor.
  • MM-151 is an oligoclonal therapeutic mixture consisting of three fully-human monoclonal antibodies designed to bind and inhibit signaling of the epidermal growth factor receptor (EGFR).
  • EGFR-mediated signaling promotes the growth and survival of cancer cells and has long been recognized as an important drug target in several types of cancer, including colon, lung, breast, pancreatic, and head and neck cancers.
  • MM-151 has previously been tested in a Phase 1 dose-escalation clinical trial in patients with advanced solid tumors.
  • Istiratumab is a tetravalent bispecific antibody designed to block tumor survival signals by inhibiting IGF-1R and ErbB3 (HER3) signaling. IGF-1R and ErbB3 complexes activate major signaling pathways that allow tumor cells to grow and develop resistance to chemotherapy.
  • istiratumab is in Phase 2 testing in patients with metastatic pancreatic cancer that have a pre-defined IGF-1 biomarker profile.
  • Seribantumab is Merrimack's wholly owned, fully human monoclonal antibody that targets ErbB3, a cell surface receptor that is activated by the ligand heregulin. Heregulin- driven ErbB 3 signaling has been implicated as a mechanism of tumor growth and resistance to targeted, cytotoxic and anti-endocrine therapies. When used in the combination setting, seribantumab is designed to block ErbB 3 signaling in order to enhance the anti-tumor effect of a combination therapy partner. Seribantumab has been investigated in multiple Phase 2 and Phase 1 clinical trials covering a broad spectrum of patient populations and drug
  • METHODS This is a Phase 1, biomarker-directed open-label study evaluating the safety, pharmacology and preliminary activity of MM-151 in combination with trametinib, MM-121, or MM-141. Patients are evaluated for KRAS/NRAS status and tumoral expression of HRG and IGF-1 and are then assigned to the study arm matching their biomarker profile. A modified "3 + 3" design is used to establish a recommended Phase 2 dose. Expansion cohorts in CRC and SCCHN will then be opened to further evaluate safety and obtain preliminary signs of efficacy. Key exploratory analyses include evaluations of PK, PD, and biomarkers of additional resistance pathways.
  • part 1 of the study cohorts of 3 or more patients will be treated at escalating doses of MM-151 in combination with MM-121, MM- 141, and trametinib until a maximum tolerated combination dose for each combination is identified.
  • patients with are treated with combination dose identified in part 1 of the study.
  • Conditions include: Colorectal Cancer, Non-small Cell Lung Cancer, and Squamous Cell Carcinoma of the Head and Neck.
  • MM-151+ trametinib Dose Escalation: MM-151 and trametinib dose escalation in lung, head and neck, and colorectal cancers. There are two MM-151 + trametinib arms.
  • MM-151+trametinib Dose Escalation: MM-151 and trametinib dose escalation in lung, head and neck, and colorectal cancers. There are two MM-151 + trametinib arms.
  • All patients enrolling in the study will provide a core needle biopsy, which will be tested for KRAS and NRAS mutations and for expression of two resistance ligands - heregulin (HRG) and insulin-like growth factor 1 (IGF-1).
  • HRG resistance ligands - heregulin
  • IGF-1 insulin-like growth factor 1
  • Patients will receive Merrimack's oligoclonal EGFR (epidermal growth factor receptor) inhibitor, MM-151, in combination with another agent that is intended to target their cancer's mechanism of resistance to EGFR inhibition.
  • Assignment to one of the four trial arms will be based on the following criteria: • Patients that test positive for HRG will be assigned to Group A and receive MM-151 in combination with seribantumab (MM- 121), a fully human antibody designed to block heregulin-driven ErbB3 pro-survival signaling.
  • Inclusion Criteria include, but are not limited to:
  • Patients must have either heregulin-positive cancer, cancer with RAS mutation, IGF-1 positive cancer, or RAS wild type cancer.
  • Exclusion Criteria include, but are not limited to:

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Abstract

L'invention concerne des procédés pour le traitement clinique de cancers positifs à l'héréguline à l'aide d'anticorps anti-ErbB3 en combinaison avec des anticorps anti-EGFR.
PCT/US2016/049027 2015-08-27 2016-08-26 Polythérapies pour le traitement de cancers positifs à l'héréguline WO2017035482A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090291085A1 (en) * 2007-02-16 2009-11-26 Merrimack Pharmaceuticals, Inc. Antibodies against erbb3 and uses thereof
US20140072563A1 (en) * 2011-09-30 2014-03-13 Regeneron Pharmaceuticals, Inc. Methods and Compositions Comprising a Combination of an Anti-ErbB3 Antibody and an Anti-EGFR Antibody
US20140234314A1 (en) * 2011-07-05 2014-08-21 Merrimack Pharmaceuticals, Inc. Antibodies against epidermal growth factor receptor (egfr) and uses thereof
US20150231238A1 (en) * 2011-03-15 2015-08-20 Merrimack Pharmaceuticals, Inc. Overcoming resistance to erbb pathway inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090291085A1 (en) * 2007-02-16 2009-11-26 Merrimack Pharmaceuticals, Inc. Antibodies against erbb3 and uses thereof
US20150231238A1 (en) * 2011-03-15 2015-08-20 Merrimack Pharmaceuticals, Inc. Overcoming resistance to erbb pathway inhibitors
US20140234314A1 (en) * 2011-07-05 2014-08-21 Merrimack Pharmaceuticals, Inc. Antibodies against epidermal growth factor receptor (egfr) and uses thereof
US20140072563A1 (en) * 2011-09-30 2014-03-13 Regeneron Pharmaceuticals, Inc. Methods and Compositions Comprising a Combination of an Anti-ErbB3 Antibody and an Anti-EGFR Antibody

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