WO2012103341A1 - Treatment of advanced solid stage tumors using anti-erbb3 antibodies - Google Patents

Abstract

Provided are methods and compositions for clinical treatment of advanced solid stage tumors using anti-ErbB3 antibodies.

Description

TREATMENT OF ADVANCED SOLID STAGE TUMORS USING ANTI-ERBB3 ANTIBODIES

REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Serial No.: 61/470,052, filed on March 31, 2011, and U.S. Provisional Application Serial No.: 61/436,779, filed on January 27, 2011, both of which are herein incorporated by reference.

BACKGROUND

Despite improvements in cancer therapies and late-stage options, there remains a critical need to optimize established therapies and develop new, promising therapies which prolong patients' lives while maintaining a high quality of life, particularly in the case of advanced cancers which can be resistant or refractory to existing therapies.

The ErbB3 receptor is 148 kD transmembrane receptor belonging to the

ErbB/EGFR receptor tyrosine kinase family although lacks intrinsic kinase activity. The ErbB receptors form homo- and heterodimeric complexes that impact the physiology of cells and organs by mediating ligand-dependent (and in some cases ligand independent) activation of multiple signal transduction pathways. ErbB3-containing heterodimers (such as ErbB2/ErbB3) in tumor cells have been shown to be the most mitogenic and oncogenic receptor complex within the ErbB family. Upon binding of heregulin (HRG), a physiological ligand for the

ErbB3 receptor, ErbB3 dimerizes with other ErbB family members,

predominantly ErbB2. ErbB3/ErbB2 dimerization results in transphosphorylation of ErbB3 on tyrosine residues contained within the cytoplasmic tail of the protein.

Phosphorylation of these sites creates SH2 docking sites for SH2-containing proteins, including PI3-kinase. ErbB3-containing heterodimeric complexes are therefore potent activators of AKT, as ErbB3 possesses six tyrosine

phosphorylation sites with YXXM motifs that, when phosphorylated, serve as excellent binding sites for phosphoinositol-3-kinase (PI3K), the action of which results in subsequent downstream activation of the AKT pathway. These six PI3K sites serve as a strong amplifier of ErbB3 signaling. Activation of this pathway further elicits several important biological processes involved in tumorigenesis, such as cell growth, migration and survival. Heregulin has been shown to be involved in several different types of cancer: breast, ovarian, endometrial colon, gastric, lung, thyroid, glioma,

medulloblastoma, melanoma as well as head and neck squamous cell carcinoma. In most of these tumor types, HRG regulates growth, invasion and angiogenesis through either over expression or the activation of an autocrine or paracrine loop. Disruption of the heregulin autocrine loop by blocking HRG binding or disruption of the ErbB2/ErbB3 dimer is considered to provide an important therapeutic approach to controlling cancer cell growth.

SUMMARY

Provided are compositions and methods for treating solid tumors, e.g., advanced solid tumors, in a human patient, comprising administering to the patient an anti-ErbB3 antibody according to a particular clinical dosage regimen (i.e., at a particular dose amount and according to a specific dosing schedule). In one embodiment, the human patient suffers from colorectal cancer, squamous cell head and neck cancer, non- small cell lung cancer, triple negative breast cancer or other solid tumors that have EGFR dependence.

An exemplary anti-ErbB3 antibody is antibody MM-121 or antigen binding fragments and variants thereof. In one embodiment, the antibody comprises variable heavy (VH) and/or variable light (VL) regions encoded by the nucleic acid sequences set forth in SEQ ID NOs: 1 and 3, respectively. In another embodiment, the antibody comprises VH and/or VL regions comprising the amino acid sequences set forth in SEQ ID NOs 2 and 4, respectively. In another embodiment, the MM-121 antibody comprises (in amino-to carboxy- terminal order) CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and/or (in amino-to carboxy- terminal order) CDRLl, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRLl) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3). In another embodiment, an antibody is used that competes for binding with and/or binds to the same epitope on human ErbB3 as the above- mentioned antibodies. In a particular embodiment, the epitope comprises residues 92- 104 of human ErbB3 (SEQ ID NO: 11). In another embodiment, the antibody competes with MM-121 for binding to human ErbB3 and has at least 90% variable region amino acid sequence identity with the above-mentioned anti-ErbB3 antibodies. See, e.g., US Patent No. 7,846,440 and US Patent Publication No. 20100266584.

Accordingly, in one aspect, methods of treating advanced solid tumors in a human patient are provided, the methods comprising administering to the patient, an effective amount of (a) an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and

CDRLl, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRLl) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, and wherein for each cycle the anti-ErbB3 antibody is

administered once per week at a dose of about 20 mg/kg. In a further

embodiment, the effective amount comprises administering the anti-ErbB3

antibody at a dose of 40 mg/kg for week 1 of cycle 1.

In another aspect, methods for treatment (e.g., effective treatment) of an advanced solid stage tumors in a human patient are provided, the methods

comprising: administering to the patient, an effective amount of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6

(CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRLl, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8

(CDRLl) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once per week at a dose of about 40 mg/kg.

In another aspect, methods for treating advanced solid stage tumors in a human patient are provided, the methods comprising: administering to the patient an effective amount of (a) an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and

CDRLl, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRLl) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once every other week at a dose of about 40 mg/kg.

In another aspect, methods for treating advanced stage solid tumors in a human patient comprising administering to the patient an effective amount of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRLl, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRLl) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once every other week at a dose of about 60 mg/kg.

In another aspect, methods for treating advanced stage solid tumors in a human patient comprising administering to the patient an effective amount of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRLl, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRLl) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), wherein the effective amount comprises administering the anti-ErbB3 antibody once every three weeks at a dose of about 40 or 60 mg/kg.

In another aspect, methods of treating advanced stage solid tumors in a human patient are provided comprising administering to the patient an effective amount of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRLl, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRLl) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once a week according to dose schedules -1, 1, 2, 3, 4, 5, or 6: Dose Level Dose (mg/kg)

-1 1

1 3.2

2 6

3 10

4 15

5 20

6 40/20

In another embodiment, the cancer is EGFR dependent.

In another embodiment, the cancer is selected from the group consisting of: colorectal cancer, colon cancer, ocular melanoma, melanoma, ovarian cancer, prostate cancer, thymic carcinoma, esophageal cancer, squamous cell skin cancer, pancreatic cancer, peritoneal cancer, salivary gland carcinoma, squamous cell head and neck cancer, non-small cell lung cancer, breast cancer, and triple negative breast cancer.

In another embodiment, the anti-ErbB3 antibody is MM-121.

In another embodiment, the antibody is formulated for intravenous administration.

In yet another aspect, kits for treating advanced solid stage tumors in a human patient are provided, the kit comprising: a dose of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth, respectively, in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth, respectively, in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), and instructions for using the anti-ErbB3 antibody in a method of the invention.

In one embodiment, a kit of the invention comprises at least 500 mg of the antibody.

In another aspect, an antiErbB3 antibody is provided, the antibody comprising: SEQ ID NO: 5 (CDRH1), SEQ ID NO: 6 (CDRH2), SEQ ID NO: 7 (CDRH3), SEQ ID NO: 8 (CDRL1), SEQ ID NO: 9 (CDRL2), and SEQ ID NO: 10 (CDRL3), for administration in at least one cycle, wherein the anti-ErbB3 antibody is administered at a weekly dose of about 20 mg/kg or 40 mg/kg.

In another aspect, an antiErbB3 antibody is provided, the antibody comprising: SEQ ID NO: 5 (CDRHl), SEQ ID NO: 6 (CDRH2), SEQ ID NO: 7 (CDRH3), SEQ ID NO: 8 (CDRL1), SEQ ID NO: 9 (CDRL2), and SEQ ID NO: 10 (CDRL3), for administration in at least one cycle, wherein the anti-ErbB3 antibody is administered once every other week at a dose of about 40 mg/kg or 60 mg/kg.

In another aspect, an antiErbB3 antibody is provided, the antibody comprising: SEQ ID NO: 5 (CDRHl), SEQ ID NO: 6 (CDRH2), SEQ ID NO: 7 (CDRH3), SEQ ID NO: 8 (CDRL1), SEQ ID NO: 9 (CDRL2), and SEQ ID NO: 10 (CDRL3), for administration in at least one cycle, wherein the anti-ErbB3 antibody is administered once every three weeks at a dose of about 40 or 60 mg/kg.

In one embodiment, the patient does not have metastatic disease. In another embodiment, the patient has metastatic disease.

In another embodiment, the treatment produces at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in number of metastatic lesions over time, complete response, partial response, stable disease, increase in overall response rate, or a pathologic complete response.

In another aspect, compositions are provided, the composition comprising a clinically proven safe and effective amount of (a) an anti-ErbB3 antibody comprising CDRHl, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRHl) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3) and (b) a carrier.

In one embodiment, the anti-ErbB3 antibody is MM- 121.

In another embodiment, the antibody is formulated for intravenous administration. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the patient enrollment and response summary for the phase I monotherapy expansion cohort.

DETAILED DESCRIPTION

I. DEFINITIONS

As used herein, the term "subject" or "patient" is a human cancer patient.

As used herein, "effective treatment" refers to treatment producing a beneficial effect, e.g., amelioration of at least one symptom of a disease or disorder. A beneficial effect can take the form of an improvement over baseline, i.e., an improvement over a measurement or observation made prior to initiation of therapy according to the method. A beneficial effect can also take the form of arresting, slowing, retarding, or stabilizing of a deleterious progression of a marker of a solid tumor. Effective treatment may refer to alleviation of at least one symptom of a solid tumor. Such effective treatment may, e.g., reduce patient pain, reduce the size and/or number of lesions, may reduce or prevent metastasis of a tumor, and/or may slow tumor growth.

The term "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. In reference to cancers, an effective amount comprises an amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation. In some embodiments, an effective amount is an amount sufficient to delay tumor development. In some embodiments, an effective amount is an amount sufficient to prevent or delay tumor recurrence. An effective amount can be administered in one or more administrations. The effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and may stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and may stop tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer. In one example, an "effective amount" is the amount of MM- 121 clinically proven to effect a significant decrease in cancer or slowing of progression of cancer, such as an advanced solid tumor, e.g., that is EGFR dependent.

The term "antibody" describes polypeptides comprising at least one antibody derived antigen binding site (e.g., VH/VL region or Fv, or

complementarity determining region - CDR) that specifically binds to ErbB3. Antibodies include known forms of antibodies. For example, the antibody can be a human antibody, a humanized antibody, a bispecific antibody, or a chimeric antibody. The antibody also can be a Fab, Fab'2, ScFv, SMIP, Affibody®, nanobody, or a domain antibody. The antibody also can be of any of the following isotypes: IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgAsec, IgD, and IgE. The antibody may be a naturally occurring antibody or may be an antibody that has been altered (e.g., by mutation, deletion, substitution, conjugation to a non-antibody moiety). For example, 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. For example, numerous such alterations are known in the art which affect, e.g., half-life, effector function, and/or immune responses to the antibody in a patient. The term antibody also includes artificial polypeptide constructs which comprise at least one antibody- derived antigen binding site.

II. ANTI-ERBB3 ANTIBODIES

Useful anti-human-ErbB3 antibodies (or VH/VL domains derived therefrom) can be made using methods well known in the art. Alternatively, art recognized anti-ErbB3 antibodies can be used. For example, Ab#3, Ab #14, Ab #17, Ab # 19, described in U.S. 7,846,440, can be used. Antibodies that compete with any of these antibodies for binding to ErbB3 also can be used. Additional art-recognized anti-ErbB3 antibodies which can be used include those disclosed in US 7,285,649; US20100310557; US20100255010, as well as antibodies IB4C3 and 2D ID 12 (U3 Pharma Ag), both of which are described in e.g.,

US2004/0197332; anti-ErbB3 antibody referred to as AMG888 (U3-1287 - U3 Pharma Ag and Amgen); and monoclonal antibody 8B8, described in US 5,968,511. An example of such an antibody is MM-121, also referred to in U.S. 7,846,440 as "Ab #6". MM-121 binds to an extracellular domain of human ErbB3 and inhibits cellular activation by heregulin that results, e.g., in increased ErbB3 and AKT phosphorylation. In one embodiment, the MM-121 antibody comprises variable heavy (VH) and/or variable light (VL) regions encoded by the nucleic acid sequences set forth therein (and included here as SEQ ID NOs: l and 3), respectively. In another embodiment, the antibody comprises VH and/or VL regions comprising the amino acid sequences set forth therein and included here as SEQ ID NOs: 2 and 4, respectively. In another embodiment, the antibody comprises CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and/or CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3). In another embodiment, the antibody competes for binding with and/or binds to the same epitope on human ErbB3 as the above-mentioned antibodies. In a particular embodiment, the epitope comprises residues 92-104 of human ErbB3 (SEQ ID NO: 11). In another embodiment, the antibody binds to human ErbB3 and has at least 90% variable region sequence identity with the above-mentioned antibodies.

In other embodiments, the antibody is a fully human monoclonal antibody, such as an IgG2, that binds to ErbB3 and prevents the HRG and EGF-like ligand- induced intracellular phosphorylation of ErbB3.

Anti-ErbB3 antibodies, such as MM-121, can be generated, e.g., in prokaryotic or eukaryotic cells, using methods well known in the art. In one embodiment, the antibody is produced in a cell line capable of glycosylating proteins, such as CHO cells.

III. PHARMACEUTICAL COMPOSITIONS

Pharmaceutical compositions suitable for administration to a patient are typically in forms suitable for parenteral administration, e.g., in a in liquid carrier, or suitable for reconstitution into liquid solution or suspension, for intravenous administration. In general, compositions typically comprise a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable" means approved by a government regulatory agency or listed in the U.S. Pharmacopeia or another generally recognized pharmacopeia for use in animals, particularly in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, glycerol polyethylene glycol ricinoleate, and the like. Water or aqueous solution saline and aqueous dextrose and glycerol solutions may be employed as carriers, particularly for injectable solutions (e.g., comprising an anti-ErbB3 antibody). Liquid compositions for parenteral administration can be formulated for administration by injection or continuous infusion. Routes of administration by injection or infusion include intravenous, intraperitoneal, intramuscular, intrathecal and subcutaneous. In one embodiment, the anti-ErbB3 antibody is administered intravenously.

MM-121 for intravenous infusion (e.g., over the course of one hour) is supplied as a clear liquid solution in sterile, single-use vials containing 10.1 ml of MM-121 at a concentration of 25 mg/ml in an aqueous solution of 20mM histidine, 150mM sodium chloride, pH 6.5, which should be stored at 2-8°C.

IV. PATIENT POPULATIONS

Provided herein are effective methods for treating solid tumors (e.g., that are advanced and/or EGFR dependent) in a human patient using an anti-ErbB3 antibody.

In one embodiment, a human patient for treatment using the subject methods and compositions has evidence of recurrent or persistent disease following primary chemotherapy. In one embodiment, the human patient suffers from colorectal cancer, colon cancer, ocular melanoma, melanoma, ovarian cancer, prostate cancer, thymic carcinoma, esophageal cancer, squamous cell skin cancer, pancreatic cancer, peritoneal cancer, salivary gland carcinoma, squamous cell head and neck cancer, non- small cell lung cancer, breast cancer, triple negative breast cancer, bladder cancer or leimyosarcoma. Patients can be tested or selected for one or more of the above described clinical attributes prior to, during or after treatment.

V. DOSAGES

As herein provided, anti-ErbB3 antibodies are administered to effect improvement in subjects having an advanced solid stage tumor. In one

embodiment, the anti-ErbB3 antibody is MM- 121.

In another embodiment, the anti-ErbB3 antibody is formulated for intravenous administration. In particular embodiments, the anti-ErbB3 antibody is administered at a dose selected from: of 60 mg/kg, 40 mg/kg, 20 mg/kg, 15 mg/kg, 10 mg/kg, 6 mg/kg and/or 3.2 mg/kg. In one embodiment, the dose of antibody is varied over time. For example, the antibody may be initially

administered at a high dose and may be lowered over time. In another

embodiment, the antibody is initially administered at a low dose and increased over time.

VI. TREATMENT PROTOCOLS

Suitable treatment protocols include, for example, those wherein the anti- ErbB3 antibody is administered to a patient (i.e., human subject) once per week (at a dose of 3.2, 6, 10, 15, 20, or 40 mg/kg). In one embodiment, the anti-ErbB3 antibody is administered to a patient once per week at a dose of about 20 mg/kg or about 40 mg/kg. In a further embodiment, the anti-ErbB3 antibody is

administered to a patient once every other week at a dose of about 40 mg/kg or about 60 mg/kg. In yet another embodiment, the anti-ErbB3 antibody is

administered to a patient once every three weeks at a dose of about 40 mg/kg or about 60 mg/kg.

In another embodiment, a cycle of administration is four weeks. In one embodiment, the administration can be repeated, as necessary.

In another embodiment, the amount of MM- 121 antibody administered is constant for each dose. In another embodiment, the amount of antibody administered varies with each dose. For example, the maintenance (or follow-on) dose of the antibody can be higher or the same as the loading dose which is first administered. In another embodiment, the maintenance dose of the antibody can be lower or the same as the loading dose.

VII. OUTCOMES

With respect to target lesions, responses to therapy may include:

In exemplary outcomes, patients treated according to the methods disclosed herein may experience improvement in at least one sign of cancer.

In one embodiment, the patient so treated exhibits CR, PR, or SD.

In another embodiment, the patient so treated experiences tumor shrinkage and/or decrease in growth rate, i.e., suppression of tumor growth. In another embodiment, unwanted cell proliferation is reduced or inhibited. In yet another embodiment, one or more of the following can occur: the number of cancer cells can be reduced; tumor size can be reduced; cancer cell infiltration into peripheral organs can be inhibited, retarded, slowed, or stopped; tumor metastasis can be slowed or inhibited; tumor growth can be inhibited; recurrence of tumor can be prevented or delayed; one or more of the symptoms associated with cancer can be relieved to some extent.

In other embodiments, such improvement is measured by a reduction in the quantity and/or size of measurable tumor lesions. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter is to be recorded) as >10 mm by CT scan (CT scan slice thickness no greater than 5 mm), 10 mm caliper measurement by clinical exam or >20 mm by chest X-ray. In one embodiment, lesions can be measured on chest x-rays or CT or MRI films.

In other embodiments, cytology or histology can be used to evaluate responsiveness to a therapy. The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease can be considered to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease.

In some embodiments, administration of effective amounts of the anti- ErbB3 antibody according to any of the methods provided herein produce at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in number of metastatic lesions appearing over time, complete remission, partial remission, stable disease, increase in overall response rate, or a pathologic complete response.

VIII. KITS AND UNIT DOSAGE FORMS

Also provided are kits that include a pharmaceutical composition containing an anti-ErbB3 antibody, such as MM-121, and a pharmaceutically-acceptable carrier, in a therapeutically effective amount adapted for use in the preceding methods. The kits optionally can include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient having cancer. In one embodiment the kit includes a syringe.

Optionally, the kits include multiple packages of the single-dose

pharmaceutical composition(s) each containing an effective amount of the antibody (e.g., MM-121) for a single administration in accordance with the methods provided above. Optionally, instruments or devices necessary for administering the

pharmaceutical composition(s) may be included in the kits. For instance, a kit may provide one or more pre-filled syringes containing an amount of MM-121 that is about 100 times the dose in mg/kg indicated for administration in the above methods.

The following examples are merely illustrative and should not be construed as limiting the scope of this disclosure in any way as many variations and equivalents will become apparent to those skilled in the art upon reading the present disclosure.

All patents, patent applications and publications cited herein are

incorporated herein by reference in their entireties.

Example 1: Phase 1 Trial in Patients Having Solid Tumors

A phase 1 trial of MM-121 is conducted in patients having advanced solid tumors.

I. STUDY DESIGN

The study is a Phase 1 and pharmacologic open-label dose-escalation trial using a modified "3+3" design, where three or four patients are initially enrolled at a dose level and evaluated for safety. Successive cohorts of three or more patients will be treated at escalating doses until a maximum tolerated dose (or maximum target dose) is identified as described below. The study will initially explore a q 7-day dosing schedule, which may be modified to longer intervals under certain circumstances described below. An Expansion Cohort will be enrolled following demonstration of adequate MM-121 concentration levels in the dose escalation phase. The expansion cohort will further characterize safety, pharmacokinetics and explore pharmacodynamic endpoints.

II. OBJECTIVES

The primary tolerability objective is to determine the Phase 2 dose based either on the maximum tolerated dose (MTD) or maximum target dose in patients with advanced solid malignancies. The primary efficacy objective is to describe any objective response to MM-121 based on RECIST.

The secondary objectives of the study include the following:

• To describe the dose limiting toxicity of MM-121;

• To determine the adverse event profile of MM- 121 ; • To determine the pharmacokinetic parameters of MM- 121;

• To explore the pharmacodynamic effects of MM- 121 on tumors; and

• To gather exploratory clinical data on a potentially predictive set of biomarkers to be measured in serum and formalin-fixed, paraffin embedded tissue.

III. DOSES

Dose Levels

The proposed dose levels for the study are shown in the table below. The starting dose is 3.2 mg/kg. Safety permitting, escalation will proceed in approximate half-log increments up to 10 mg/kg and then in lesser increments up to the target maximum doses. Following the completion of enrollment in cohort 6 (40/20 mg/kg) and further evaluation of the PK data, additional intermediary cohorts may be explored. Such cohorts may evaluate alternative dosing regimens (e.g. loading dose with different maintenance dose schedule) or weekly dosing at doses < 40 mg/kg. Additional cohorts will utilize the same 3 + 3 design and only doses < 40 mg/kg will be explored.

Following this cohort, intermediate dose levels may be explored.

Decision Process for Dose Escalation

Decisions to escalate dose will be documented along with a summary of the information supporting the decision. Following the decision to escalate beyond Cohort 6, a recommendation to proceed to the next dose level and frequency will be made based upon the available safety, efficacy and

pharmacokinetic data.

Data to be Considered for Dose Escalation Decisions

Decisions to escalate the dose for a new cohort of patients will be made after the third (or fourth) patient in a cohort has completed cycle 1. Escalation decisions will be based exclusively on safety data. Immunogenicity and pharmacokinetic data may be available, but will not be required for decisions on dose escalation.

Decision Criteria for Dose Escalation

The dose will escalate to the next level only if three or more patients have been evaluated at the current dose level and the criteria for MTD have not been met.

Potential Lengthening of Dosing Interval

When the MTD or target optimal dose is identified using the q 7-day infusion schedule, consideration will be given to lengthening the dosing interval. A decision will be made based upon the MM- 121 terminal half-life, other PK parameters, the nature of any observed toxicities and time to resolution. If such a decision is made, then the next cohort of patients will be treated at longer dosing intervals using a dose (mg/kg) that has determined to be safe at a q 7-day infusion schedule. If no DLT is observed in 3 patients at this dose level, the data will be reviewed with FDA. With FDA concurrence, dose escalation using a schedule with a longer dosing interval will continue as described for q7d dosing. Separate MTDs or target dose levels may be identified for q 7-day dosing and any other dosing schedule tested.

Definition and Management of Dose Limiting Toxicity (DLT)

Dose Limiting Toxicity Definitions

Any drug related Grade 3-4 hematological or non-hematological toxicity, including Grade 3-4 infusion reactions, will be considered dose limiting. Nausea, vomiting and diarrhea are dose-limiting when Grade 3-4 toxicity occurs despite the use of standard anti-emetic or anti-diarrheal agents. In addition, an inability to deliver fewer than three of the planned doses over the first cycle of treatment due to drug-related toxicities will be considered a dose-limiting effect. Retreatment after Dose-Limiting Toxicity

Ordinarily a patient who experiences a dose-limiting toxicity may not receive additional doses of MM-121 and will be removed from the study. If there is evidence that a patient who experiences a DLT has also derived clinical benefit from treatment with MM-121, then the specifics of the case will be reviewed. Such a patient may continue on study at the next lower dose level if the consensus judgment, with FDA concurrence, is that continued treatment is in the patient' s best interest. Patients should have recovered from toxicity to baseline or grade 1 (except alopecia) prior to re-treatment. For hemoglobin DLTs, patients should recover to their baseline grade before re-treatment.

Maximum Tolerated Dose

If one of 3-4 patients at a dose level experiences a Dose Limiting Toxicity (DLT), then up to three additional participants will be enrolled in the study at that same dose level. The MTD is defined as the highest dose level in which a DLT is experienced by fewer than two patients in a cohort of 3-6 patients. When a DLT is observed in at least two participants in a cohort of three to six, the Maximum Tolerated Dose (MTD) will be determined to have been exceeded and an additional three patients (up to a total of six) are to be treated at the next lower dose level.

IV. PATIENT SELECTION AND DISCONTINUATION

Number of Patients

25-35 patients for the dose escalation and 10-15 patients for the expansion cohort, depending on the observed toxicity profile of MM-121.

Inclusion Criteria

In order to be considered for inclusion in the study, patients must have/be:

• Histological or cytological confirmed advanced solid tumors that have recurred or progressed following standard therapy, or that have not responded to standard therapy, or for which there is no standard therapy, or who are not candidates for standard therapy;

• > 18 years of age;

• Able to understand and sign an informed consent, or have a legal

representative able and willing to do so; • Evaluable or measurable tumor(s);

• ECOG Performance Score (PS) of 0 or 1. Patients with a PS of 2, who are fully ambulatory and have been stable for at least two weeks, may be considered for enrollment;

• Adequate bone marrow reserves as evidenced by:

o ANC > l,500^1 and

o Platelet count > 100,000/μ1

o Hemoglobin > 9 g/dL;

• Adequate hepatic function as evidenced by:

o Serum total bilirubin < 1.5 x ULN

o AST, ALT and Alkaline Phosphatase normal or up to CTCAE Grade 1;

• Adequate renal function as evidenced by a serum creatinine < 1.5 x ULN;

• Recovered from the effects of any prior surgery, radiotherapy or other antineoplastic therapy. Up to CTCAE Grade 1 is acceptable for patients with known peripheral neuropathy;

• Willing to abstain from sexual intercourse or to use an effective form of contraception during the study and for 90 days following the last dose of MM- 121 (an effective form of contraception is an oral contraceptive or a double barrier method). This applies to women of childbearing potential as well as fertile men and their partners;

Additional Inclusion Criteria for Patients in the Expansion Cohort In addition to the criteria noted above, patients to be enrolled the

Expansion Cohort must have/be:

• One of the following patient populations:

o Advanced/metastatic breast cancer with histological/cytological documentation of ER-, PR-, Her2/neu non-overexpressing status (triple negative breast cancer); OR,

o Advanced/metastatic breast cancer with histologically or cytologically confirmed ER+ and/or PR+, Her2/neu non- overexpressing; OR, o Advanced/metastatic histological confirmation of epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer; OR, o Additional tumor types such as metastatic colorectal, advanced non small cell lung cancer, or others may be considered on a per-patient basis;

• Tumor tissue amenable to biopsy;

• Platelet counts, partial thromboplastin time (PTT) and international

normalized ratio (INR) within normal limits;

• Willing to undergo tumor biopsy twice (once before and once after

treatment with MM- 121); and

• Blocks of archived formalin-fixed, paraffin-embedded, unstained tumor tissue available for submission. Patients with no available archived tumor tissue available must receive approval prior to enrollment.

Exclusion Criteria

Patients must meet all the inclusion criteria listed above and none of the following exclusion criteria:

• Potentially curative antineoplastic therapy is available;

• Pregnant or lactating;

• Active infection or with an unexplained fever > 38.5°C during screening visits or on the first scheduled day of dosing. (At the discretion of the investigator, patients with tumor fever may be enrolled.);

• Untreated and/or symptomatic CNS malignancies (primary or metastatic); patients with CNS metastases who have undergone surgery or

radiotherapy, whose disease is stable, and who have been on a stable dose of corticosteroids for at least 2 weeks prior to the first scheduled day of dosing will be eligible for the trial;

• Known hypersensitivity to any of the components of MM- 121 or who have had hypersensitivity reactions to human monoclonal antibodies (patients who have a history of hypersensitivity to cetuximab, a chimeric antibody, are not excluded);

• Received other recent antitumor therapy including:

o Investigational therapy administered within the 30 days prior to the first scheduled day of dosing MM-121 o Any standard chemotherapy or radiation within 14 days (and having passed the time of any actual or anticipated toxicities) prior to the first scheduled dose of MM-121

• NYHA Class III or IV congestive heart failure or LVEF < 55%;

• History of allogeneic transplant (Patients with a history of autologous bone marrow or stem cell transplant may be enrolled.);

• Known HIV, hepatitis B or C (active, previously treated or both); or

• Any other medical condition, including mental illness or substance abuse, deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results.

Doses and Administration of MM-121

MM-121 will be administered weekly (or in some circumstances, on other schedules, as described above).

MM-121 should be brought to room temperature prior to administration. Vials of MM-121 should not be shaken. The appropriate quantity of MM-121 will be removed from the vial, diluted in 250 mis of 0.9% normal saline and administered over 90 minutes for the first administration. MM-121 should be administered using a low protein binding 0.22 micrometer in-line filter. In the absence of an infusion reaction, subsequent doses may be administered over 60 minutes.

A patient' s body weight at the start of a cycle is to be used to calculate the dose used throughout the cycle. Should a patient's body weight change by 10%, a new total dose should be calculated to reflect this change.

Statistical Analysis

Categorical variables will be summarized by frequency distributions (number and percentages of patients) and continuous variables will be

summarized by descriptive statistics (mean, standard deviation, median, minimum, maximum).

Both efficacy and safety analyses will be performed using all the patients who received at least one infusion of study drug. Efficacy Analysis

The primary efficacy endpoint for this study is the objective response defined using RECIST.

Safety Analysis

Treatment emergent adverse events will be presented by treatment cohort, by patient, by NCI CTCAE grade and by MedDRA system organ class. Separate listings will be presented for total adverse events, serious adverse events, adverse events related to MM- 121 and Grade 3/4 adverse events will be presented.

Laboratory data will be presented by dose cohort and by visit. Abnormal laboratory values will be assessed according to NCI CTCAE grade, where possible.

Evaluation of QTc will be based upon Fridericia' s correction method. CTCAE criteria will be applied to the QTc_F (i.e. Grade 3 = QTc > 500 msec).

All the safety analyses will be performed by dose level, treatment cycle and week, where appropriate.

Pharmacokinetics Analysis

Pharmacokinetic parameters will be derived from the blood PK samples and will be analyzed using descriptive statistics, including the median, mean and 95% confidence intervals around parameter estimates by dose level. PK parameters will include C_max, T_max, AUC (area under the concentration curve), clearance, volume of distribution at steady state (Vdss), and the terminal elimination half-life. Estimation of the pharmacokinetic parameters will be performed using standard non-compartmental methods.

VII. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST V1.0)

Response and progression will be evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST, vl .O) Committee [JNCI 92(3):205-216, 2000] . Changes in only the largest diameter (one-dimensional measurement) of the tumor lesions are used in the RECIST criteria. Note: Lesions are either measurable or non- measurable using the criteria provided below. Measurable disease

Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques (CT, MRI, x-ray) or as >10 mm with spiral CT scan. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).

Target lesions

All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at screening. Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference by which to characterize the objective tumor response.

Non-target lesions

All other lesions (or sites of disease) should be identified as non-target lesions and should also be recorded at screening. Non-target lesions include measurable lesions that exceed the maximum number per organ or total of all involved organs as well as non-measurable lesions. Measurements of these lesions are not required, but the presence or absence of each should be noted throughout follow-up.

Guidelines for Evaluation of Measurable Disease

All measurements should be taken and recorded in metric notation using a ruler or calipers. Tumor lesions that are situated in a previously irradiated area will not be considered measurable. The following are not considered measurable lesions; bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, abdominal masses that are not confirmed and followed by imaging techniques and cystic lesions.

Evaluation of best overall response

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.

Target Lesions Non-Target New Lesions Overall Response

Lesions

CR CR No CR

CR IR/SD No PR

PR Non-PD No PR

SD Non-PD No SD

PD Any Yes or No PD

Any PD Yes or No PD

Any Any Yes PD

Patients with a global deterioration of health status requiring

discontinuation of treatment without objective evidence of disease progression at that time should be classified as having "symptomatic deterioration." Every effort should be made to document the objective progression, even after discontinuation of treatment.

In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When the evaluation of complete response depends on this determination, it is recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before confirming the complete response status.

Confirmatory Measurement/Duration of Response

Confirmation

To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat assessments that should be performed every 8 weeks and at termination after the criteria for response are first met. In the case of SD, follow-up measurements must have met the SD criteria at least once after study entry at a minimum interval of 8 weeks.

Duration of overall response

The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.

Duration of stable disease

Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started.

Time -to -Progression

Time-to-Progression is measured from the start of the treatment until the criteria for progression are met, taking as reference the screening measurements.

Survival Time

Survival Time is measured from the start of the treatment until death of the patient. When the last patient reaches the End of Treatment visit, all patients in the survival/follow-up period will be removed from this protocol and survival status will be monitored outside of this protocol.

VIII. RESULTS

A dose escalation study had been performed in 25 patients having advanced solid stage tumors and 6 dose levels (3.2, 6, 10, 15, 20, or 40 mg/kg). MM-121 was well tolerated with a favorable safety profile. Six patients displayed a clinical benefit, as demonstrated by stable disease.

Fifteen patients have been enrolled in the expansion cohort (40 mg/kg loading dose; 20 mg/kg weekly). Summaries of patient responses are provided in Figure 1. As shown, four patients have displayed a clinical benefit as

demonstrated by stable disease.

Claims

CLAIMS WE CLAIM:

1. A method of treating advanced stage solid tumors in a human patient comprising administering to the patient an effective amount of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once per week at a dose of about 20 mg/kg.

2. The method of claim 1, wherein said effective amount comprises administering the anti-ErbB3 antibody at a dose of 40 mg/kg for week 1 of cycle 1.

3. A method of treating advanced stage solid tumors in a human patient comprising administering to the patient an effective amount of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once per week at a dose of about 40 mg/kg.

4. A method of treating advanced stage solid tumors in a human patient comprising administering to the patient an effective amount of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRLl) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once every other week at a dose of about 40 mg/kg.

5. A method of treating advanced stage solid tumors in a human patient comprising administering to the patient an effective amount of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRLl, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRLl) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once every other week at a dose of about 60 mg/kg.

6. A method of treating advanced stage solid tumors in a human patient comprising administering to the patient an effective amount of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRLl, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRLl) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), wherein the effective amount comprises administering the anti-ErbB3 antibody once every three weeks at a dose of about 40 or 60 mg/kg.

7. A method of treating advanced stage solid tumors in a human patient comprising administering to the patient an effective amount of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRLl, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRLl) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once a week according to dose schedules -1, 1, 2, 3, 4, 5, or 6:

8. The method of any one of claims 1-6, wherein the cancer is EGFR dependent.

9. The method of any one of claims 1-6, wherein the cancer is selected from the group consisting of: colorectal cancer, colon cancer, ocular melanoma, melanoma, ovarian cancer, prostate cancer, thymic carcinoma, esophageal cancer, squamous cell skin cancer, pancreatic cancer, peritoneal cancer, salivary gland carcinoma, squamous cell head and neck cancer, non-small cell lung cancer, breast cancer, and triple negative breast cancer.

10. The method of any one of claims 1-6, wherein the anti-ErbB3 antibody is MM-121.

11. The method of claim 1 or 4, wherein the antibody is formulated for intravenous administration.

12. A kit for treating advanced solid stage tumors in a human patient, the kit comprising: a dose of an anti-ErbB3 antibody comprising CDRHl, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth, respectively, in SEQ ID NO: 5 (CDRHl) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth, respectively, in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), and instructions for using the anti- ErbB3 antibody in the method of any one of claims 1-6.

13. The kit of claim 10 which comprises at least 500 mg of the antibody.

14. An anti-ErbB3 antibody comprising: SEQ ID NO: 5 (CDRHl), SEQ ID NO: 6 (CDRH2), SEQ ID NO: 7 (CDRH3), SEQ ID NO: 8 (CDRL1), SEQ ID NO: 9 (CDRL2), and SEQ ID NO: 10 (CDRL3), for administration in at least one cycle, wherein the anti-ErbB3 antibody is administered at a weekly dose of about 20 mg/kg or 40 mg/kg.

15. An anti-ErbB3 antibody comprising: SEQ ID NO: 5 (CDRHl), SEQ ID NO: 6 (CDRH2), SEQ ID NO: 7 (CDRH3), SEQ ID NO: 8 (CDRL1), SEQ ID NO: 9 (CDRL2), and SEQ ID NO: 10 (CDRL3), for administration in at least one cycle, wherein the anti-ErbB3 antibody is administered once every other week at a dose of about 40 mg/kg or 60 mg/kg.

16. An anti-ErbB3 antibody comprising: SEQ ID NO: 5 (CDRHl), SEQ ID NO: 6 (CDRH2), SEQ ID NO: 7 (CDRH3), SEQ ID NO: 8 (CDRL1), SEQ ID NO: 9 (CDRL2), and SEQ ID NO: 10 (CDRL3), for administration in at least one cycle, wherein the anti-ErbB3 antibody is administered once every three weeks at a dose of about 40 or 60 mg/kg.

17. The method of any one of claims 1-6, wherein the patient does not have metastatic disease.

18. The method of any one of claims 1-6, wherein the patient has metastatic disease.

19. The method of any one of claims 1-6, wherein the treatment produces at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in number of metastatic lesions over time, complete response, partial response, stable disease, increase in overall response rate, or a pathologic complete response.

20. A composition for use in treating solid tumors in a human patient, the composition comprising a clinically proven safe and effective amount of (a) an anti-ErbB3 antibody comprising CDRHl, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRHl) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3) and (b) a carrier.

21. The composition of claim 20, wherein the anti-ErbB3 antibody is MM- 121.

22. The composition of claim 20 or 21, wherein the antibody is formulated for intravenous administration.