AU2012294326A1 - Treatment of advanced solid tumors using combination of anti-ErbB3 immunotherapy and selected chemotherapy - Google Patents

Abstract

Provided are methods and compositions for clinical treatment of solid tumors (e.g., advanced solid tumors) using anti-ErbB3 antibodies combined with a second agent selected from the group consisting of gemcitabine, carboplatin, pemetrexed, and cabazitaxel. Also provided are methods and compositions for clinical treatment of solid tumors using anti-ErbB3 antibodies combined with cetuximab and irinotecan.

Description

WO 2013/023043 PCT/US2012/050124 TREATMENT OF ADVANCED SOLID TUMORS USING COMBINATION OF ANTI-ERBB3 IMMUNOTHERAPY AND SELECTED CHEMOTHERAPY CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority of U.S. Provisional Application 61/522,063 filed August 10, 2011, U.S. Provisional Application No. 61/530,935 filed September 2, 2011, U.S. Provisional Application No. 61/638,611 filed April 26, 2012, U.S. Provisional Application No. 61/535,303 filed September 15, 2011, U.S. Provisional Application No. 61/616,902 filed March 28, 2012, French Application No. 1255209 filed June 5, 2012, and French Application No. 1256174 filed June 28, 2012, all of which are incorporated herein 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 1 WO 2013/023043 PCT/US2012/050124 docking sites for SH2-containing proteins, including P13-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 (P13K), the action of which results in subsequent downstream activation of the AKT pathway. These six P13K 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 may provide an important therapeutic approach to controlling growth in certain in cancers. SUMMARY Provided are compositions and methods for treating advanced solid tumors in a human patient, comprising administering to the patient a combination of an anti-ErbB3 antibody and gemcitabine, carboplatin, pemetrexed, cabazitaxel, or cetuximab and irinotecan, wherein the combination is administered (or is for administration) 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 Antibody A 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, 2 WO 2013/023043 PCT/US2012/050124 respectively. In another embodiment, the 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) 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 comprises a heavy chain having the amino acid sequence set forth in SEQ ID NO: 12 and a light chain having the amino acid sequence set forth in SEQ ID NO: 13. 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 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, the invention pertains to a method of treating advanced stage solid tumors in a human patient comprising administering to the patient an effective amount of (a) an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and 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 second agent, gemcitabine, wherein the method comprises at least one cycle, wherein the cycle is a period of 3 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once per week at a dose of 6, 12, or 20 mg/kg and the gemcitabine is administered at a dose of 800, 1000 or 1250mg/m2 at day 1 and day 8. In another aspect, the invention pertains to a method of treating advanced stage solid tumors in a human patient comprising administering to the patient an effective amount of (a) an anti-ErbB3 antibody comprising CDRH1, CDRH2, and 3 WO 2013/023043 PCT/US2012/050124 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), and (b) a second agent, carboplatin, wherein the method comprises at least one cycle, wherein the cycle is a period of 3 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once per week at a dose of 6, 12, or 20 mg/kg and the carboplatin is administered at a dose having a target AUC of 5 or 6 mg-min/mL at day 1. In one embodiment, the carboplatin dose is calculated using the Calvert formula. In another aspect, the invention pertains to a method of treating advanced stage solid tumors in a human patient comprising administering to the patient an effective amount of (a) an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and 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 second agent, pemetrexed, wherein the method comprises at least one cycle, wherein the cycle is a period of 3 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once per week at a dose of 6, 12, or 20 mg/kg and the pemetrexed is administered at a dose of 375 or 500 mg/m2 at day 1. In still another aspect, the invention pertains to a method of treating advanced stage solid tumors in a human patient comprising administering to the patient an effective amount of (a) an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and 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 second agent, cabazitaxel, wherein the method comprises at least one cycle, 4 WO 2013/023043 PCT/US2012/050124 wherein the cycle is a period of 3 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once per week at a dose of 6, 12, or 20 mg/kg and the cabazitaxel is administered at a dose of 20 or 25 mg/m2 at day 1. In one embodiment, the second agent is administered immediately following the anti-ErbB3 antibody. In still another aspect, methods of treating cancer 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 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) cetuximab, wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, wherein for each cycle the anti-ErbB3 antibody is administered at a weekly dose of 6, 12, 20, or 40 mg/kg and the cetuximab is administered at a dose of 200 or 250 mg/m 2 once per week, except for week 1 of the first cycle, wherein the cetuximab optionally may be administered at 400 mg/m 2 . In another aspect, methods for 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 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) cetuximab and (c) irinotecan, wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, wherein for each cycle the anti-ErbB3 antibody is administered at a weekly dose of 6, 12, 20, or 40 mg/kg and the cetuximab is administered at a dose of 250 or 200 mg/m 2 once per week, except week 1 of the first cycle, wherein the cetuximab optionally may be administered at 400 5 WO 2013/023043 PCT/US2012/050124 mg/m 2 , and the irinotecan optionally may be administered at a dose of 120, 150, or 180 mg/m 2 once every two weeks. In another aspect, methods for treating cancer 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 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) cetuximab and (c) irinotecan wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, and wherein the antibody and cetuximab are administered according to Dose Schedules -1,1, 2a, 2b, 3a, 3b or 4 as follows: Dose Level Antibody Dose' (mg/kg) Cetuximab Dose (mg/m 2 ) -1 6 400 (loading dose) 200 (weekly maintenance dose) 1 12 400 (loading dose) 200 (weekly maintenance dose) 2a 20 400 (loading dose) 200 (weekly maintenance dose) 2b 12 400 (loading dose) 250 (weekly maintenance dose) 3a 40 (loading dose) 400 (loading dose) 20 (weekly maintenance dose) 200 (weekly maintenance dose) 3b 20 400 (loading dose) 250 (weekly maintenance dose) 4 40 (loading dose) 400 (loading dose) 20 (weekly maintenance dose) 250 (weekly maintenance dose) and the irinotecan is administered at a dose of 120, 150, or 180 mg/m 2 once per two weeks. In another aspect, methods are provided for treating cancer in a human patient, comprising administering to the patient, an effective amount of each of (a) an anti ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the 6 WO 2013/023043 PCT/US2012/050124 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), and (b) inrinotecan, wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, wherein for each cycle the anti-ErbB3 antibody is administered at a weekly dose of 6, 12, 20, or 40 mg/kg and the irinotecan is administered at a dose of 120, 150 or 180 mg/m 2 once every two weeks. In one embodiment, the cetuximab and/or irinotecan are administered immediately after the anti-ErbB3 antibody. In one embodiment, the cancer is EGFR dependent. In another embodiment, the cancer is selected from the group consisting of: colorectal cancer, squamous cell head and neck cancer, non-small cell lung cancer, and triple negative breast cancer. In another embodiment, the anti-ErbB3 antibody is Antibody A. In another embodiment, the anti-ErbB3 antibody is administered at a dose of 12, 20, or 40 mg/kg for week 1 of cycle 1. In another embodiment, the antibody is formulated for intravenous administration at a dose of 20 mg/kg. In further embodiments, the treatment produces at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in number of metastasic lesions over time, complete response, partial response, stable disease, increase in overall response rate, or a pathologic complete response. In another aspect, the invention pertains to a kit (e.g., for treating a solid tumor in a human patient) comprising a dose of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth, respectively, in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino 7 WO 2013/023043 PCT/US2012/050124 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 methods described herein. In one embodiment, the kit comprises at least 500 mg of the antibody. In another embodiment, the kit further comprises at least 1 mg of a second agent selected from the group consisting of: gemcitabine, carboplatin, pemetrexed, cabazitaxel, cetuximab, and irinotecan. In another embodiment, the kit comprises one or both of cetuximab and irinotecan. 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 co-administration with cetuximab in at least one cycle, wherein the anti-ErbB3 antibody is administered at a weekly dose of 6, 12, 20, or 40 mg/kg and the cetuximab is administered at a dose of 400, 250 or 200 mg/m 2 once per week. In one embodiment, the antibody is further co-administered with irinotecan. In another embodiment, the irinotecan is administered at a dose of 120, 150, or 180 mg/m 2 once every two weeks. In another aspect, a method of treating cancer in a human patient is provided, the method comprising concomitantly administering to the patient, an effective amount of each of (a) an anti-human-ErbB3 antibody that inhibits cellular activation by heregulin, (b) an anti- human-EGFR antibody that inhibits cellular activation by EGF, and (c) a camptothecin topoisomerase I inhibitor. In one embodiment, the anti human-ErbB3 antibody is MM-121, the anti- human-EGFR antibody is cetuximab, and the camptothecin topoisomerase I inhibitor is irinotecan. 8 WO 2013/023043 PCT/US2012/050124 BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 depicts the mean mouse body weight throughout treatment period of NCI N87 xenograft. Group 1: vehicle (PBS); Group 2: Antibody A; Group 3: Cabazitaxel 9.3 mg/kg; Group 4: Cabazitaxel 15mg/kg; Group 5: Antibody A + Cabazitaxel 9.3 mg/kg; Group 6: Antibody A + Cabazitaxel 15mg/kg. Figure 2 plots tumor volume of NCI-N87 xenografts treated with mono or combination therapy. Figure 3 graphically depicts tumor volume at the end of study (day 36) of NCI-N87 xenografts treated with mono or combination therapy (** p less than 0.001; *** p less than 0.0001). Figure 4 graphically shows total ErbB3 expression in xenografts collected at the end of study (day 36) of NCI-N87 xenografts treated with mono or combination therapy. Figure 5 shows the results of preclinical studies conducted in the LoVo human colon cancer xenograft model in which therapy with Antibody A, cetuximab and irinotecan has an additive effect in doublet and triplet combination. Figure 6 shows the effects of Antibody A in combination with cetuximab on ACHN and HCC827 cells. Figure 7 illustrates the two parts of the phase I study in patients having solid tumors treated with Antibody A in combination with cetuximab and irinotecan. In Part 1, doses of Antibody A and cetuximab will be escalated (or decreased), to determine the maximum tolerated dose (MTD) of the combination. Part 2 will then determine the MTD for the cetuximab plus Antibody A combination in conjunction with irinotecan. DETAILED DESCRIPTION I. Definitions As used herein, the term "subject" or "patient" is a human cancer patient. 9 WO 2013/023043 PCT/US2012/050124 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 cancer. Effective treatment may refer to alleviation of at least one symptom of cancer. 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 Antibody A and the amount of a second agent clinically proven to effect a significant decrease in cancer or slowing of progression of cancer, such as an advanced solid tumor. 10 WO 2013/023043 PCT/US2012/050124 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: IgGI, IgG2, IgG3, IgG4, IgM, IgA1, 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. Ila. Gemcitabine Gemcitabine (gemcitabine for injection, USP) is a nucleoside metabolic inhibitor that exhibits antitumor activity. Gemcitabine HCl is 2'-deoxy-2',2' difluorocytidine monohydrochloride (-isomer). The structural formula is as follows: NH2-HCI N HO" HYH oHl F 11 WO 2013/023043 PCT/US2012/050124 The empirical formula for gemcitabine HCl is C9H11F2N304 - HCl. It has a molecular weight of 299.66. Ib. Carboplatin Carboplatin is a platinum coordination compound. The chemical name for carboplatin is platinum diamine [1,1-cyclobutane-dicarboxylato(2-O,']-,(SP-4-), and has the following structural fomula: X 70

H

3 N 0 Pemetrexed disodium heptahydrate has the chemical name L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo- 1H-pyrrolo[2,3-d]pyrimidin-5 yl)ethyl]benzoyl]-, disodium salt, heptahydrate. It is a white to almost-white solid with a molecular formula of C20H19N5Na2O6-7H20 and a molecular weight of 597.49. The structural formula is as follows: 0 CO 2 Na+ 0 N -7H 2 0 HN H / \ C 0 2 Na+

H

2 N N CO a H Ic. Cabazitaxel Cabazitaxel is an antineoplastic agent belonging to the taxane class. It is prepared by semi-synthesis with a precursor extracted from yew needles. The 12 WO 2013/023043 PCT/US2012/050124 chemical name of cabazitaxel is (2a,5p,7p,10p,13a)-4-acetoxy-13-({(2R,3S)-3 [(tertbutoxycarbonyl) amino] -2-hydroxy-3-phenylpropanoyl I oxy)- 1 -hydroxy-7,10 dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate - propan-2-one(1:1). Cabazitaxel has the following structural formula: 0 0 OH 0~ 0HO 0 Ild. Anti-EGFR Antibodies Cetuximab (marketed as Erbitux*) is a recombinant, human/mouse chimeric monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). Cetuximab is thus an anti-human-EGFR antibody. Cetuximab is composed of the Fv regions of a murine anti-EGFR antibody with human IgGI heavy and kappa light chain constant regions and has an approximate molecular weight of 152 kDa. Other anti-human-EGFR antibodies include panitumumab, nimotuzumab, zalutumumab and matuzumab. Ile. Camptothecin Topoisomerase I Inhibitors Irinotecan (marketed as CAMPTOSAR* Injection (irinotecan hydrochloride injection)) is an antineoplastic agent of the topoisomerase I inhibitor class. Irinotecan hydrochloride is a semisynthetic derivative of camptothecin, an alkaloid extract from plants such as Camptotheca acuminata or is chemically synthesized. Camptothecin and its derivatives are referred to as camptothecins, and irinotecan is referred to as a camptothecin. The chemical name is (S)-4,11-diethyl-3,4,12,14-tetrahydro-4 hydroxy-3,14-dioxo lH pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-9-yl 13 WO 2013/023043 PCT/US2012/050124 [1,4'bipiperidine]-l'-carboxylate, monohydrochloride, trihydrate. Its structural formula is as follows: CHHC 00 HO CCN rinotecan Hydrochlorde Irinotecan hydrochloride is a pale yellow to yellow crystalline powder, with the empirical formula C33H38N406-HCl-3H20 and a molecular weight of 677.19. It is slightly soluble in water and organic solvents. Irinotecan is also known as CPT-11. Other camptothecin topoisomerase I inhibitors include 9-aminocamptothecin, 7 ethylcamptothecin, 10-hydroxycamptothecin, 9-nitrocamptothecin, 10,11 methylenedioxycamptothecin, 9-amino- 10,11 -methylenedioxycamptothecin, 9 chloro- 10,11 -methylenedioxycamptothecin, irinotecan, topotecan, lurtotecan, silatecan, (7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20(S) camptothecin, 7-(4-methylpiperazinomethylene)- 10,11 -methylenedioxy-20(S) camptothecin and 7-(2-N-isopropylamino)ethyl)-(20S)-camptothecin. 1f. Anti-ErbB3 Antibodies Useful anti-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; US20200310557; US20100255010, as well as antibodies IB4C3 and 2D1D12 (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 14 WO 2013/023043 PCT/US2012/050124 monoclonal antibody 8B8, described in US 5,968,511. One example of such an antibody is Antibody A having heavy and light chains comprising the amino acid sequences set forth in SEQ ID NOs 12 and 13, respectively. Antibody A is referred to as "Ab #6" in US 7,846,440, which is hereby incorporated by reference. In one embodiment, the anti-ErbB3 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 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 anti-ErbB3 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 Antibody A, can be generated, e.g., in prokaryotic or eukaryotic cells, using methods well know in the art. In one embodiment, the antibody is produced in a cell line capable of glycosylating proteins, such as CHO cells. 15 WO 2013/023043 PCT/US2012/050124 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, both anti-ErbB3 antibody and a second agent selected from the group consisting of gemcitabine, carboplatin, pemetrexed, and cabazitaxel are administered intravenously (e.g., separately or together, each, e.g., over the course of, e.g., 5 to 90 minutes). Antibody A 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 Antibody A 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. Gemcitabine (gemcitabine for injection, USP) is a nucleoside metabolic inhibitor that exhibits antitumor activity. Gemcitabine HCl is 2'-deoxy-2',2' difluorocytidine monohydrochloride (-isomer). Gemcitabine HCl is a white to off 16 WO 2013/023043 PCT/US2012/050124 white solid. It is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents. The clinical formulation is supplied in a sterile form for intravenous use only. Vials of Gemzar contain either 200 mg or 1 g of gemcitabine HCl (expressed as free base) formulated with mannitol (200 mg or 1 g, respectively) and sodium acetate (12.5 mg or 62.5 mg, respectively) as a sterile lyophilized powder. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment. Carboplatin for injection is supplied as a sterile, pyrogen-free 10 mg/ml aqueous solution of carboplatin. Carboplatin is a crystalline powder with the molecular formula of CH12,N 2

O

4 Pt and a molecular weight of 371.25. It is soluble in water at a rate of approximately 14 mg/ml and the pH of a 1% solution is 5-7. It is virtually insoluble in ethanol acetone, and dimethylacetarnide. Pemetrexed is supplied as a sterile lyophilized powder for intravenous infusion available in single-dose vials of either 100 or 500 mg. The product is a white to either light yellow or green-yellow lyophilized solid. Reconstitution of either size vial gives a solution containing 25 mg/mL pemetrexed. The resulting solution is clear and ranges in color from colorless to yellow or green-yellow. The pH of the reconstituted solution is between 6.6 and 7.8. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH. Each 100-mg or 500-mg vial of Pemetrexed contains pemetrexed disodium equivalent to 100 mg pemetrexed and 106 mg mannitol or 500 mg pemetrexed and 500 mg mannitol, respectively. Cabazitaxel is an antineoplastic agent belonging to the taxane class. It is prepared by semi-synthesis with a precursor extracted from yew needles. Cabazitaxel is a white to off-white powder with a molecular formula of C45H57NO14.C3H60 and a molecular weight of 894.01 (for the acetone solvate) / 835.93 (for the solvent free). It is lipophilic, practically insoluble in water and soluble in alcohol. Cabazitaxel Injection 60 mg/1.5 mL is a sterile, non-pyrogenic, clear yellow to brownish-yellow viscous solution and is available in single-use vials containing 60 mg cabazitaxel (anhydrous and solvent free) and 1.56 g polysorbate 80. Each mL contains 40 mg cabazitaxel (anhydrous) and 1.04 g polysorbate 80. Diluent for cabazitaxel is a clear, 17 WO 2013/023043 PCT/US2012/050124 colorless, sterile, and non-pyrogenic solution containing 13% (w/w) ethanol in water for injection, approximately 5.7 mL. Cabazitaxel requires two dilutions prior to intravenous infusion, with the supplied diluent, followed by dilution in either 0.9% sodium chloride solution or 5% dextrose solution. Cetuximab is produced in mammalian (murine myeloma) cell culture. Cetuximab is a sterile, clear, colorless liquid of pH 7.0 to 7.4, which may contain a small amount of easily visible, white, amorphous cetuximab particulates. Cetuximab is supplied at a concentration of 2 mg/mL in either 100 mg (50 mL) or 200 mg (100 mL), single-use vials. Cetuximab is formulated in a solution with no preservatives, which contains 8.48 mg/mL sodium chloride, 1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.41 mg/mL sodium phosphate monobasic monohydrate, and Water for Injection, USP Irinotecan hydrochloride was clinically investigated as CPT- 11. Irinotecan is supplied as a sterile, pale yellow, clear, aqueous solution. It is available in two single-dose sizes in brown glass vials: 2 mL-fill vials contain 40 mg irinotecan hydrochloride and 5 mL-fill vials contain 100 mg irinotecan hydrochloride. Irinotecan is also available in three single-dose sizes in amber-colored polypropylene CYTOSAFE vials: 2 mL-fill vials contain 40 mg irinotecan hydrochloride, 5 mL-fill vials contain 100 mg irinotecan hydrochloride and 15 mL-fill vials contain 300 mg irinotecan hydrochloride. Each milliliter of solution contains 20 mg of irinotecan hydrochloride (on the basis of the trihydrate salt), 45 mg of sorbitol, NF, and 0.9 mg of lactic acid, USP. The pH of the solution has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid. Irinotecan is intended for dilution with 5% Dextrose Injection, USP (D5W), or 0.9% Sodium Chloride Injection, USP, prior to intravenous infusion. The preferred diluent is 5% Dextrose Injection, USP. 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 a combination of an anti 18 WO 2013/023043 PCT/US2012/050124 ErbB3 antibody and gemcitabine, carboplatin, pemetrexed, cabazitaxel, or cetuximab and irinotecan. 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, squamous cell head and neck cancer, non-small cell lung cancer, or triple negative breast cancer. In another embodiment, a patient has Kras wild-type metastatic colorectal cancer. In one embodiment, the patient has no standard treatment options remaining. In one embodiment, a patient meets both of these criteria. In another embodiment, a patient has recurrent or metastatic squamous cell carcinoma of the head and neck. In one embodiment, a patient has failed prior platinum-based therapy. In one embodiment, a patient meets both of these criteria. In another embodiment, a patient has non-small cell lung cancer. In one embodiment, a patient has advanced/metastatic carcinoma of the lung. In one embodiment, a patient has no standard treatment options remaining. In one embodiment, a patient meets both of these criteria. In another embodiment, a patient has previously received EGFR TKI therapy and had a response to treatment but have subsequently progressed and become resistant to this therapy. Such subjects may meet the following criteria as adapted from Jackman, et al [Jackman D, et al. Clinical Definition ofAcquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer. J Clin Oncol, 2009. (Epub ahead of print) doi: 10.1200/JCO.2009.25.8574] and Mok [Mok TS. Living with Imperfection. J Clin Oncol, 2009. (Epub ahead of print) doi: 10. 1200/JCO.2009.24.7049]: e Previously received treatment with a single-agent EGFR TKI (e.g. gefitinib or erlotinib); 19 WO 2013/023043 PCT/US2012/050124 e Subsequent systemic progression of disease while on continuous treatment with gefitinib or erlotinib for minimum of 30 days; AND, e A tumor that harbors an EGFR mutation known to be associated with drug sensitivity (ie, G719X, exon 19 deletion, L858R, L861Q). In one embodiment, a patient has triple negative breast cancer (TNBC), e.g., recurrent or metastatic TNBC. In one embodiment, a patient has documented ER-, PR-, Her2- (non-overexpressing) status. In one embodiment, a patient has failed at least one standard chemotherapy regimen. In one embodiment, a patient has no standard treatment options remaining. In one embodiment, a patient meets all of these criteria. In another embodiment, a patient has a solid tumor that may have EGFR dependence. In one embodiment, a patient has a solid tumor that has previously responded to EGFR therapies or patients with known EGFR mutations or amplifications. In one embodiment, a patient has no standard treatment options remaining. In one embodiment, a patient meets both of these criteria. In another embodiment, the cancer undergoing treatment is advanced. In one aspect, the term "advanced" cancer denotes a cancer above Stage II. In another, "advanced" refers to a stage of disease where chemotherapy is typically recommended, which is any one of the following: 1. in the setting of recurrent disease: any stage or grade; 2. stage IC or higher, any grade; 3. stage IA or IB, grade 2 or 3; or 4. in the setting of incomplete surgery or suspected residual disease after surgery (where further surgery can not be performed): any stage or grade. Patients can be tested or selected for one or more of the above described clinical attributes prior to, during or after treatment. V. Combination Therapy As herein provided, anti-ErbB3 antibodies are administered adjunctively with an additional agent or agents selected from the group consisting of gemcitabine, carboplatin, pemetrexed, cabazitaxel, or cetuximab and irinotecan, to effect 20 WO 2013/023043 PCT/US2012/050124 improvement in subjects having a solid tumor (e.g., an advanced solid tumor). In one embodiment, the anti-ErbB3 antibody is Antibody A. As used herein, adjunctive or combined administration (co-administration) includes simultaneous administration of the compounds in the same or different dosage form, or separate administration of the compounds (e.g., sequential administration). For example, the antibody can be simultaneously administered with an additional agent or agents selected from the group consisting of gemcitabine, carboplatin, pemetrexed, cabazitaxel, or cetuximab and irinotecan, wherein both the antibody and the agent(s) are formulated together. Alternatively, the antibody can be administered in combination with an additional agent or agents selected from the group consisting of gemcitabine, carboplatin, pemetrexed, cabazitaxel, or cetuximab and irinotecan, wherein both the antibody and the agent(s) are formulated for separate administration and are administered concurrently or sequentially. For example, the antibody can be administered first followed by (e.g., immediately followed by) the administration of the agent(s), or vice versa. Such concurrent or sequential administration preferably results in both Antibody A and the agent(s) being simultaneously present in treated patients. In another embodiment, anti-ErbB3 antibody is formulated for intravenous administration. In particular embodiments, the anti-ErbB3 antibody is administered at a dose selected from: 40 mg/kg, 20 mg/kg, 12 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. In one embodiment, the anti-ErbB3 antibody is administered as a monotherapy prior to the combination therapy. In another embodiment, a dose of 12, 20, or 40 mg/kg of Antibody A antibody is administered once per week for the initial week of combination therapy, followed in subsequent weeks by a dose of 6, 12, or 20 mg/kg. In yet another embodiment, the second agent 21 WO 2013/023043 PCT/US2012/050124 is administered at an amount that is the standard of care for treatment of cancer. Exemplary treatment protocols are set forth in more detail below. VI. Treatment Protocols Suitable treatment protocols include the following protocols. Gemcitabine In the case of gemcitabine, an exemplary treatment protocol comprises 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 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 second agent, gemcitabine, wherein the method comprises at least one cycle, wherein the cycle is a period of 3 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once per week at a dose of 6, 12, or 20 mg/kg and the gemcitabine is administered at a dose of 800, 1000 or 1250 mg/m 2 at day 1 and day 8. Carboplatin In the case of carboplatin, an exemplary treatment protocol comprises 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 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 second agent, carboplatin, wherein the method comprises at least one cycle, wherein the cycle is a period of 3 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once per week at a dose of 6, 22 WO 2013/023043 PCT/US2012/050124 12, or 20 mg/kg and the carboplatin is administered at a dose of AUC 5 or AUC 6 at day 1. As used herein, the term AUC refers to the "area under the concentration versus time cure in mg/mL* min" and can be calculated by one of ordinary skill in the art. For example, the Calvert formula for carboplatin dosing can be used: Total Dose (mg) = (target AUC) x (GFR + 25) (see, e.g., Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol. 1989;7:1748 1756). In one embodiment, GFR can be measured by 5 1 Cr-EDTA clearance. Pemetrexed In the case of pemetrexed, and exemplary treatment protocol comprises 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 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 second agent, pemetrexed, wherein the method comprises at least one cycle, wherein the cycle is a period of 3 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once per week at a dose of 6, 12, or 20 mg/kg and the pemetrexed is administered at a dose of 375 or 500 mg/m 2 at day 1. Cabazitaxel In the case of cabazitaxel, an exemplary treatment protocol comprises 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 CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and 23 WO 2013/023043 PCT/US2012/050124 SEQ ID NO: 10 (CDRL3), and (b) a second agent, cabazitaxel, wherein the method comprises at least one cycle, wherein the cycle is a period of 3 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once per week at a dose of 6, 12, or 20 mg/kg and the cabazitaxel is administered at a dose of 20 or 25 mg/m 2 at day 1. Cetuximab and Irinotecan In the case of cetuximab and irinotecan, in an exemplary treatment protocol, (A) the anti-ErbB3 antibody is administered to a patient (i.e., human subject) once per week (at a dose of 6, 12, 20, or 40 mg/kg), and (B) the cetuximab is administered to a patient i) once per week for one week at a dose of 400 mg/m2 and then ii) once per week for the following at a dose of 250 or 200 mg/m 2 . In a further embodiment, irinotecan is also administered to a patient once per two weeks at a dose of 180, 150, or 120 mg/m 2 . In one embodiment, the anti-ErbB3 antibody is administered as a monotherapy prior to anti-ErbB3 antibody/cetuximab/irinotecan combination therapy. In one embodiment, anti-ErbB3 antibody monotherapy is administered for one week. In another embodiment, anti-ErbB3 antibody monotherapy is administered for two weeks, wherein the anti-ErbB3 antibody is administered at i) 40 mg/kg for two weeks or ii) 40 mg/kg the first week and at 20 mg/kg the second week. In another embodiment, cetuximab is administered in combination with an amount of Antibody A at an interval measured of at least seven days. A suitable weekly dosage of cetuximab is 400, 250 or 200 mg/m 2 . In another embodiment, the amount of cetuximab administered is constant for each dose. In another embodiment, the amount of cetuximab administered varies with each dose. For example, the maintenance (or follow-on) dose of cetuximab can be higher or the same as the loading dose which is first administered. In another embodiment, the maintenance dose of the cetuximab can be lower or the same as the loading dose. In one embodiment, cetuximab is administered at a loading dose of 400 mg/m2 during the first 24 WO 2013/023043 PCT/US2012/050124 week of cycle one, followed by a dose of 250 or 200 mg/m 2 during subsequent weeks of cycle one and weeks one to four of subsequent cycles. Exemplary Anti-ErbB3 Antibodies Exemplary anti-ErbB3 antibodies for use in the invention include Antibody A, and antibodies having the heavy and light chain CDRs or variable regions of Antibody A. In one embodiment, the amount of 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. In another embodiment, the anti-ErbB3 antibody is administered at a higher (loading) dose during the initial week of combination therapy. For example, during week 1 of cycle 1, the anti-ErbB3 antibody can be administered at a dose of 12, 20, or 40 mg/kg. In another embodiment, a total of three doses of Antibody A are administered three times in a 3-week cycle, i.e., one dose per week. The administration cycle can be repeated, as necessary. VII. Outcomes With respect to target lesions, responses to therapy may include: Complete Response (CR) Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm Partial Response (PR) At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) At least a 20% increase in the sum of the 25 WO 2013/023043 PCT/US2012/050124 diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Stable Disease (SD) 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. With respect to non-target lesions, responses to therapy may include: Complete Response (CR) Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non pathological in size (<10 mm short axis). If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete 26 WO 2013/023043 PCT/US2012/050124 clinical 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) Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. In exemplary outcomes, patients treated according to the methods disclosed herein may experience improvement in at least one sign of cancer, such as an advanced solid tumor. 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. The size of non-target 27 WO 2013/023043 PCT/US2012/050124 lesions, e.g., pathological lymph nodes can also be measured for improvement. 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 further embodiments, administration of effective amounts of the anti-ErbB3 antibody and a second agent 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 metastasic lesions appearing over time, complete remission, partial remission, stable disease, increase in overall response rate, or a pathologic complete response. In some embodiments, the provided methods of treatment produce a comparable clinical benefit rate (CBR = CR+ PR+ SD > 6 months) better than that achieved by the second agent alone. In other embodiments, the improvement of clinical benefit rate is about 20% 20%, 30%, 40%, 50%, 60%, 70%, 80% or more compared to the second agent alone. VIII. Kits and Unit Dosage Forms Also provided are kits that include a pharmaceutical composition containing an anti-ErbB3 antibody, such as Antibody A, and a pharmaceutically-acceptable carrier, in a therapeutically effective amount adapted for use in the preceding methods. The kits can optionally also 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 further comprises gemcitabine, carboplatin, pemetrexed, cabazitaxel, or cetuximab. In 28 WO 2013/023043 PCT/US2012/050124 another embodiment, the kit further comprises irinotecan. In another 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., Antibody A) 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 Antibody A that is about 100 times the dose in mg/kg indicated for administration in the above methods. Optionally, the kit may further comprise gemcitabine, carboplatin, pemetrexed, cabazitaxel, or cetuximab and irinotecan in a desired unit dosage form (e.g., a unit dosage form distributed by the manufacturer) for administration. 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. EXAMPLES Example 1: Combination of Cabazitaxel and Antibody A in Gastric Cancer Model The present study was designed to evaluate the combination of Cabazitaxel and Antibody A in treating tumors. The gastric cancer cell line NCI-N87, possessing HER2 amplification, was selected for the study. Nu/Nu female mice (Charles River Laboratories #088) were inoculated subcutaneously in the right flank with 5 x 106 NCI-N87 cells suspended 1:1 in reduced growth factor matrigel. Mice were randomized in groups of 10 when average tumor volume reached 150-200 mm 3 . The control group were treated with PBS (ip. Q3D). Cabazitaxel was administered at 9.3 mg/kg and 15 mg/kg once a week, by ip until the end of the study. Antibody A was 29 WO 2013/023043 PCT/US2012/050124 administered at 30 mg/kg/inj once a day every three days. The combination conditions were as follows: Cabazitaxel at 9.3 mg/kg, weekly administered with Antibody A at 30mg/kg once a day every three days; or Cabazitaxel at 15 mg/kg, weekly administered with Antibody A at 30mg/kg once a day every three days. For the evaluation of anti-tumor activity of conjugates, animals were weighed and tumors were measured by caliper three times a week. A dosage producing a 20% weight loss at nadir (mean of group) or a 15% weight loss (mean of group) three successive times or drug deaths, was considered an excessively toxic dosage. Animal body weights included the tumor weights. The primary efficacy end points were T/C value and significant tumor growth inhibition at the end of study (day 36), evaluated by one way analysis of variance (ANOVA). At study completion, mice were euthanized by a mix of 02/CO2 (20/80%), and tumors were resected and cut into 100-150 mg fragments. Each fragment was placed in Precellys tube containing 2.8mm ceramic beads (CK28-R kit Ozyme #BER1030) and stored at -80'C. Protein extracts were prepared by mechanical dissociation using a bead beating Precellys homogenizer 24 (Ozyme #BER 1011) with a Cryolys cooling system (2 runs of 2 x 30 seconds at 6000 rpm) in lysis buffer [10 mM Tris pH 7.5 (InVitrogen #15567-027), 100 mM NaCl (Sigma #S5150), 1 mM EDTA pH 8 (Invitrogen #15575-038), 1 mM EGTA pH 8 (Sigma #E4378), 1% Triton (Sigma #T9284), 1 mM NaF (Sigma #S7920), 20 mM Na4P207 (Sigma #S6422), 1 mM activated Na3VO4 (Sigma #S6508), 10% glycerol (Fisher Scientific #W353X) supplemented with protease inhibitor tablets (Roche Diagnostics #11836145001)]. The samples were incubated 2 hours at 4'C to extract membrane proteins, clarified by a 16000xg centrifugation for 15 minutes at 4'C, and supernatants were collected, aliquoted and stored at -80'C until analysis. Protein concentrations were determined with the BCA protein assay kit with a standard curve of Bovine Serum Albumin (Thermo Fisher #23225) in 96-well plate format. Samples were diluted to 1/10 in PBS pH 7.4 (Invitrogen #10010-05-500mL). Levels of protein ErbB3 were determined using Multi-Spot 96-4-Spot HB Prototype Total 30 WO 2013/023043 PCT/US2012/050124 ErbB3 from MSD (# N45ZB-1) with a 1/5 dilution of tumor lysates in lysis buffer. Samples were analyzed in duplicate. Results were normalized by protein concentration (mg/mL). Parameters Tumor growth inhibition analysis (T/C value) was performed to assess therapeutic efficacy. The median tumor volume of each group is divided by the median tumor volume of control group. This value expressed as percentage indicates antitumor effectiveness. ErbB3 protein expression is expressed as arbitrary units of fluorescence normalized by total protein sample content. The change of ErbB3 expression induced by Cabazitaxel and/or Antibody A treatments was calculated as % of control [(mean ErbB3 of treated group / mean of ErbB3 of control group]* 100. A T/C value less than 42% was considered significant anti-tumor activity Statistical analyses Tumor volume at the end of study (Day 36). Turkey's multiple comparison tests were performed to identify which means are significantly different from one another. A 95% confidence value was used (p less than 0.05). Body weight change from start of experimentation. Results The results are depicted in Figures 1-4. Based on the mean body weight change calculated from beginning of treatment to end of study, no significant body weight loss (20% weight loss at nadir) was observed in monotherapy treated groups. Weight loss and other health complication were observed in groups treated with combination therapy. More specifically, 2 mice treated with combination of Cabazitaxel at 9.3mg/kg and Antibody A died. One mouse died on day 33, and one 31 WO 2013/023043 PCT/US2012/050124 mouse was dehydrated on day 36, provided saline and found dead on day 37. In the group treated with combination of Cabazitaxel at 15 mg/kg and Antibody A, 4 mice had significant weight loss. Antibody A was suspended for those four mice on day 10 only. All animals recovered above the weight loss threshold and did not show significant body weight loss after subsequent dosing of either Antibody A or Cabazitaxel. Treatment groups receiving monotherapy did not show significant tumor growth inhibition as measured by T/C Value (%): Antibody A 88.6% (at 30mg/kg); Cabazitaxel 70.18% (9.3 mg/kg) and Cabazitaxel 64.06% (15mg/kg). A T/C equal or less than 42% is considered significant anti-tumor activity. At the end of experiment (Day 36), Cabazitaxel 15mg/kg treated group showed a significant difference when compared to control group (p=0.001). The combination treatment of Cabazitaxel at 9.3 mg/kg with Antibody A was marginally active measured by T/C value (46.65%) but was highly significant at the end of study (p less than 0.0001). This group showed one partial regression (more than 50% reduction from initial tumor size) and one complete regression (below measurable size for three consecutive time points). The combination of Cabazitaxel at 15 mg/kg with Antibody A (35.29%) showed significant tumor growth inhibition by T/C value. At the end of study (day 36), it also showed a highly significant difference when compared to control (p < 0.0001). This group had one partial regression. Single administration of Antibody A induced a decrease of ErbB3 expression in NCI-N87 tumor bearing mice compared to control (-40%, p<0.05). This effect also was observed when Antibody A combined with Cabazitaxel at the two doses of 9.3mg/kg and 15mg/kg (-56%, p<0.05). Compared to single agent administration of Antibody A, combination of Antibody A and Cabazitaxel at 9.3mg/kg and 15mg/kg induced significantly more ErbB3 down-expression (-40% for Antibody A single agent and -56% for Antibody A + Cabazitaxel at the two dose of 9.3mg/kg and 15mg/kg, p<0.05). 32 WO 2013/023043 PCT/US2012/050124 Conclusion Antibody A as single agent was well-tolerated. Cabazitaxel administered alone or in combination with Antibody A did not induce marked weight loss. No added toxicity was observed with the combination. Based upon the evaluation criteria of antitumor activity (T/C) in NCI-N87 xenografts, the combination of Antibody A and Cabazitaxel (e.g., 15mg/kg) showed significant tumor growth inhibition and ErbB3 down-expression. Example 2: Inhibition of tumor growth in vivo by combination treatment with Antibody A, cetuximab and irinotecan An analysis of the anti-tumor efficacy and tolerability of Antibody A treatment of tumor-bearing mice was carried out using human colorectal adenocarcinoma LoVo cells (ATCC # CL-229) implanted as xenografts in nu/nu nude mice. LoVo cells are derived from a human metastatic tumor and express moderate levels of HRG and EGFR, two biomarkers that have been previously correlated with Antibody A response in xenografts. In these xenograft studies, nu/nu nude mice are obtained from Charles River Laboratories International. The mice are housed in Tecniplast Individually Ventilated polycarbonate (Macrolon) Cages (IVC) set in climate-controlled rooms and have free access to food and acidified water. 8 x 106 cells are mixed 1:1 in reduced growth factor matrigel (BD Biosciences, Cat # 35230) and implanted by subcutaneous injection into the left flank of female, 4-5 week old nu/nu mice. Tumors are allowed to reach 150 mm 3 in size before randomization. Dose escalation study A dose escalation study was performed to determine suboptimal doses of Antibody A, CPT- 11 and cetuximab in preparation for combination therapy for the LoVo xenograft model. 33 WO 2013/023043 PCT/US2012/050124 Xenograft bearing mice were randomized into 11 groups of 8 mice, containing mice with a similar size distribution of tumors. Four groups were treated with escalating intraperitoneal (i.p.) doses of Antibody A (75, 150, 300 or 600 pg, Q3D per group), 3 groups were treated with escalating doses of CPT-11(irinotecan) (12.5, 25 or 50 mg/kg, Q7D, per group), 3 groups were treated with escalating doses of cetuximab (0.5, 1, 2 mg/kg, Q3D) and one control group was treated with PBS, Q3D. Treatment was continued for 4 weeks. Tumors were measured twice weekly and tumor volume was calculated as p/6 x length x width 2 , where the width was the for inhibition of tumor growth were observed for Antibody A, CPT- 11, and cetuximab. The suboptimal doses selected for future studies with combination therapy in LoVo xenografts were: 600 pg Q3D for Antibody A, 50 mg/kg for CPT1 1 Q7D and 2mg/kg Q3D for cetuximab. Combination therapy study A combination therapy study was performed to determine the effects of various combinations of Antibody A, cetuximab, and irinotecan. Xenograft bearing mice were randomized into 7 groups of 10 mice each, containing mice with a similar size distribution of tumors. Four groups were treated with i.p. doses of Antibody A (600 p g Q3D), CPT- 11 (50 mg/kg Q7D), cetuximab (2 mg/kg Q3D), or PBS (Q3D) alone as a control. Three groups were treated with a combination therapy of Antibody A + CPT 11, Antibody A + cetuximab or Antibody A + CPT-1 1 + cetuximab with the doses described above. Treatment was continued for 7 weeks. Tumors were measured twice weekly and tumor volume is calculated as p/6 x length x width 2 , where the width is the shorter measurement. Results As shown in Figure 5, while Antibody A, CPT-1 1 and cetuximab, as well as the dual combinations, each inhibited tumor growth in vivo, mice receiving a combination therapy of Antibody A + CPT- 11 + cetuximab exhibited a statistically significant improvement of tumor growth inhibition when compared to that obtained with each of the individual treatments or treatment with pairs of these agents. 34 WO 2013/023043 PCT/US2012/050124 Example 3: Co-inhibition of ErbB3 and EGFR Assessment of the effects of anti-EGFR therapy with an anti-EGFR ligand blocking antibody in combination with anti-ErbB3 therapy with an anti-ErbB3 ligand blocking antibody. ACHN renal carcinoma cells were seeded at 1000 cells/well in 96-well culture plates, and HCC827 NSCLC cells were seeded at 2000 cells/well in 96-well culture plates. Cells were grown overnight, then switched to low serum media (0.5% FBS) for 24 hours before treating with multiple doses of Antibody A (an anti-ErbB3 ligand blocking antibody), cetuximab (an anti-EGFR ligand-blocking antibody), or Antibody A + cetuximab, for 3 days. ATP levels were measured using CellTitre Glo@ (Promega Corp.) assay and then normalized to a vehicle control. Bliss synergy/additivity analysis was then performed. Per the Bliss analysis, the fractional response if two drugs are exactly additive was calculated by taking the product of control normalized data for each drug alone. Then the difference between the observed and calculated fractional response was divided by the calculated fractional response to get a bliss index value that is negative (synergy), close to zero (additive), or positive (antagonism). The data (Figure 6) show that in Antibody A-cetuximab combinations synergistically inhibit ACHN cell growth, as assessed by Bliss additivity-synergy analysis (Fitzgerald, JB, et al., Nat Chem Biol.2006 (9):458-66). Example 4: Phase 1 Trial in Patients Having Advanced Solid Tumors (Antibody A in combination with gemcitibine, carboplatin, pemetrexed or cabazitaxel) A phase 1 trial of Antibody A in combination with gemcitibine, carboplatin, pemetrexed or cabazitaxel is conducted in patients having advanced solid tumors to demonstrate the safety and efficacy of administering Antibody A as part of a combination treatment comprising gemcitibine, carboplatin, pemetrexed or cabazitaxel. 35 WO 2013/023043 PCT/US2012/050124 Objectives The primary objectives of this study are to evaluate the safety and tolerability of escalating doses of the Antibody A + anticancer therapies and to determine the maximum tolerated dose (MTD) or maximum required pharmacological dose of Antibody A in combination with anticancer therapies and to characterize dose limiting toxicities (DLTs) associated with these combinations. The primary expansion phase objectives are to continue to characterize the safety and tolerability of the Antibody A in combination with other anticancer therapies and to correlate a pre-specified five biomarker panel reflective of ErbB3 signalling activity with the clinical outcome of the patients. The secondary objectives of the study are to characterize the efficacy of the combination of Antibody A with anticancer therapies using objective response rate, clinical benefit rate defined as CR+PR+SD at 6 months, and other key efficacy indicators; to determine the pharmacokinetics (PK) of Antibody A when administered in combination with anticancer therapies; and to determine the immunogenicity of Antibody A when administered in combination with anticancer therapies. The exploratory objectives are: to evaluate changes in the following pharmacodynamic (PD) biomarkers; to investigate the relationship between these changes and Antibody A exposure and anti-tumor activity: e tErbB3, pErbB3, pAKT and pERK in readily obtained tumor tissue; e Heregulin levels in plasma e Additional molecular predictors may also be identified and evaluated; and to explore the utility and feasibility of a potentially predictive set of biomarkers to be measured in tumor tissue, blood, ascites/pleural fluid. 36 WO 2013/023043 PCT/US2012/050124 Study Design This study is a Phase 1 and pharmacologic dose-escalation trial of Antibody A and anticancer therapies. The dose-escalation portion of the study employs a 3 + 3 design to assess the safety, tolerability, and pharmacokinetics of Antibody A administered weekly in combination with anticancer therapies in patients with advanced/recurrent cancer. Doses of Antibody A will be escalated when given in combination with a fixed dose of anticancer therapy in this study until either the MTD is identified or the combination is shown to be tolerable at the highest planned doses. Within each regimen, each cohort of three patients must be followed for at least 3 weeks before enrolling the next cohort of three patients on that combination. Three combination regimens are currently planned: gemcitabine, carboplatin and pemetrexed. Additional anticancer combinations and dosing cohorts may be added, as appropriate. The rationale and related discussions between the Investigators and Sponsor to include additional combinations will be documented in the study file along with planned dose levels of the additional combinations. Dose limiting toxicities will be defined for each combination regimen, depending on the existing known safety profile of the standard component of the combination therapy. Dose escalation will occur separately within each combination regimen. Within a given dose level cohort of 3 patients: if no DLTs are observed, dose escalation can occur; if 2 or more patients have DLTs, dose escalation for that combination will cease; if a DLT is experienced by one of the 3 first patients, 3 additional patients will be enrolled at that dose level and followed for at least 3 weeks each. If one (or more) additional patients experiences a DLT out of this expanded group of patients, enrollment in that combination cohort will be suspended, and continuation of the study for this combination cohort will be discussed between the Investigators and the Sponsor. The Investigators and Sponsor may choose to evaluate lower doses of the combination therapy or Antibody A, as appropriate. Continued escalation of the combination therapy and Antibody A may also be evaluated, 37 WO 2013/023043 PCT/US2012/050124 however, any resulting changes to the dose escalation schema or protocol will be made and submitted for appropriate approvals prior to continuing escalation. Patients will be considered for one of the combination therapies based upon presenting diagnosis and current disease status. The Investigator will use his/her discretion to enroll patients appropriate for the combination treatment. All patients will participate in up to 28 days of screening, during which time they will complete all screening procedures. Patients will be re-assessed for evidence of disease progression in accordance with current RECIST v1.1 criteria after 6 weeks of study treatment or sooner if the Investigator suspects progression has occurred based on clinical signs and symptoms. Disease staging will continue every 6 weeks until study discontinuation. Blood samples will be taken at various timepoints to determine the pharmacokinetic properties of the combination. The combination treatment will be administered in 3-week cycles, with Antibody A given weekly and the standard component of the regimen given on its appropriate schedule. On day 1 of the cycle, the combination chemotherapy will be given immediately following Antibody A therapy. Cycles will be repeated every 3 weeks until disease progression, intolerable toxicity or other reason for study termination. Local radiologist and/or PI assessment is accepted for efficacy evaluation. For each combination, specific PK, PD and safety parameters will be assessed. In case of evident clinical benefit but discontinuation of the combined agent(s) due to toxicity, Antibody A treatment alone can be continued until disease progression or unacceptable toxicity. In the event a patient experiences a DLT which resolves or returns to baseline grade, the Investigator may elect to resume combination treatment in accordance with standard practices for the standard component of the combination therapy (e.g. reduced doses, etc.) after discussion with the sponsor. In this case, the Antibody A dose will remain unchanged. Patients within the dose escalation portion of the study will be asked to undergo optional pre-treatment and post-treatment biopsies to collect information regarding the pharmacodynamic effects of the Antibody A + anticancer therapy at varying dose levels; however, biopsies will not be required for participation in this 38 WO 2013/023043 PCT/US2012/050124 portion of the study. Additional biomarker samples will be collected and analyzed for all patients at various timepoints throughout the study (e.g. blood, pleural effusion, ascites). Once tolerability and safety are assessed in six patients at a dose level in the dose escalation phase, an Expansion Phase will be opened for enrollment at the final dose level identified for each combination cohort. During the Expansion Phase, patients will undergo mandatory pre-treatment and post-treatment biopsies to evaluate pharmacodynamic effects of the Antibody A + anticancer therapies. Intermediate dose levels (using a lower dose of either/both Antibody A or the combination therapy) or altering schedules may also be evaluated in the Expansion Phase. Prior to initiating enrollment in intermediate Expansion phase dose levels or schedules, the Sponsor and Investigators will make recommendations for additional dose levels or schedules based upon available data, including but not limited to pharmacokinetic, pharmacodynamic, efficacy and safety data. Upon agreement, this recommendation will be documented as part of the routine Investigator meeting minutes and notifications will be submitted, as required, to the necessary reviewing committees. The exact number of patients to be enrolled in the Dose Escalation portion of the study will depend on the exact number of patients required to identify the MTD of the combination or to reach the maximum planned dose of the combination. It is estimated that 18-48 patients will be enrolled in this portion of the study. Approximately 6 patients will be enrolled in each Expansion phase to confirm safety data and further evaluate the safety and pharmacodynamics of the combination. It is estimated that approximately 18-24 patients may be enrolled in this portion of the study. It is anticipated that approximately 3-4 sites in NA/EU will participate in this study. Additional sites may be added, as deemed appropriate. Inclusion Criteria In order to be included, patients must have/be: e Pathologically confirmed advanced-stage solid tumors 39 WO 2013/023043 PCT/US2012/050124 e disease for whom the selected combined chemotherapy is indicated or is a reasonable option (as per tumor characteristics and previous treatments) > 18 years of age. e Able to understand and sign an informed consent (or have a legal representative who is able to do so) e Measurable disease according to RECIST v1.1. e If available; unstained tumor tissue for analysis from most recent e ECOG Performance Score (PS) of 0 or 1. e Recovered from the effects of any prior surgery, radiotherapy or other antineoplastic therapy. Patients with a known peripheral neuropathy must present as Grade 1 or less, according to National Cancer Institute common terminology criteria [NCI CTCAE], version 4.0, to be eligible for inclusion. e Adequate bone marrow reserves as evidenced by: o ANC > 1,500/p1 without the use of hematopoietic growth factors; and o Platelet count > 100,000/p1; and o Hemoglobin > 9 g/dL e Adequate hepatic function as evidenced by: o Serum total bilirubin < 1.5 x ULN " Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and Alkaline Phosphatase < 2.5 x ULN (< 5 x ULN is acceptable if liver metastases are present, and < 5 x ULN of Alkaline Phosphatase is acceptable if bone metastases are present). e Adequate renal function as evidenced by a serum creatinine < 1.5 x ULN. For serum creatinine between 1-1.5 x ULN, a CrCl>60ml/min is required. e Have a negative pregnancy test prior to the study entry and be practicing an effective form of contraception. e For patients in the expansion phase, willing to undergo a pre-treatment and post treatment biopsy: 40 WO 2013/023043 PCT/US2012/050124 o Availability of a cancerous lesion for biopsy that is in a location amenable to biopsy o Of adequate size (i.e.diameter at least 1 cm) to permit biomarker evaluation in sample - per investigator's judgement Exclusion Criteria Patients must meet all the inclusion criteria listed above and none of the following exclusion criteria: e Prior radiation therapy to >25% of bone marrow-bearing areas. e Evidence of any other active malignancy. e 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.) e Symptomatic CNS disease. e Known hypersensitivity to any of the components of Antibody A or who have had hypersensitivity reactions to fully human monoclonal antibodies. e Received other recent antitumor therapy including: o Systemic therapy administered within the 30 days prior to the first scheduled day of dosing in this study o Radiation within 14 days prior to the first scheduled dose in this study, including, in addition (if necessary), the timeframe for resolution of any actual or anticipated toxicities from such radiation e Received any investigational therapy within 30 days prior to the first scheduled day of dose in this study e NYHA Class III or IV congestive heart failure or LVEF < LLN for Institution (but not less than 55%). Patients with a significant history of cardiac disease (i.e. uncontrolled blood pressure, unstable angina, myocardial infarction within 1 year or ventricular arrhythmias requiring medication) are also excluded. 41 WO 2013/023043 PCT/US2012/050124 e Known HIV, hepatitis B or C (active, previously treated or both). e Any other medical condition deemed 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. Dose Levels Antibody A has been well tolerated up to doses of 40 mg/kg (loading dose) and 20 mg/kg (weekly) as a monotherapy. Ongoing studies are evaluating the combination of Antibody A with other agents. The proposed dose levels for the study are shown in the tables below, per regimen. Dosing is administered weekly for Antibody A, and as noted for the combination therapy. Intermediate dose levels of Antibody A (between Levels 1 and 2) or the combination agents may be evaluated to determine the optimal combination dose. Decreased doses may be explored in the event of toxicities or if the PK data suggest adequate concentration levels may be achieved at lower doses. Alternate dosing schedules (e.g. every two or three week dosing of Antibody A) may also be evaluated once safety has been determined at the weekly dosing regimen. The following combinations are currently planned: Cohort A1= Antibody A (20 mg/kg loading dose x1 followed by 12mg/kg/week)+ gemcitabine 1000mg/m 2 at Day 1 and Day 8 of every 3 week cycle Cohort A2 = Antibody A (40 mg/kg loading dose x1 followed by 20mg/kg/week)+ gemcitabine 1000 mg/m 2 at Day 1 and Day 8 of every 3 week cycle Cohort A3*= Antibody A (20 mg/kg loading dose x1 followed by 12mg/kg/week)+ gemcitabine 1250mg/m 2 at Day 1 and Day 8 of every 3 week cycle Cohort A4*= Antibody A (40 mg/kg loading dose x1 followed by 20mg/kg/week)+ gemcitabine 1250 mg/m 2 at Day 1 and Day 8 of every 3 week cycle *Please note that initiation of cohorts A3 and A4 will be confirmed following the completion of cohorts Al and A2 and evaluation of the safety profile in cohorts Al and A2. 42 WO 2013/023043 PCT/US2012/050124 Cohort B1=Antibody A (20 mg/kg loading dose x1 followed by 12mg/kg/week)+ carboplatin AUC 6 at Day 1 of every 3 week cycle Cohort B2 = Antibody A (40 mg/kg loading dose x1 followed by 20mg/kg/week)+ carboplatin AUC 6 at Day 1 of every 3 week cycle Cohort C1 = Antibody A (20 mg/kg loading dose x1 followed byl2mg/kg/week)+ pemetrexed 500 mg/m 2 Day 1 of every 3 week cycle Cohort C2 = Antibody A (40 mg/kg x1 loading dose followed by 20mg/kg/week) + pemetrexed 500 mg/m 2 Day 1 of every 3 week cycle Description of Antibody A Antibody A will be supplied in sterile, single-use vials containing 10.1 mL of Antibody A at a concentration of 25 mg/ml in 20 mM histidine, 150 mM sodium chloride, pH 6.5. Antibody A appears as a colorless liquid solution and may contain a small amount of visible, white, amorphous, Antibody A particulates. Antibody A drug product should be stored at 2-8'C. Antibody A has been shown to be compatible with Alaris, Paclitaxel, Lifeshield and Kawasumi infusion sets that utilize an in-line 0.2 micron filter. Doses and Administration Antibody A will be administered weekly as an IV infusion. Antibody A should be brought to room temperature prior to administration. Vials of Antibody A should not be shaken. The appropriate quantity of Antibody A will be removed from the vial, diluted in 250 mls of 0.9% normal saline and administered as an IV infusion over 90 minutes (for the first infusion) or 60 minutes (for subsequent infusions in the absence of infusion reactions) using a low protein binding 0.22 micrometer in-line filter. A patient's body weight at the start of a cycle, at a minimum, is to be used to calculate the dose used throughout the cycle. If site-specific policies advise more 43 WO 2013/023043 PCT/US2012/050124 frequent measurement of a patient's body weight to calculate dose, that is acceptable. Should a patient's body weight change by more than 10%, a new total dose shall be calculated to reflect this change. Treatment Regimen: Antibody A + gemcitabine All patients receiving gemcitabine should be premedicated as per the package insert and any local institutional guidelines. Antibody A will be administered over 90 minutes for the first infusion (Day 1), and then weekly thereafter over 60 minutes. Gemcitabine 1000 mg/m 2 will be administered on day 1 and day 8 of all cycles, following the Antibody A dose. Gemcitabine should be administered by IV infusion over 30 minutes. Treatment with this regimen will be continued until disease progression, unacceptable toxicity, or withdrawal of consent. Cohorts A3 and A4 may be considered with a Gemcitabine dose of 1250mg/M 2 based on the conclusion of cohorts Al and A2 and a review of the safety profile of the combination. The table below illustrates an exemplary treatment regimen for Antibody A + gemcitabine. This regimen follows a 3-week treatment cycle following the first dose of gemcitabine. Level Gemcitabine Antibody A" (mg/m 2 )a -2 800 12/6 -1 1000 12/6 1 1000 20/12 2 1000 40/20 3c 1250 20/12 4c 1250 40/20 a. First dose administration in conjunction with first dose of Antibody A. Chemotherapy to be given after Antibody A infusion. b. Loading dose (mg/kg) x 1/followed by maintenance dose (mg/kg) thereafter. c. Escalation to cohorts A3 and A4 will be determined following the completion of cohorts Al and A2 and a review of the safety profile in cohorts Al and A2. 44 WO 2013/023043 PCT/US2012/050124 Treatment Regimen: Antibody A + carboplatin All patients receiving carboplatin should be premedicated as per the package insert and any local institutional guidelines. Antibody A will be administered over 90 minutes for the first infusion (Day 1), and then weekly thereafter over 60 minutes. Carboplatin will be administered on Day 1 of all cycles, following the Antibody A dose. Carboplatin should be administered by IV infusion over 60 minutes. Treatment with this regimen will be continued until disease progression, unacceptable toxicity, or withdrawal of consent. The table below illustrates an exemplary treatment regimen for Antibody A + carboplatin. This regimen follows a 3-week treatment cycle following the first dose of carboplatin. Note: the dose levels listed below may be non-sequential. If dose level 1 is not tolerated, it may be de-escalated to dose level -1A; if dose level -1A is tolerated, the MM-121 dose may be escalated to dose level -1B. Level Carboplatin Antibody A' (mg)" -1A AUC 5 20/12 -1Bd AUC 5 40/20 1 AUC 6 20/12 2 AUC 6 40/20 a. First dose administration in conjunction with first dose of Antibody A. Chemotherapy to be given after Antibody A infusion. b. Dose calculated using Calvert formula [Total Dose(mg) = (target AUC)*(GFR+25)] c. Loading dose (mg/kg) x 1/followed by maintenance dose (mg/kg/week) thereafter. d. In the event that dose level -1A is tolerated, the option to escalate the Antibody A dose exists. If a patient's glomerular filtration rate (GFR) GFR is estimated based on serum creatinine measurements by the IDMS method, FDA recommends that physicians consider capping the dose of carboplatin for desired exposure (AUC) to avoid potential toxicity due to overdosing. Based on the Calvert formula described in the carboplatin label, the maximum doses can be calculated as: 45 WO 2013/023043 PCT/US2012/050124 Total Carboplatin Dose (mg)= (target AUC) x (GFR +25) [Calvert formula] Maximum Carboplatin Dose (mg) = target AUC (mg.min/mL) x (150 mL/min) The maximum dose is based on a GFR estimate that is capped at 125 mL/min for patients with normal renal function. No higher estimated GFR values should be used. For a target AUC = 6, the maximum dose is 6 x 150 = 900 mg For a target AUC = 5, the maximum dose is 5 x 150 = 750 mg For a target AUC = 4, the maximum dose is 4 x 150 = 600 mg Treatment Regimen: Antibody A + pemetrexed All patients receiving pemetrexed should be premedicated as per the package insert and any local institutional guidelines, including folic acid and vitamin B12. General guidelines for folic acid and vitamin B 1 2 supplementation are as follows: A low dose folic acid preparation (eg 400 micrograms) must be taken on a daily basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first dose of pemetrexed; and dosing should continue during the full course of therapy and for 21 days after the last dose of pemeterexed. Patients must also receive one (1) intramuscular injection of vitamin B 12 (1000 micrograms) during the week preceding the first dose of pemetrexed and every 3 cycles thereafter. Subsequent vitamin B 1 2 injections may be given the same day as pemetrexed. In addition, for treatment details and dose modifications, sites should also refer to their institutional guidelines. Antibody A will be administered over 90 minutes for the first infusion (Day 1), and then weekly thereafter over 60 minutes. Pemetrexed 500 mg/m 2 will be administered following the Antibody A dose, every three weeks, beginning on on Day 1 of the first cycle, by IV infusion over 10 minutes. Treatment with this regimen will be continued until disease progression, unacceptable toxicity, or withdrawal of consent. 46 WO 2013/023043 PCT/US2012/050124 The table below illustrates an exemplary treatment regimen for Antibody A + pemetrexed. This regimen follows a 3-week treatment cycle following the first dose of pemetrexed. Pemetrexed Antibody A Level (mg/m 2 )' (mg/kg)) -2 375 12/6 -1 500 12/6 1 500 20/12 2 500 40/20 a. First dose administered in conjunction with the first dose of Antibody A. Chemotherapy to be given after Antibody A infusion. b. Loading dose (mg/kg) x 1/followed by maintenance dose (mg/kg) thereafter. Treatment Regimen: Antibody A + cabazitaxel The table below illustrates an exemplary treatment regimen for Antibody A + cabazitaxel. This regimen follows a 3-week treatment cycle following the first dose of cabazitaxel. Cabazitaxel Antibody A Level (mg/rn 2 ) (mg/kg)" -2 15 12/6 -1 20 12/6 1 20 20/12 2 20 40/20 3 25 40/20 a. Loading dose (mg/kg) x 1/followed by maintenance dose (mg/kg/week) thereafter. Decision Criteria for Dose Escalation The dose will escalate to the next level only after the safety data have been evaluated at the current dose level (once the last patient enrolled in the cohort completes the first cycle of treatment) and the criteria for MTD have not been met. If a patient experiences a treatment-related toxicity qualifying as a DLT, up to 3 additional patients will be enrolled at that dose level for that treatment group. If no additional DLTs are observed, the dose escalation will resume. If a second patient 47 WO 2013/023043 PCT/US2012/050124 experiences a treatment-related toxicity qualifying as a DLT at that dose, that dose will be considered the toxic dose. The safety assessment period for purposes of DLT evaluation and dose escalation decisions will be 28 days after the first dose of Antibody A. In addition, any drug-related toxicities of Grade 3 or higher that arise after Cycle 1 will be assessed for their potential relationship to cumulative Antibody A dose and considered in the decision to escalate dose. Immunogenicity and PK data may be available, but will not be required for decisions on dose escalation. Management of Toxicities Combination with gemcitabine: The following adverse events are relatively common (occurring in > 20% of patients) with gemcitabine monotherapy treatment and to be expected with the combination of Antibody A and gemcitabine: anemia, leukopenia, neutropenia, thrombocytopenia, LFT elevations, proteinuria, hematuria, nausea and vomiting, fever, rash and dyspnea. Additional adverse events may be anticipated, as described in the package insert for gemcitabine. The following events, occurring during cycle 1 of the study combination, will be considered DLTs whether drug related or not and if not related to disease progression: e grade 3 or 4 neutropenia complicated by fever > 38.5 'C (i.e febrile neutropenia) and/or documented infection; e grade 4 neutropenia >7 days; e grade 3-4 thrombocytopenia and/or anemia >7 days or any grade 3-4 thrombocytopenia complicated with hemorrhage; e inability to begin subsequent treatment course within 14 days of the scheduled date, due to study drug toxicity; e any grade 3-4 non-hematologic toxicity (except fatigue/asthenia < 2 weeks in duration, anorexia, nausea / vomiting in the absence of optimal anti emetics, diarrhea in the absence of optimal antidiarrheals or alkaline phosphatase changes). 48 WO 2013/023043 PCT/US2012/050124 The table below details dose adjustments for gemcitabine. ANC x10 6 /L Platelets x10 6 /L % Previous dose Number consecutive reductions allowed before discontinuation 1000-1500 Or 50,000-100,000 75 2 <1000 Or <50,000 50 1 Combination with carboplatin The following adverse events are relatively common (occurring in >30% of patients) with carboplatin monotherapy treatment and to be expected with the combination of Antibody A and carboplatin: bone marrow suppression, nausea and vomiting, hepatic impairment and electrolyte changes. Additional adverse events may be anticipated, as described in the package insert for carboplatin. The following events, occurring during cycle 1 of the study combination, will be considered DLTs whether drug related or not and if not related to disease progression: o grade 3 or 4 neutropenia complicated by fever > 38.5 'C (i.e febrile neutropenia) or documented infection; o grade 4 neutropenia >7 days; o grade 3-4 thrombocytopenia and/or anemia >7 days or any grade 3-4 thrombocytopenia complicated with hemorrhage; o inability to begin subsequent treatment course within 14 days of the scheduled date due to study drug toxicity; o any grade 3-4 non-hematologic toxicity (except fatigue/asthenia < 2 weeks in duration, anorexia, nausea / vomiting in the absence of optimal anti-emetics, diarrhea in the absence of optimal antidiarrheal or alkaline phosphatase changes) The table below details dose adjustments for carboplatin. ANC x10 6 /L Platelets x10 6 /L % Previous dose Number consecutive reductions allowed before discontinuation 1000-1500 Or 50,000-100,000 75 2 49 WO 2013/023043 PCT/US2012/050124 <1000 Or <50,000 50 1 Combination with pemetrexed: The following adverse events are relatively common (occurring in >10% patients) with pemetrexed monotherapy treatment and to be expected with the combination of Antibody A and pemetrexed: anemia, leucopenia, neutropenia, hepatic dysfunction, fatigue, nausea and vomiting, anorexia, stomatitis, diarrhea and rash. Additional adverse events may be anticipated, as described in the package insert for pemetrexed. The following events, occurring during cycle 1 of the study combination, will be considered DLTs whether drug related or not and if not related to disease progression: o grade 3 or 4 neutropenia complicated by fever > 38.5 'C (i.e. febrile neutropenia) or documented infection; o grade 4 neutropenia >7 days; o grade 3-4 thrombocytopenia and/or anemia >7 days or any grade 3-4 thrombocytopenia complicated with hemorrhage; o inability to begin subsequent treatment course within 14 days of the scheduled date due to study drug toxicity; o any grade 3-4 non-hematologic toxicity (except fatigue/asthenia < 2 weeks in duration, anorexia, nausea / vomiting in the absence of optimal anti-emetics, diarrhea in the absence of optimal antidiarrheals or alkaline phosphatase changes) The table below details dose adjustments for pemetrexed. ANC x10 6 /L Platelets x10 6 /L % Previous Number consecutive dose reductions allowed before discontinuation 1000-1500 Or 50,000-100,000 75 2 <1000 Or <50,000 50 1 50 WO 2013/023043 PCT/US2012/050124 For non-hematological Toxicities: (excluding neurotoxicity) % previous dose of pemetrexed Any Grade 3 or 4 toxicities except mucositis 75 Grade 3 or 4 diarrhea or any grade diarrhea 75 requiring hospitalization Grade 3 or 4 mucositis 50 For neurotoxicity: CTCAE Grade % previous dose of pemnetrexed 0-1 100 2 100 3 or 4 DISCONTINUE For all treatment regimens: If a patient with known liver metastasis and abnormality in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase of Grade 2 at baseline experiences a DLT due to Grade 3 abnormalities of these enzymes, then enrollment of subsequent patients at that dose level will be restricted to baseline abnormalities of these enzymes of no more than 2.5 x ULN. Patients whose cardiac function deteriorates as follows will be discontinued from the study: a 10% decline in LVEF to below the lower limit of normal or an absolute LVEF of 45%, or a 20% decline in LVEF at any level. Pharmacokinetic Analysis Serum concentrations will be used to determine the PK parameters using standard non-compartmental techniques. The PK parameters will be summarized using descriptive statistics, including the median, mean and 95% confidence intervals (CI) around parameter estimates by dose level. Pharmacokinetic parameters will include maximum serum concentration (Cmax), time to Cmax (Tmax), area under the concentration-time curve calculated to the last observable concentration at time t (AUCt),AUC from time 0 extrapolated to infinity (AUCo-inf), AUC, clearance (CL), 51 WO 2013/023043 PCT/US2012/050124 volume of distribution at steady state (Vdss), and the tm/ 2 , when applicable. Dose proportionality analysis at all dose regimen levels will be performed using AUCs. Biomarker Analysis This study will explore four main questions based on data from this study in addition to similar biomarker information from other studies that are ongoing and in parallel: 1. Do biomarker levels change between time of diagnosis and time of treatment? 2. Can biomarkers levels at time of treatment be used to predict response to Antibody A in combination with standard-of-care chemotherapies? 3. Does chemotherapy induce upregulation of heregulin, does Antibody A block ErbB3 signaling when this occurs, and does this provide benefit? 4. How do cytotoxic agents change the mechanism of action of Antibody A and what are the key molecular events that correlate with response? In order to address these questions, tumor samples will be collected from each patient at both initial diagnosis and time of metastasis (if available). As comparison to these historical samples and in order to adequately evaluate the biomarker profile of the Antibody A plus chemotherapy combination, direct sampling of the patient's tumor will also be completed through biopsies in the Expansion phase. This material will be processed to obtain quantitative measurements of staining by immunohistochemistry of the following receptors EGFR (ErbB 1), Her-2-neu (Erb-B2), Her-3 (Erb-B3). In addition, the messenger RNA expression of the ligands Betacellulin and Heregulin (neuregulin- 1), and possibly other ligands and receptors related to sensitivity or resistance or toxicity of the combination, will be assessed using reverse transcription polymerase chain reaction (RT-PCR). These tumor samples will be analyzed as paired samples (pre- and post treatment measures from each patient). The data will be characterized using 52 WO 2013/023043 PCT/US2012/050124 means and 95% confidence intervals for pre-treatment concentrations for the population and the mean and 95% confidence intervals for normalized change from baseline in paired samples. In general for the main biomarker analysis patients will be classified into "marker positive" (likely to respond to Antibody A) and "marker negative" (unlikely to respond to Antibody A) group once response data is available and cut points have been set across all patients. The proportion of patients who are marker positive based on archived tissue block will be compared against the prevalence prediction made from a tumor survey result. In addition, exploratory analyses and biomarker measurements will be obtained from serum samples collected at baseline and throughout the course of the study to evaluate whether serum markers correlate with findings from the tumor sample analyses and/or overall efficacy findings (e.g. serum Heregulin and CTCs, for example). Complete and formal statistical analysis plans for the biomarker analysis will be written and maintained by the Sponsor, as such plans will be implemented across this and possibly additional studies. In the event tissue samples are received from two time points in the course of the patient's disease progression (e.g. at the time of original diagnosis and at the time of metastasis), the same prevalence rate will be calculated based on tissue samples obtained in the metastatic setting. In addition, the patient's biomarker classification (as determined by the samples received from the two time points) will be compared to evaluate any significant changes in the level of any biomarker. Key efficacy endpoints (e.g., response rate and change in tumor burden) and change in biomarker level (e.g. change in serum Heregulin) as well as safety endpoints (e.g.. percent of patients experiencing Grade 3 or higher adverse event) will be compared between groups and for "marker positive" and "marker negative" patients to see if the treatment or safety effects are greater in the "marker positive" group versus the "marker negative" group. The marker positive or negative classification could be based on single biomarker or a 53 WO 2013/023043 PCT/US2012/050124 composite score from multiple biomarkers from tissue samples or serum samples. The above univariate exploratory analyses will be performed separately for serum samples, archived tissue samples at diagnosis and the tumor tissue samples obtained in the metastatic setting (biopsy or archived). In addition, multivariate analyses of disease outcome endpoints will be performed for the marker positive group based on the best biomarker classifier from the univariate analysis after appropriate adjustment for other key clinical prognostic factors. The results from these post hoc univariate and multivariate analyses will be used to guide further diagnostic and predictive biomarker development and validation. Pharmacodynamic Analysis Within the Expansion phase, biopsy samples will be collected pre treatment and post-treatment. This material will be frozen upon collection and subsequently processed to obtain quantitative measurements of key biomarkers (including, but not limited to, total ErbB3, phosphorylated ErbB3, phosphorylated AKT, and phosphorylated Erk). The levels of these markers will be measured at baseline (pretreatment) and compared to post-treatment levels to characterize the pharmacodynamic effects of Antibody A administration. Assuming that 50% of the patients within the target populations demonstrate ErbB3 pathway inhibition, which is conservative statistically, and a 40% reduction in pErb3 from baseline level is representative pErB3 pathway inhibition, if an activation rate of 50% is observed, N=6 per expansion group will provide a 90% CI of [ 16.4%, 83.6%] for the true population pErb3 pathway activation rate. Disease Parameters 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 by chest x-ray, as > 10 mm with CT scan, or > 10 mm with calipers by clinical exam. All tumor 54 WO 2013/023043 PCT/US2012/050124 measurements are recorded in millimeters. Tumor lesions that are situated in a previously irradiated area are considered measurable if there is incontrovertible evidence of interval progression since completion of prior radiation, documented on relevant imaging. Malignant Lymph Nodes To be considered pathologically enlarged and measurable, a lymph node is > 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis is measured and followed. Non-measurable Disease All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with > 10 to < 15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non measurable. Non-measurable also includes lesions that are < 20 mm by chest x-ray. Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non- measurable) since they are, by definition, simple cysts. "Cystic lesions" thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions. Target Lesions All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend 55 WO 2013/023043 PCT/US2012/050124 itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions is calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum of the diameters is used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target Lesions All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, but the presence or absence of unequivocal progression of each should be noted throughout follow-up. Methods for Evaluation of Measurable Disease All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before registration. The same method of assessment and the same technique is used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. Clinical Lesions Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes) and >10 mm in diameter as assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. Chest X-ray Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable. 56 WO 2013/023043 PCT/US2012/050124 Conventional CT and MRI This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). Use of MRI is complex. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up must be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if possible. PET-CT At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or serially performed. 57 WO 2013/023043 PCT/US2012/050124 Ultrasound Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and measurements are taken from one assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. Endoscopy, Laparoscopy The utilization of these techniques for objective tumor evaluation is not advised. However, such techniques may be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response (CR) or surgical resection is an endpoint. Cytology, Histology These techniques can be used to differentiate between partial responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain). 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 is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease. FDG-PET While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm: a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new lesion, as long as there is clinical corroboratory evidence of a malignancy. 58 WO 2013/023043 PCT/US2012/050124 b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD is the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD. c. FDG-PET, if negative (-), may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. However, both approaches may lead to false positive CR due to limitations of FDGPET and biopsy resolution/sensitivity. A "positive" FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image. Response Criteria Evaluation of Target Lesions Complete Response (CR) Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR) At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters Progressive Disease (PD) At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). 59 WO 2013/023043 PCT/US2012/050124 Stable Disease (SD) 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. Evaluation of Non-Target Lesions Complete Response (CR) Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical 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) Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. When the patient also has measurable disease, there must be an overall level of substantial worsening in non-target disease such that, even in the presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest "increase" in the size of one or more non-target lesions is usually not sufficient to qualify for unequivocal progression status. The designation of overall progression solely on the basis of change in non-target disease in the face of SD or PR of target disease will therefore be extremely rare. When the patient only has non-measurable disease, the increase in overall disease burden should be comparable in magnitude to the increase that would be 60 WO 2013/023043 PCT/US2012/050124 required to declare PD for measurable disease: i.e., an increase in tumor burden from "trace" to "large", an increase in nodal disease from "localized" to "widespread", or an increase sufficient to require a change in therapy. Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator). Evaluation of New Lesions The appearance of new lesions constitutes Progressive Disease (PD). Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence or non-protocol therapy (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 measurement criteria. For Patients with Measurable Disease (i.e., Target Disease) Target Non-Target New Best Overall Remarks Lesions Lesions Lesions* Response CR CR No CR CR Non- No PR CR/Non-PD CR Not No PR evaluated PR Non-PD/not No PR evaluated SD Non-PD/not No SD Documented evaluated at least once > 6 weeks from baseline PD Any Yes or No PD No prior SD, PR or CR 61 WO 2013/023043 PCT/US2012/050124 Any PD** Yes or No PD Any Any Yes PD * See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. ** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression. Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as "symptomatic deterioration. " Every effort should be made to document the objective progression even after discontinuation of treatment. Duration of Response 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 progressive 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, including the baseline measurements. 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. Example 5: Phase 1 Trial in Patients Having Solid Tumors (Antibody A in combination with cetuximab and irinotecan) A phase 1 trial of Antibody A in combination with cetuximab and irinotecan is conducted in patients having advanced solid tumors to demonstrate the safety and efficacy of administering Antibody A as part of a combination treatment comprising cetuximab and irinotecan. 62 WO 2013/023043 PCT/US2012/050124 The study is a Phase 1 and pharmacologic dose-escalation study of Antibody A plus cetuximab plus irinotecan. The dose-escalation portion of the study employs a modified 3 + 3 design to assess the safety, tolerability, and pharmacokinetics of Antibody A, cetuximab and irinotecan when administered in combination in patients with colorectal cancer, squamous cell head and neck cancer, non-small cell lung cancer, triple negative breast cancer and other tumors with EGFR dependence. This is an open-label study in which Antibody A, cetuximab and irinotecan will be administered as sequential infusions. Antibody A will be administered as a 1 hour infusion (following an initial infusion of 90 minutes for the first dose). Cetuximab will be administered as a 1 hour infusion after an initial infusion of 2 hours for the loading dose and irinotecan will be administered as a 90 minute infusion. There will be two parts to this Phase 1 Study. Each part will comprise a dose escalation cohort as well as an expansion cohort. In Part 1, doses of Antibody A and cetuximab will be escalated (or decreased, as described below), to determine the maximum tolerated dose (MTD) of the combination. Part 2 will then determine the MTD for the cetuximab/Antibody A combination in conjunction with irinotecan. Part 2 can begin enrolling patients in parallel with the Part 1 Expansion Cohort. The general scheme of the study is depicted in Figure 7. The primary objective of the dose escalation phase is to evaluate the safety and tolerability of escalating doses of the Antibody A plus cetuximab and the Antibody A plus cetuximab plus irinotecan combination. The primary objective of the expansion cohort is to evaluate the molecular pharmacodynamic response of proteins predicted to be affected by Antibody A treatment. The secondary objectives of the study include the following: e To determine the pharmacokinetic parameters of Antibody A plus cetuximab and Antibody A plus cetuximab plus irinotecan when administered in combination 63 WO 2013/023043 PCT/US2012/050124 e To determine the immunogenicity parameters of Antibody A when administered in combination with cetuximab and irinotecan e To describe the response to treatment with the Antibody A plus cetuximab and Antibody A plus cetuximab plus irinotecan combination using objective response rate Key exploratory objectives of this study include the following: e To gather exploratory clinical data on a potentially predictive set of biomarkers to be measured in tumor tissue samples and serum samples for predicting response to the Antibody A plus cetuximab and Antibody A plus cetuximab plus irinotecan combination e To evaluate changes in the following pharmacodynamic (PD) biomarkers and to investigate the relationship between these changes and Antibody A exposure and anti-tumor activity: " tErbB3, pErbB3, pAKT and pERK in pre-treatment and post treatment tumor tissue; o Heregulin and other biomarker levels in serum e To explore and evaluate additional PD biomarkers necessary to further understand the mechanism of action of Antibody A and the Antibody A plus cetuximab and/or irinotecan combination Dose Escalation Scheme Part 1 The proposed dose escalation scheme for Part 1 of the study is outlined in the table shown below. Part 1 Dose Escalation Dose Antibody A Dose' Cetuximab Dose' (mg/m 2 ) Level 2 (mg/kg) -1 6 400 (loading dose) 200 (weekly maintenance dose) 64 WO 2013/023043 PCT/US2012/050124 1 12 400 (loading dose) 200 (weekly maintenance dose) 2a 20 400 (loading dose) 200 (weekly maintenance dose) 2b 12 400 (loading dose) 250 (weekly maintenance dose) 3a 40 (loading dose) 400 (loading dose) 20 (weekly maintenance 200 (weekly maintenance dose) dose) 3b 20 400 (loading dose) 250 (weekly maintenance dose) 4 40 (loading dose) 400 (loading dose) 20 (weekly maintenance 250 (weekly maintenance dose) dose) Antibody A and cetuximab will be administered weekly 2Additional dose levels and alternate dosing schedules may be explored upon agreement of Sponsor, Medical Monitor and Investigators Dosing will begin at Dose Level 1. If no MTD is defined in a cohort of at least 3 patients, escalation will proceed in parallel cohorts to Levels 2a and 2b. This will permit concurrent evaluation of independent escalating doses of Antibody A and cetuximab. Patients will be assigned between the two dose levels in an alternating fashion, as assigned by a designee of the sponsor at the time of enrollment, to permit fair evaluation of the dose level. If dose levels within Levels 2a and 2b are determined to be safe in a cohort of at least 3 patients (within each cohort), additional escalations to dose level 3a and 3b will begin in parallel. If there are no safety concerns observed at Dose Levels 3a and 3b, the next escalation would be to Dose Level 4. At any time, if a DLT is experienced within one group of 3 patients, that block will be expanded and an additional 3 patients will be enrolled. Cetuximab will be administered with the loading dose/maintenance dose for all cohorts at the level indicated. A loading dose of Antibody A will be given only for Levels 3a and 4. All doses will be administered weekly. The first infusion of Antibody A is administered over 90 minutes and the first administration of cetuximab is given over 2 hours. 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) 65 WO 2013/023043 PCT/US2012/050124 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. Different MTDs may be established for Antibody A and cetuximab. If an MTD is defined in one of the two parallel levels; that drug (the one with the higher dose being tested) will no longer be escalated. Escalations will only occur in the other drug. Decreased doses or alternate dosing schedules may be evaluated in the event of a DLT or in the event that pharmacokinetic or pharmacodynamic data support the evaluation of a slightly lower dose of one or both drugs. Decisions for the next dosing group will be made during regularly scheduled, documented discussions between the Sponsor, Investigators and Medical Monitor. In the event two possible MTDs are defined, a dose will be selected by the Sponsor, Investigator and Medical Monitor based on available data. Once the MTD (or target optimal dose) has been established for the Antibody A and cetuximab combination, it will be studied in an expansion cohort of 12 patients to confirm safety. Part 2 can begin enrolling patients in parallel. PART 2 Part 2 of the Dose Escalation phase will evaluate the cetuximab plus Antibody A combination in conjunction with irinotecan, according to the scheme depicted in the table below. A proposed starting dose is indicated as Dose Level 1 shown below. Alternative starting dosing levels may be chosen based on the toxicity profiles determined from the Part 1 Dose Escalation component. Similarly, adjustments may be made as the doses are escalated in Part 2 to ensure that Dose Levels do not surpass those shown to be toxic from Part 1. Part 2 Dose Escalation 66 WO 2013/023043 PCT/US2012/050124 Dose Level 3 Antibody A Cetuximab Irinotecan Dose' Dose' Dose 2 (mg/kg) (mg/m 2

)

4 (mg/m 2 ) -2 MTD -2' 150 -1 MTD -2' 180 1 MTD -1' 180 2 MTD 5 180 Antibody A/cetuximab will be administered weekly. 2 Irinotecan will be administered once every 2 weeks. 3Additional dose levels and alternate dosing schedules may be explored upon agreement of Sponsor, Medical Monitor and Investigators. 4 In the event of observed toxicity with the triplet, cetuximab may be removed and dose escalation may proceed in order to evaluate Antibody A plus irinotecan combination therapy. 5 Dosing for the Antibody A + cetuximab combination will be based upon the MTD (or target optimal dose) defined in Part 1. In the event of toxicity, the combination dose will be reduced by one dose level to the next lowest combination dose observed without toxicity. Dosing will begin at Dose Level 1. If no MTD is defined in a cohort of at least 3 patients, escalation will proceed to Dose Level 2. At any time, if a DLT is experienced within one group of 3 patients, that block will be expanded and an additional 3 patients will be enrolled. 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. Decreased doses may be evaluated in the event of a DLT or in the event that pharmacokinetic or pharmacodynamic data support the evaluation of a lower dose. In addition to the dose escalation portion of the study, once safety is confirmed in the planned dose escalation cohorts, an Expansion Cohort will be opened for enrollment. The Part 2 expansion cohort will be restricted to patients with colorectal cancer. The exact number of patients in each Expansion Cohort will 67 WO 2013/023043 PCT/US2012/050124 depend on the quality of tissue samples received and interpretability of data from the first 3 patients enrolled. Following enrollment of the Expansion Cohort at this dose level, reduced dose levels (e.g. those determined to be safe during the dose escalation phase in a cohort of at least 3 patients) or alternate dosing schedules (e.g. every other week dosing, etc) may be explored. During the Expansion Cohort for both Part 1 and Part 2, patients will undergo pre-treatment and post-treatment biopsies to evaluate pharmacodynamic effects of the Antibody A plus cetuximab plus irinotecan treatment. If required, additional patients may be enrolled in both the Expansion Cohorts to support the safety and PK data. Following enrollment of the Expansion Cohorts at the specified dose levels, reduced dose levels or alternate dosing schedules (e.g. every other week dosing, etc) may be explored. One treatment cycle will consist of weekly treatments for 4 weeks. Cycles will be repeated every 4 weeks until disease progression, intolerable toxicity or other reason for study termination. Definition and Management of Dose Limiting Toxicity (DLT) Dose Limiting Toxicity Definitions for Part 1 As a general rule, any drug related Grade 3 or 4 toxicity will be considered dose limiting in Part 1 (cetuximab and Antibody A) of this study if they occur during Cycle 1, with the following exceptions/modifications: e Grade 3 or 4 nausea, vomiting or diarrhea are not considered dose limiting unless they occur despite the use of maximal anti-emetic or anti-diarrheal management e Grade 3 rash that improves within 7 days will not be considered dose limiting. A Grade 3 rash that persists beyond 7 days despite treatment or a Grade 4 rash will be considered dose-limiting e Grade 3 or 4 infusion reactions 68 WO 2013/023043 PCT/US2012/050124 e Grade 3 hyponatremia, hypokalemia, hypomagnesemia, hypophosphatemia are only considered dose limiting if they continue > 5 days despite maximal medical management o In instances where a drug-toxicity leads to a > Grade 3 electrolyte abnormality, then the causative toxicity will be used to determine if the event is a DLT. For example, if diarrhea leads to hypokalemia, then the grade of the diarrhea will determine whether the event was a DLT. e Any other toxicity preventing the patient to receive > 3 doses of Antibody A will be considered dose limiting. Dose Limiting Toxicity Definitions for Part 2 As a general rule, any drug related Grade 3 or 4 toxicity will be considered dose limiting in Part 2 (cetuximab, irinotecan and Antibody A) of this study if they occur during Cycle 1, with the following exceptions/modifications: e Grade 3 or 4 nausea, vomiting or diarrhea are not considered dose limiting unless they occur despite the use of maximal anti-emetic or anti-diarrheal management e Grade 3 rash that improves within 7 days will not be considered dose limiting. A Grade 3 rash that persists beyond 7 days despite treatment or a Grade 4 rash will be considered dose-limiting e Grade 3 or 4 infusion reactions e Grade 3 hyponatremia hypokalemia, hypomagnesemia, hypophosphatemia are only considered dose limiting if they continue > 5 days despite maximal medical management o In instances where a drug-toxicity leads to a > Grade 3 electrolyte abnormality, then the causative toxicity will be used to determine if the event is a DLT. For example, if diarrhea leads to hypokalemia, then the grade of the diarrhea will determine whether the event was a DLT. 69 WO 2013/023043 PCT/US2012/050124 e Any Grade 4 neutropenia of > 7 days duration or Grade 3 neutropenia complicated by infection and Grade 3 febrile neutropenia will be considered dose limiting. e Any Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding will be considered dose limiting. e Any other toxicity preventing the patient to receive > 3 doses of Antibody A will be considered dose limiting. Definition of Maximum Tolerated Dose (MTD) If one of 3 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. For a patient to be considered evaluable for DLT analysis, they must receive full doses in Cycle 1. Scientific Objectives of the Expansion Cohort In addition to obtaining additional safety data, a key primary biological objective of this phase of the study is to evaluate the molecular pharmacodynamic response of certain biomarkers of the ERB signaling pathway in conjunction with pharmacokinetic assessment. Determination of this pharmacodynamic response will be based upon comparison of paired pre- and post-treatment specimens from tumor biopsy obtained from patients in the expansion phases of the study. The exploratory endpoints of interest would be changes in the expression and activation levels of the ERB signaling pathway components. The primary clinical objective will be to build upon the safety profile of the combination and to describe any anti-tumor effects correlating with the observed pharmacodynamic changes. 70 WO 2013/023043 PCT/US2012/050124 A secondary scientific objective in this phase of the study will be to explore the feasibility of correlating tumor response with pre-treatment molecular characteristics determined from both archived and more recently obtained paraffin-embedded tumor samples from these same patients as well as exploring the feasibility of using less invasive sampling such as serum-based assays. Pharmacodynamic Correlates in the Expansion Cohort Pharmacodynamic correlates that will be measured in the tumor biopsy samples and serum samples from patients in the Expansion Cohort, include levels of phospho-AKT, phospho-ErbB3, VEGF and Ki-67 and potentially other correlates including those of the ras MAPK pathway such as Phospho-ERK. These levels will be assessed by ELISA, Bioplex or by IHC. Additional serum samples will be evaluated for the presence of correlative biomarkers, including ligands, proteins and MicroRNA. Pre-Treatment Molecular Characteristics ErbB1, ErbB2, ErbB3, HRG and BTC, as well as P13K genotype, have been identified as potentially predictive markers for response to Antibody A. These markers have been used to identify cell lines that respond to Antibody A in vitro and in vivo. Tumors that express ErbB1, ErbB2, ErbB3, HRG and BTC proteins and/or specific P13K mutations may be more likely to respond to Antibody A treatment. These markers will be assessed after screening by quantitative immunofluorescence, reverse transcription polymerase chain reaction (RTPCR) or other appropriate analysis methods, performed upon tumor sections obtained from pretreatment and post-treatment as well as archived formalin-fixed, paraffin embedded primary tumor samples. Measurement of these tumor characteristics will permit pilot feasibility testing of this predictive molecular test before more rigorous testing in Phase 2 trials. 71 WO 2013/023043 PCT/US2012/050124 This analysis will also be performed on archived tumor samples obtained from patients in the dose-escalation phase of the trial for the purpose of developing the methodology in advance of the start of the Expansion Cohort. Mutations related to AKT/ERK and other pathways may also be characterized in the samples obtained. Treatment and Safety Assessments Antibody A and cetuximab will be administered as a one hour intravenous infusion once per week (+/- 2 days); except the first dose of Antibody A will be given over 90 minutes and the loading dose of cetuximab will be given over 2 hours. Irinotecan will be administered as a 90 minute intravenous infusion once every 2 weeks (+/- 2 days). Patient Selection and Discontinuation Number of Patients Dose Escalation * 27 - 54 patients, depending on the number of expansions and additional cohorts required to reach MTD or target optimal dose Expansion Cohort * 18 patients (If required, additional patients may be enrolled to support the safety and PK data or if biomarker samples collected are not analyzable) Inclusion Criteria In order to be included in the study, patients must have/be: e One of the following cancers: Colorectal Cancer e Kras wild-type metastatic colorectal cancer e No standard treatment options remaining (Part 1) 72 WO 2013/023043 PCT/US2012/050124 Head and Neck Cancer e Recurrent or metastatic squamous cell carcinoma of the head and neck e Failed prior platinum-based therapy Non-Small Cell Lun2 Cancer e Advanced/Metastatic carcinoma of the lung e No standard treatment options remaining e Subjects that have previously received EGFR TKI therapy and had a response to treatment but have subsequently progressed and become resistant to this therapy. Such subjects must meet the following criteria as adapted from Jackman, et al [Jackman D, et al. Clinical Definition of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer. J Clin Oncol, 2009. (Epub ahead of print) doi: 10.1200/JCO.2009.25.8574] and Mok [Mok TS. Living with Imperfection. J Clin Oncol, 2009. (Epub ahead of print) doi: 10. 1200/JCO.2009.24.7049]: o Previously received treatment with a single-agent EGFR TKI (e.g. gefitinib or erlotinib); o Subsequent systemic progression of disease while on continuous treatment with gefitinib or erlotinib for minimum of 30 days; AND, o A tumor that harbors an EGFR mutation known to be associated with drug sensitivity (ie, G719X, exon 19 deletion, L858R, L861Q) Triple Ne2ative Breast Cancer (TNBC) e Recurrent or metastatic TNBC 73 WO 2013/023043 PCT/US2012/050124 e Documented ER-, PR-, Her2- (non-overexpres sing) status e Failed at least one standard chemotherapy regimen e No standard treatment options remaining Other Solid Tumors That May Have EGFR Dependence e Patients with solid tumors that have previously responded to EGFR therapies or patients with known EGFR mutations or amplifications e No standard treatment options remaining e Measurable disease as defined by RECIST vl.1 e Unstained, archived tumor tissue available for analysis e Willing to undergo a pre-treatment and post-treatment biopsy (for patients enrolled in the Expansion Cohort, both Part 1 and Part 2). e ECOG Performance Score (PS) of 0 or 1 e Adequate bone marrow reserves as evidenced by: e ANC > 1, 5 0 0

/

1 k without the use of hematopoietic growth factors; and e Platelet count > 1 0 0

,

0 0 0 /p 1 ; and e Hemoglobin > 9 g/dL e Adequate hepatic function as evidenced by: e Serum total bilirubin < 1.5 x ULN Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) and Alkaline Phosphatase (ALK PHOSAP) < 2.5 x ULN (5 5 x ULN is acceptable if liver metastases are present) e Adequate renal function as evidenced by a serum creatinine < 1.5 x ULN 74 WO 2013/023043 PCT/US2012/050124 e Recovered from the effects of any prior surgery, radiotherapy or other anti neoplastic therapy. Patients with a known peripheral neuropathy must present as Grade 2 or less, according to National Cancer Institute common terminology criteria [NCI CTCAE], version 4.0, to be eligible for inclusion. e 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 Antibody A (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. * 18 years of age or above Exclusion Criteria Patients must meet all the inclusion criteria listed above and none of the following exclusion criteria: e History of any secondary active malignancy in the last 3 years. Patients with prior history of in-situ cancer or basal or squamous cell skin cancer are eligible. Patients with other malignancies are eligible if they have been continuously disease free for at least 3 years. e History of primary central nervous system (CNS) disease. Subjects with a history of prior treated brain metastasis are eligible provided that 1 month following treatment they are stable by CT scan or MRI without evidence of cerebral edema, and have no requirements for corticosteroids Prior radiotherapy to >25% of the bone marrow-bearing areas (Part 2 patients only) e Presentation of an active infection or with an unexplained fever > 38.5 0 C during screening visits or on the first scheduled day of dosing, which in the investigator's opinion might compromise the patient's participation in the trial or affect the 75 WO 2013/023043 PCT/US2012/050124 study outcome. At the discretion of the investigator, patients with tumor fever may be enrolled. e Known hypersensitivity to any of the components of Antibody A or who have had hypersensitivity reactions to fully human monoclonal antibodies e Documented history of Gilbert's Syndrome or Crigler-Najar Syndrome or possessing the UGT1A1*28 homozygous allele (Part 2 patients only) e Received other recent antitumor therapy including: e Investigational therapy administered within the 30 days prior to the first scheduled day of dosing in this study e Radiation therapy or other standard systemic therapy within 14 days prior to the first scheduled dose in this study, including, in addition (if necessary), the timeframe for resolution of any actual or anticipated toxicities from such radiation e NYHA Class III or IV congestive heart failure or LVEF < 55%. Patients with a significant history of cardiac disease (i.e. uncontrolled blood pressure, unstable angina, myocardial infarction within 1 year or ventricular arrhythmias requiring medication) are also excluded e Recent (within 1 year) cerebral vascular accident (CVA) e Pregnant or breast feeding e History of severe allergic reactions to cetuximab (Part 1 and Part 2 patients) or irinotecan (Part 2 patients) or any of their excipients e Presence of any other contraindications for cetuximab (Part 1 and Part 2 patients) or irinotecan (Part 2 patients) 76 WO 2013/023043 PCT/US2012/050124 INVESTIGATIONAL PRODUCT AND STUDY TREATMENT Description of Antibody A Antibody A will be supplied in sterile, single-use vials containing 10.1 mL of Antibody A at a concentration of 25 mg/ml in 20 mM histidine, 150 mM sodium chloride, and pH 6.5. Antibody A appears as a colorless liquid solution and may contain a small amount of visible, white, amorphous, Antibody A particulates. Antibody A has been shown to be compatible infusion sets that utilize an in-line 0.2 micron filter and are made of polyethylene lined non-DEHP, PVC non-DEHP, or PVC with DEHP. PVC infusion bags and tubing with and without DEHP have been tested and are acceptable for use with Antibody A. Antibody A must be stored refrigerated (2 to 8'C, 36 to 46'F) with protection from light. Light protection is not required during infusion. Antibody A must not be frozen. Doses and Administration of Antibody A Antibody A will be administered weekly. Antibody A should be brought to room temperature prior to administration. Vials of Antibody A should not be shaken. The appropriate quantity of study drug will be removed from the vial, diluted in approximately 250 mL of 0.9% normal saline and administered over 90 minutes (for loading dose, if applicable) or 60 minutes (for all infusions other than loading dose and in the absence of infusion reactions) using a low protein binding 0.22 micrometer in-line filter. A patient's body weight at the start of each visit should be used to calculate the dose to be administered for that visit. No premedication is required prior to the administration of Antibody A. Description of Cetuximab Cetuximab is supplied as a sterile, clear, colorless liquid of pH 7.0 to 7.4, which may contain a small amount of easily visible, white, amorphous cetuximab particulates. Cetuximab is supplied at a concentration of 2 mg/mL in either 100 mg 77 WO 2013/023043 PCT/US2012/050124 (50 mL) or 200 mg (100 mL), single-use vials. Cetuximab is formulated in a preservative-free solution containing 8.48 mg/mL sodium chloride, 1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.41 mg/mL sodium phosphate monobasic monohydrate, and Water for Injection, USP. Cetuximab should be stored in original cartons between 2'-8'C (36'-46'4F). Cetuximab will be provided to the patient by the hospital pharmacy commercial supply or by individual patient prescription. Cetuximab dosing should begin immediately after the first dose of Antibody A on Cycle 1 Day 1. Cetuximab should be administered weekly, as an IV infusion over 120 minutes for loading dose and over 60 minutes for all subsequent infusions. Refer to Table 1 and Table 2 in Section 4 for details on the dose levels of cetuximab for each cohort in Part 1 and Part 2. All patients receiving cetuximab should be pre-medicated as per the local institutional guidelines. In accordance with current labeling, all patients should be premedicated with an H 1 antagonist. Vigilant and aggressive repletion of electrolytes (i.e. potassium, magnesium and calcium) is required. Values should be checked weekly prior to treatment and corrected, as appropriate, over the course of treatment. Patients may get their electrolytes replenished and be treated with cetuximab on the same day. Routine checks should continue for the duration of treatment and through 60 days following end of treatment. Description of Irinotecan Irinotecan is a sterile, pale yellow, clear, aqueous solution of pH 3.0 to 3.8. It is supplied at a concentration of 40 mg in 2 mL vials or 100 mg in 5 mL vials. Each milliliter of solution contains 20 mg of irinotecan hydrochloride, 45 mg of sorbitol NF powder, and 0.9 mg of lactic acid, USP. Irinotecan should be stored in original cartons between 15'-30'3C (59' 86'8F) and protected from light. Irinotecan will be provided to the patient by the hospital pharmacy commercial supply or by individual patient prescription. 78 WO 2013/023043 PCT/US2012/050124 Irinotecan should be administered only to patients enrolled in Part 2 of the study and administration should begin immediately after the first doses of Antibody A and cetuximab on Cycle 1 Day 1. Irinotecan should be administered once every 2 weeks, as an IV infusion over 90 minutes. Refer to Table 2 in Section 4 for details on the dose levels of irinotecan for each cohort. All patients receiving irinotecan should be pre-medicated as per the local institutional guidelines. Premedication with antiemetics is recommended. Considerations for Patients with Reduced UGT1A1 Activity (Part 2, Irinotecan treatment) As noted in the current irinotecan approved labeling, individuals who are homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype) are at increased risk for neutropenia following initiation of irinotecan treatment. In a study of 66 patients who received single-agent irinotecan (350 mg/m 2 once every-3-weeks), the incidence of Grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 50%, and in patients heterozygous for this allele (UGT1A1 6/7 genotype) the incidence was 12.5%. No Grade 4 neutropenia was observed in patients homozygous for the wild type allele (UGT1A1 6/6 genotype). In a prospective study (n=250) to investigate the role of UGT1A1*28 polymorphism in the development of toxicity in patients treated with irinotecan (180 mg/m2) in combination with infusional 5-FU/LV, the incidence of Grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 4.5%, and in patients heterozygous for this allele the incidence was 5.3%. Grade 4 neutropenia was observed in 1.8% of patients homozygous for the wild-type allele. In another study in which 109 patients were treated with irinotecan (100-125 mg/m 2 ) in combination with bolus 5-FU/LV, the incidence of Grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 18.2%, and in patients heterozygous for this allele the incidence was 11.1%. Grade 4 neutropenia was observed in 6.8% of patients homozygous for the wild-type allele. 79 WO 2013/023043 PCT/US2012/050124 When administered in combination with other agents, or as a single-agent, a reduction in the starting dose by at least one level of irinotecan should be considered for patients known to be homozygous for the UGT1A1*28 allele. However, the precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment. General Considerations for Irinotecan Treatment A reduction in the starting dose by one dose level of irinotecan may be considered for patients with any of the following conditions: prior pelvic/abdominal radiotherapy, or increased bilirubin levels. However, dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients. The sponsor and medical monitor should be notified of such elective dose level reductions. Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms. Important Cetuximab and Irinotecan Interactions Investigators should refer to the current cetuximab and irinotecan approved package inserts for information regarding precautions and toxicities. Dose Modification Requirements for Parts 1 and 2 Study drug infusion may be delayed for up to 2 weeks to allow for recovery from toxicity. If a patient does not recover from toxicity related to Antibody A or irinotecan within 2 weeks, the patient's continuation on study should be discussed between investigator and sponsor regarding risks and benefits of continuation. Patients who do not recover from cetuximab related toxicity in 2 weeks must be discontinued from treatment. Patients who discontinue cetuximab therapy due to adverse event in Part 2 of the study, may continue to receive Antibody A plus irinotecan at the discretion of the investigator. 80 WO 2013/023043 PCT/US2012/050124 Management of Toxicity Related to Cetuximab Cetuximab therapy may be held for up to 2 weeks to allow for recovery from toxicity. If a patient does not recover from toxicity within 2 weeks, they must discontinue cetuximab treatment. An acneiform rash is a common toxicity of cetuximab treatment. In patients with Grade 1 or 2 skin toxicity, treatment should continue without dose modification. If a patient experiences a Grade 3 acneiform rash, the investigator should discuss the case with the sponsor and use their clinical judgment in managing the rash. If the investigator feels that a dose modification is appropriate, a recommended dose modification strategy for cetuximab is outlined herein below. Patients with a Grade 4 acneiform rash must hold cetuximab until the rash has resolved to < Grade 1. Patients with a Grade 4 rash will be discontinued from the study unless clinical benefit has been demonstrated and the case has been discussed in detail with the medical monitor. Patients restarting will have their cetuximab dose reduced by 50 mg/m 2 and their Antibody A dose reduced to the prior dose level. 81 WO 2013/023043 PCT/US2012/050124 Dose Modification for Acneiform Rash CTCAE Grade Action Taken Outcome Cetuximab Dose 3 Acneiform Rash 1 " occurrence Delay infusion by 1 to Improvement 100% 2 weeks No Discontinue Improvement 2" occurrence Delay infusion by 1 to Improvement Reduce dose by 50 2 weeks mg/m 2 No Discontinue Improvement 3 d occurrence Delay infusion by 1 to Improvement Reduce current dose 2 weeks by 50 mg/m 2 No Discontinue Improvement 4h occurrence Discontinue treatment with cetuximab In the event of Grade 2 or worsening pulmonary symptoms unrelated to underlying cancer or co-morbid conditions, cetuximab treatment should be stopped and symptoms investigated. Cetuximab treatment may resume at one lower dose level when symptoms resolve to < Grade 1 and cetuximab-related pneumonitis is ruled out. For > Grade 3 cough, dyspnea, hypoxia, pneumonitis, or pulmonary infiltrates, hold all study drug treatments until symptoms improve < Grade 1 or baseline toxicity. In case a patient's cetuximab dose is reduced due to an adverse event, it must remain reduced for the remainder of the study; re-escalation to a previous level is not permitted. Management of Toxicity Related to Irinotecan A new cycle of treatment with irinotecan should not begin until the toxicity has recovered to NCI CTCAE v. 4.0 Grade 1 or baseline value. All dose modifications should be based on the worst preceding toxicity. Treatment may be delayed by up to 82 WO 2013/023043 PCT/US2012/050124 2 weeks to allow for recovery from toxicity. If a patient does not recover from toxicity related to irinotecan within 2 weeks, the patient's continuation on study should be discussed between Investigator and Sponsor. Dose reductions to the following dose levels are allowed for management of toxicity related to irinotecan. Dose reductions of irinotecan during cycle 1 should be discussed with the sponsor and may be considered a DLT. Dose reductions for irinotecan can be made according to the following table: Dose Levels for Reduction of Irinotecan Dose Drug Starting Dose Dose Reduction Dose Reduction Level A Level B Irinotecan 180 mg/m2 150 mg/m2 120 mg/m2 Hematological Toxicity Related to Irinotecan Prior to the start of a new cycle of therapy with irinotecan, patients are required to have ANC 1.5 x 10 9 /L and platelets 100 x 10 9 /L. Treatment may be delayed for up to 2 weeks to allow for recovery. Upon recovery, patients should be re-treated using the guidelines in the table below: 83 WO 2013/023043 PCT/US2012/050124 Dose Modification for Neutropenia, and Thrombocytopenia CTCAE Grade' During a Cycle of Therapy At the Start of Subsequent Cycle of Therapy Grade 1 Maintain Dose Level Maintain Dose Level (Neutrophils: 1500 to 1999/mm3) (platelets: <LLN - 75,000/mm3; <LLN -75.0 x 10e9 /L) Grade 2 Reduce Dose to Level A Maintain Dose Level (Neutrophils: 1000 to 1499/mm 3 ) (patelets: <75,000 50,000/mm3; <75.0 - 50.0 x 10e9 /L) Grade 3 Omit dose until resolved to Reduce Dose to Level (Neutrophils: 500 to 999/mm 3 ) < Grade 2, then resume at A; if previously (platelets: <50,000 - 25,000/mm3; Level A dose; if previously reduced, resume at 25.0 x 10e9 /L) reduced, resume at Level B Level B Grade 4 Omit dose until resolved to Reduce Dose to Level B (Neutrophils: <500/mm 3 ) < Grade 2, then resume at (platelets: <25,000/mm3; <25.0 x 10e9 Level B dose /L) Neutropenic Fever or Omit dose until resolved, then resume at Level B dose Thrombocytopenia with bleeding Recurrence of Grade 2 or 3 Reduce Dose to Level B Reduce Dose to Level B toxicity after Level A dose reduction Recurrence of a toxicity that Discontinue irinotecan. At the discretion of the would require a 3rd dose investigator. These pts may continue on Antibody A reduction or recurrence of Grade and cetuximab alone once they recover to< Grade 1 4 toxicity, Neutropenic Fever or toxicity or neutropenic fever or thrombocytopenic Thrombocytopenia with bleeding bleeding episode resolves 1 CTCAE Grades as noted in the approved irinotecan labeling and are consistent with CTCAE v.4 Non-Hematological Toxicity related to Irinotecan A new cycle of treatment should not begin until the toxicity has recovered to Grade 1 or baseline value. 84 WO 2013/023043 PCT/US2012/050124 Diarrhea As per the currently approved irinotecan labeling, irinotecan can induce both early and late forms of diarrhea that appear to be mediated by different mechanisms. Both forms of diarrhea may be severe. Early diarrhea (occurring during or shortly after infusion of irinotecan) may be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping. Early diarrhea and other cholinergic symptoms may be prevented or ameliorated by atropine. Late diarrhea (generally occurring more than 24 hours after administration of irinotecan) can be life threatening since it may be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis. Late diarrhea should be treated promptly with loperamide. Patients with diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated or antibiotic therapy if they develop ileus, fever, or severe neutropenia. After the first treatment, patient with active diarrhea should return to pre-treatment bowel function without requiring anti-diarrheal medications for at least 24 hours before the next irinotecan administration. Administration of irinotecan should be interrupted and subsequent doses reduced if severe diarrhea occurs despite maximal medical management. Upon recovery, patients should be re-treated using the guidelines in the tables below: Dose Modification of Irinotecan for Diarrhea CTCAE Grade During a Cycle of At the Start of Therapy Subsequent Cycle of Therapy Grade 1 (2-3 stools/day > Delay dose until resolved Maintain dose level pretreatment) to baseline, then resume at same dose Grade 2 (4-6 stools/day > Omit dose until resolved Maintain dose level pretreatment) to baseline, then reduce to Level A Grade 3 (7-9 stools/day > Omit dose until resolved Reduce dose to Level pretreatment) to baseline, then reduce to A; if already reduced, Level A; if already resume at Level B 85 WO 2013/023043 PCT/US2012/050124 reduced, resume at Level B Grade 4 (> 10 stools/day > Omit dose until resolved Reduce dose to Level B pretreatment) to baseline, then reduce to Level B Recurrence of Grade 2 or 3 Reduce Dose to Level B Reduce dose to Level B diarrhea after Level A dose reduction Recurrence of toxicity which Discontinue would require a 3rd dose reduction or recurrence of Grade 4 diarrhea Dose Modification of Irinotecan for Other Non-Hematological Toxicity CTCAE Grade During a Cycle of At the Start of Therapy Subsequent Cycle of Therapy Grade 1 Maintain Dose Level Maintain dose level Grade 2 Omit dose until resolved Maintain dose level to < Grade 1, then reduce to Level A Grade 3 Omit dose until resolved Reduce dose to Level to < Grade 2, then reduce A; if already reduced, to Level A; if already resume at Level B reduced, resume at Level B Grade 4 Omit dose until resolved Reduce dose to Level B to < Grade 2, then reduce to Level B 86 WO 2013/023043 PCT/US2012/050124 Recurrence of Grade 2 or 3 toxicity Reduce Dose to Level B Reduce dose to Level B after Level A dose reduction Recurrence of toxicity which Discontinue would require a 3rd dose reduction or recurrence of Grade 4 toxicity Concomitant Therapy All concurrent medical conditions and complications of the underlying malignancy will be treated at the discretion of the Investigator according to acceptable local standards of medical care. Patients should receive analgesics, antiemetics, antibiotics, anti-pyretics, and blood products as necessary. Use of granulocyte colony-stimulating factors (G-CSF) is permitted to treat patients with neutropenia or neutropenic fever; prophylactic use of G-CSF will be permitted only in those patients who have had at least one episode of Grade 3/4 neutropenia or neutropenic fever while receiving study therapy. All concomitant medications, including transfusions of blood products, will be recorded on the appropriate case report form. Extent of Disease Assessment Tumor response will be evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, to establish disease progression by CT or MRI. In addition, other radiographic or scintigraphic procedures (such as radionuclide bone scans), as deemed appropriate by the Investigator, will be performed to assess sites of neoplastic involvement. The same method of assessment must be used throughout the study. Investigators should select target and non-target lesions in accordance with RECIST v1.1 guidelines. Follow up measurements and overall response should also be in accordance with these guidelines. To be assigned a status of confirmed partial response (PR) or complete response (CR), changes in tumor measurements must be confirmed by repeated assessments that should be performed >28 days after the criteria for response are first met. The extent of disease assessment should be completed until it has been determined the patient has progressive disease (in accordance with RECIST vi.1). In the event the patient discontinues study treatment for reasons other than disease progression, an extent of disease assessment should be completed as soon as possible relative to the date of study 87 WO 2013/023043 PCT/US2012/050124 termination to ensure disease progression is not present and to assess overall disease status. In such patients, this assessment should occur no later than the date of the 30 day follow up visit. Pharmacokinetic Assessments Serum levels of Antibody A, cetuximab and irinotecan will be measured lab using an ELISA based assay. In order to better understand the PK and safety profile of Antibody A and cetuximab combination, additional analytes may also be measured. Pharmacogenetic Screening Patients in Part 2 of the study (to be treated with irinotecan) should be tested for a genetic variation, UGT1A1*28 (UDP-glucuronosyltransferase). Patients that are homozygous for the UGT1A1*28 allele are excluded from Part 2 study participation. Pharmacodynamic and Biomarkers Assessments Biomarkers will be analyzed throughout the study, at the time points specified below. The following assessments are included as part of routine study follow up for all patients participating in the study. Serum Biomarker Characterization Blood samples will be collected to conduct exploratory studies to further characterize and correlate possible biomarkers that may help to predict or evaluate response to Antibody A. Archived Tumor Samples Archived tumor blocks or unstained slides containing tumor tissue, prepared at the time of initial diagnosis and at the time of metastasis (if available), are requested from each patient. These samples will be used to evaluate potentially predictive biomarkers and complete other correlative studies. Relative mutations may also be evaluated, as required. Archived paraffin blocks may be used if available. Approximately 125 [m of tumor sample (at each time point submitted) is required for this purpose. 88 WO 2013/023043 PCT/US2012/050124 Pre and Post Treatment Tumor Tissue Samples Patients enrolled in the expansion cohort will also undergo pre-treatment and post treatment biopsies in order to conduct a comparison with the archived tumor samples and to adequately evaluate the pharmacodynamic profile and biomarkers that could predict response to the Antibody A plus cetuximab plus irinotecan combination. Statistical Considerations Sample Size Dose Escalation Phase The total number of patients enrolled in the Dose Escalation Phase will depend on the number of dose cohorts required to identify the MTD. Escalation to the next dose cohort will depend on the background toxicity rate (i.e., probability of DLT at a given dose). When 1 of 3 patients develops a DLT and the cohort is expanded to 6 subjects, the proposed plan for dose escalation provides a 91% probability that dose escalation will proceed at doses associated with DLT probability of <10%. The following table shows the probability of escalation from cohort to cohort with various toxicity rates. Backgroun 1 5% 10 20 30 40 50 d Toxicity % % % % % % Rate Probability 0.999 0.973 0.906 0.709 0.494 0.309 0.172 of Dose Escalation Expansion Cohort In the Expansion Cohort, approximately 18 patients will be enrolled. These additional patients will provide additional cumulative toxicity at the MTD or recommended Phase 2 dose, as well as provide a range of values of markers within the ERB signaling pathway sufficient to provide a population mean and measure of variance that will guide the design of future trials. 89 WO 2013/023043 PCT/US2012/050124 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 partial infusion of study drug. 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 Cmax, Tmax, 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. Additional exploratory analysis may be performed on the PK sample, to help clarify any safety or PK issues related to Antibody A and/or Antibody A in combination with cetuximab and irinotecan that arise during the course of the study. Biomarker Analysis This study will explore four main questions with respect to biomarkers: e Do biomarker levels change between time of diagnosis and time of treatment? e Can biomarkers levels at time of treatment be used to predict response to Antibody A in combination with another ErbB targeted therapy (cetuximab)? e What are the molecular changes associated with the treatment of Antibody A and cetuximab in the inhibition of EGFR? e How does a cytotoxic agent (irinotecan) change the mechanism of action of Antibody A in the context of dual ErbB inhibition and what are the key molecular events that correlate with response? 90 WO 2013/023043 PCT/US2012/050124 In order to address these questions, tumor samples will be collected from each patient at both initial diagnosis and time of metastasis (if available). As comparison to these historical samples and in order to adequately evaluate the biomarker profile of the Antibody A plus cetuximab plus irinotecan combination, direct sampling of the patient's tumor will also be completed through biopsies in the Expansion cohort. This material will be processed to obtain quantitative measurements of staining by immunohistochemistry of the following receptors EGFR (ErbB 1), Her-2-neu (Erb-B2), Her-3 (Erb-B3). In addition, the messenger RNA expression of the ligands Betacellulin and Heregulin (neuregulin-1), and possibly other ligands and receptors related to sensitivity or resistance or toxicity of the combination, will be assessed using reverse transcription polymerase chain reaction (RT-PCR). These tumor samples will be analyzed as paired samples (pre- and post-treatment measures from each patient). The data will be characterized using means and 95% confidence intervals for pre-treatment concentrations for the population and the mean and 95% confidence intervals for normalized change from baseline in paired samples. In general for the main biomarker analysis patients will be classified into "marker positive" (likely to respond to Antibody A) and "marker negative" (unlikely to respond to Antibody A) group once response data is available and cut points have been set across all patients. The proportion of patients who are marker positive based on archived tissue block will be compared against the prevalence prediction made from the tumor survey results. In addition, exploratory analyses and biomarker measurements will be obtained from serum samples collected at baseline and throughout the course of the study to evaluate whether serum markers correlate with findings from the tumor sample analyses and/or overall efficacy findings (e.g. serum Heregulin and CTCs, for example). Complete and formal statistical analysis plans for the biomarker analysis will be written and maintained by the Sponsor, as such plans will be implemented across this and possibly additional studies. In the event tissue samples are received from two time points in the course of the patient's disease progression, the same prevalence rate will be calculated based on tissue 91 WO 2013/023043 PCT/US2012/050124 samples obtained in the metastatic setting. In addition, the patient's biomarker classification (as determined by the samples received from the two time points) will be compared to evaluate any significant changes in the level of any biomarker. Key efficacy endpoints (e.g., response rate and change in tumor burden) and change in biomarker level (e.g. change in serum Heregulin) as well as safety endpoints (e.g.. percent of patients experiencing Grade 3 or higher adverse event) will be compared between groups and for "marker positive" and "marker negative" patients to see if the treatment or safety effects are greater in the "marker positive" group versus the "marker negative" group. The marker positive or negative classification could be based on single biomarker or a composite score from multiple biomarkers from tissue samples or serum samples. The above univariate exploratory analyses will be performed separately for serum samples, archived tissue samples at diagnosis and the tumor tissue samples obtained in the metastatic setting (biopsy or archived). In addition, multivariate analyses of disease outcome endpoints will be performed for the marker positive group based on the best biomarker classifier from the univariate analysis after appropriate adjustment for other key clinical prognostic factors. The results from these post hoc univariate and multivariate analyses will be used to guide further diagnostic and predictive biomarker development and validation. Phamacodynamic Marker Analysis Within the Expansion Cohort, biopsy samples will be collected pre-treatment and post-treatment. This material will be frozen upon collection and subsequently processed to obtain quantitative measurements of key biomarkers (including, but not limited to, total ErbB3, phosphorylated ErbB3, phosphorylated AKT, and phosphorylated Erk). The levels of these markers will be measured at baseline (pretreatment) and compared to post-treatment levels to characterize the pharmacodynamic effects of Antibody A administration. Assuming that 50% of the patients within the target populations demonstrate ErbB3 pathway activation, which is conservative statistically, and a 40% reduction in pErb3 from baseline level is representative pErB3 pathway activation, if an activation rate of 50% is observed, N=12 per group within the Antibody A + cetuximab expansion cohort will provide a 90% CI of [26.3%, 73.7%] for the true population pErb3 pathway activation rate; N=6 per 92 WO 2013/023043 PCT/US2012/050124 group within the Antibody A + cetuximab + irinotecan expansion group will provide a 90% CI of [ 16.4%, 83.6%] for the true population pErb3 pathway activation rate. Response Criteria Evaluation of Target Lesions Complete Response (CR) Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR) At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters Progressive Disease (PD) At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression.) Stable Disease (SD) 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. Evaluation of Non-Target Lesions Complete Response (CR) Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 93 WO 2013/023043 PCT/US2012/050124 NOTE: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical 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) Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. When the patient also has measurable disease, there must be an overall level of substantial worsening in non-target disease such that, even in the presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest "increase" in the size of one or more non-target lesions is usually not sufficient to qualify for unequivocal progression status. The designation of overall progression solely on the basis of change in non-target disease in the face of SD or PR of target disease will therefore be extremely rare. When the patient only has non-measurable disease, the increase in overall disease burden should be comparable in magnitude to the increase that would be required to declare PD for measurable disease: i.e., an increase in tumor burden from "trace" to "large", an increase in nodal disease from "localized" to "widespread", or an increase sufficient to require a change in therapy. Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator). Evaluation of New Lesions The appearance of new lesions constitutes Progressive Disease (PD). 94 WO 2013/023043 PCT/US2012/050124 Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence or non-protocol therapy (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 measurement criteria. For Patients with Measurable Disease (i.e., Target Disease) Target Non- New Best Tet Target New Overall Remarks Lesions Response CR CR No CR Non CR CR/Non- No PR PD Not CR NtNo PR evaluated Non PR PD/not No PR evaluated Non- Documented at SD Pnot No SD least once > 6 evaluated weeks from baseline PD Any Yes or PD No Yes or No prior SD, PR or Any PD** No PD CR Any Any Yes PD * See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. ** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression. Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as "symptomatic deterioration. " Every effort should be made to document the objective progression even after discontinuation of treatment. 95 WO 2013/023043 PCT/US2012/050124 Duration of Response 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 progressive 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, including the baseline measurements. 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. Those skilled in the art will recognize, and is able to ascertain and implement using no more than routine experimentation, many equivalents of the specific embodiments described herein. Such equivalents are intended to be encompassed by the following claims. Any combinations of the embodiments disclosed in the dependent claims are within the scope of the disclosure. All patents, patent applications and publications cited herein are incorporated herein by reference in their entireties. 96 WO 2013/023043 PCT/US2012/050124 Table of Sequences Q DESIGNATION SOURCE TYPE SEQUENCE ) OR FORMAT Heavy Chain Human DNA gaggtgcagc tgctggagag cggcggaggg Variable Region VH ctggtccagc caggcggcag cctgaggctg CVH) ofAntibody tcctgcgccg ccagcggctt caccttcagc cactacgtga tggcctgggt gcggcaggcc A ccaggcaagg gcctggaatg ggtgtccagc atcagcagca gcggcggctg gaccctgtac gccgacagcg tgaagggcag gttcaccatc agcagggaca acagcaagaa caccctgtac ctgcagatga acagcctgag ggccgaggac accgccgtgt actactgcac caggggcctg aagatggcca ccatcttcga ctactggggc cagggcaccc tggtgaccgt gagcagc Heavy Chain Human PROTEIN Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Variable Region VH Leu Val Gln Pro Gly Gly Ser Leu Arg Leu VH)ofAntibody Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr Val Met Ala Trp Val Arg Gln Ala A Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Ser Ser Gly Gly Trp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Thr Arg Gly Leu Lys Met Ala Thr Ile Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Light Chain Human DNA cagtccgccc tgacccagcc cgccagcgtg Variable Region VL agcggcagcc caggccagag catcaccatc VL) of Antibody agctgcaccg gcaccagcag cgacgtgggc agctacaacg tggtgtcctg gtatcagcag A caccccggca aggcccccaa gctgatcatc tacgaggtgt cccagaggcc cagcggcgtg agcaacaggt tcagcggcag caagagcggc aacaccgcca gcctgaccat cagcggcctg cagaccgagg acgaggccga ctactactgc tgcagctacg ccggcagcag catcttcgtg atcttcggcg gagggaccaa ggtgaccgtc cta Light Chain Human PROTEIN Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Variable Region VL Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile VL)ofAntibody Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr Asn Val Val Ser Trp Tyr Gln Gln A His Pro Gly Lys Ala Pro Lys Leu Ile Ile Tyr Glu Val Ser Gln Arg Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser Ser Ile Phe Val Ile Phe Gly Gly Gly Thr Lys Val Thr Val Leu Heavy Chain Human PROTEIN His Tyr Val Met Ala 97 WO 2013/023043 PCT/US2012/050124 CDR1(CDRH1) CDRH1 of Antibody A Heavy Chain Human PROTEIN Ser Ile Ser Ser Ser Gly Gly Trp Thr Leu CDR2 (CDRH2) CDRH2 Tyr Ala Asp Ser Val Lys Gly of Antibody A Heavy Chain Human PROTEIN Gly Leu Lys Met Ala Thr Ile Phe Asp Tyr CDR3 (CDRH3) CDRH3 of Antibody A Light Chain Human PROTEIN Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr CDR1 (CDRL1) CDRL1 Asn Val Val Ser of Antibody A Light Chain Human PROTEIN Glu Val Ser Gln Arg Pro Ser CDR2 (CDRL2) CDRL2 of Antibody A D Light Chain Human PROTEIN Cys Ser Tyr Ala Gly Ser Ser Ile Phe Val CDR3 (CDRL3) CDRL3 Ile of Antibody A Human ErbB3 Human PROTEIN Ser Glu Val Gly Asn Ser Gln Ala Val Cys Pro Gly Thr Leu Asn Gly Leu Ser Val Thr Gly Asp Ala Glu Asn Gln Tyr Gln Thr Leu Tyr Lys Leu Tyr Glu Arg Cys Glu Val Val Met Gly Asn Leu Glu Ile Val Leu Thr Gly His Asn Ala Asp Leu Ser Phe Leu Gln Trp Ile Arg Glu Val Thr Gly Tyr Val Leu Val Ala Met Asn Glu Phe Ser Thr Leu Pro Leu Pro Asn Leu Arg Val Val Arg Gly Thr Gln Val Tyr Asp Gly Lys Phe Ala Ile Phe Val Met Leu Asn Tyr Asn Thr Asn Ser Ser His Ala Leu Arg Gln Leu Arg Leu Thr Gln Leu Thr Glu Ile Leu Ser Gly Gly Val Tyr Ile Glu Lys Asn Asp Lys Leu Cys His Met Asp Thr Ile Asp Trp Arg Asp Ile Val Arg Asp Arg Asp Ala Glu Ile Val Val Lys Asp Asn Gly Arg Ser Cys Pro Pro Cys His Glu Val Cys Lys Gly Arg Cys Trp Gly Pro Gly Ser Glu Asp Cys Gln Thr Leu Thr Lys Thr Ile Cys Ala Pro Gln Cys Asn Gly His Cys Phe Gly Pro Asn Pro Asn Gln Cys Cys His Asp Glu Cys Ala Gly Gly Cys Ser Gly Pro Gln Asp Thr Asp Cys Phe Ala Cys Arg His Phe Asn Asp Ser Gly Ala Cys Val Pro Arg Cys Pro Gln Pro Leu Val Tyr Asn Lys Leu Thr Phe Gln Leu Glu Pro Asn Pro His Thr Lys Tyr Gln Tyr Gly Gly Val Cys Val Ala Ser Cys Pro His Asn Phe Val Val Asp Gln Thr Ser Cys Val Arg Ala Cys Pro Pro Asp Lys Met Glu Val Asp Lys Asn Gly Leu Lys Met Cys Glu Pro Cys Gly Gly Leu Cys Pro Lys Ala Cys Glu Gly Thr Gly Ser Gly Ser Arg Phe Gln Thr Val Asp Ser Ser Asn Ile Asp Gly Phe Val Asn Cys Thr Lys Ile Leu Gly Asn Leu Asp Phe Leu Ile Thr Gln Gly Asp Pro Trp His Lys Ile Pro Ala Leu Asp Pro 98 WO 2013/023043 PCT/US2012/050124 Glu Lys Leu Asn Val Phe Arg Thr Val Arg Glu Ile Thr Gly Tyr Leu Asn Ile Gln Ser Trp Pro Pro His Met His Asn Phe Ser Val Phe Ser Asn Leu Thr Thr Ile Gly Gly Arg Ser Leu Tyr Asn Arg Gly Phe Ser Leu Leu Ile Met Lys Asn Leu Asn Val Thr Ser Leu Gly Phe Arg Ser Leu Lys Glu Ile Ser Ala Gly Arg Ile Tyr Ile Ser Ala Asn Arg Gln Leu Cys Tyr His His Ser Leu Asn Trp Thr Lys Val Leu Arg Gly Pro Thr Glu Glu Arg Leu Asp Ile Lys His Asn Arg Pro Arg Arg Asp Cys Val Ala Glu Gly Lys Val Cys Asp Pro Leu Cys Ser Ser Gly Gly Cys Trp Gly Pro Gly Pro Gly Gln Cys Leu Ser Cys Arg Asn Tyr Ser Arg Gly Gly Val Cys Val Thr His Cys Asn Phe Leu Asn Gly Glu Pro Arg Glu Phe Ala His Glu Ala Glu Cys Phe Ser Cys His Pro Glu Cys Gln Pro Met Glu Gly Thr Ala Thr Cys Asn Gly Ser Gly Ser Asp Thr Cys Ala Gln Cys Ala His Phe Arg Asp Gly Pro His Cys Val Ser Ser Cys Pro His Gly Val Leu Gly Ala Lys Gly Pro Ile Tyr Lys Tyr Pro Asp Val Gln Asn Glu Cys Arg Pro Cys His Glu Asn Cys Thr Gln Gly Cys Lys Gly Pro Glu Leu Gln Asp Cys Leu Gly Gln Thr Leu Val Leu Ile Gly Lys Thr His Leu Thr Met Ala Leu Thr Val Ile Ala Gly Leu Val Val Ile Phe Met Met Leu Gly Gly Thr Phe Leu Tyr Trp Arg Gly Arg Arg Ile Gln Asn Lys Arg Ala Met Arg Arg Tyr Leu Glu Arg Gly Glu Ser Ile Glu Pro Leu Asp Pro Ser Glu Lys Ala Asn Lys Val Leu Ala Arg Ile Phe Lys Glu Thr Glu Leu Arg Ser Leu Lys Val Leu Gly Ser Gly Val Phe Gly Thr Val His Lys Gly Val Trp Ile Pro Glu Gly Glu Ser Ile Lys Ile Pro Val Cys Ile Lys Val Ile Glu Asp Lys Ser Gly Arg Gln Ser Phe Gln Ala Val Thr Asp His Met Leu Ala Ile Gly Ser Leu Asp His Ala His Ile Val Arg Leu Leu Gly Leu Cys Pro Gly Ser Ser Leu Gln Leu Val Thr Gln Tyr Leu Pro Leu Gly Ser Leu Leu Asp His Val Arg Gln His Arg Gly Ala Leu Gly Pro Gln Leu Leu Leu Asn Trp Gly Val Gln Ile Ala Lys Gly Met Tyr Tyr Leu Glu Glu His Gly Met Val His Arg Asn Leu Ala Ala Arg Asn Val Leu Leu Lys Ser Pro Ser Gln Val Gln Val Ala Asp Phe Gly Val Ala Asp Leu Leu Pro Pro Asp Asp Lys Gln Leu Leu Tyr Ser Glu Ala Lys Thr Pro Ile Lys Trp Met Ala Leu Glu Ser Ile His Phe Gly Lys Tyr Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ala Glu Pro Tyr Ala Gly Leu Arg Leu Ala Glu Val Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Ala Gln Pro Gln Ile Cys Thr Ile Asp Val Tyr Met Val Met Val Lys Cys Trp Met Ile Asp 99 WO 2013/023043 PCT/US2012/050124 Glu Asn Ile Arg Pro Thr Phe Lys Glu Leu Ala Asn Glu Phe Thr Arg Met Ala Arg Asp Pro Pro Arg Tyr Leu Val Ile Lys Arg Glu Ser Gly Pro Gly Ile Ala Pro Gly Pro Glu Pro His Gly Leu Thr Asn Lys Lys Leu Glu Glu Val Glu Leu Glu Pro Glu Leu Asp Leu Asp Leu Asp Leu Glu Ala Glu Glu Asp Asn Leu Ala Thr Thr Thr Leu Gly Ser Ala Leu Ser Leu Pro Val Gly Thr Leu Asn Arg Pro Arg Gly Ser Gln Ser Leu Leu Ser Pro Ser Ser Gly Tyr Met Pro Met Asn Gln Gly Asn Leu Gly Glu Ser Cys Gln Glu Ser Ala Val Ser Gly Ser Ser Glu Arg Cys Pro Arg Pro Val Ser Leu His Pro Met Pro Arg Gly Cys Leu Ala Ser Glu Ser Ser Glu Gly His Val Thr Gly Ser Glu Ala Glu Leu Gln Glu Lys Val Ser Met Cys Arg Ser Arg Ser Arg Ser Arg Ser Pro Arg Pro Arg Gly Asp Ser Ala Tyr His Ser Gln Arg His Ser Leu Leu Thr Pro Val Thr Pro Leu Ser Pro Pro Gly Leu Glu Glu Glu Asp Val Asn Gly Tyr Val Met Pro Asp Thr His Leu Lys Gly Thr Pro Ser Ser Arg Glu Gly Thr Leu Ser Ser Val Gly Leu Ser Ser Val Leu Gly Thr Glu Glu Glu Asp Glu Asp Glu Glu Tyr Glu Tyr Met Asn Arg Arg Arg Arg His Ser Pro Pro His Pro Pro Arg Pro Ser Ser Leu Glu Glu Leu Gly Tyr Glu Tyr Met Asp Val Gly Ser Asp Leu Ser Ala Ser Leu Gly Ser Thr Gln Ser Cys Pro Leu His Pro Val Pro Ile Met Pro Thr Ala Gly Thr Thr Pro Asp Glu Asp Tyr Glu Tyr Met Asn Arg Gln Arg Asp Gly Gly Gly Pro Gly Gly Asp Tyr Ala Ala Met Gly Ala Cys Pro Ala Ser Glu Gln Gly Tyr Glu Glu Met Arg Ala Phe Gln Gly Pro Gly His Gln Ala Pro His Val His Tyr Ala Arg Leu Lys Thr Leu Arg Ser Leu Glu Ala Thr Asp Ser Ala Phe Asp Asn Pro Asp Tyr Trp His Ser Arg Leu Phe Pro Lys Ala Asn Ala Gln Arg Thr 2 Heavy Chain of human PROTEIN I EVQLLESGGG LVQPGGSLRL SCAASGFTFS Antibody A heavy HYVMAWVRQA PGKGLEWVSS 51 ISSSGGWTLY ADSVKGRFTI SRDNSKNTLY chai LQMNSLRAED TAVYYCTRGL 101 KMATIFDYWG QGTLVTVSSA STKGPSVFPL APCSRSTSES TAALGCLVKD 151 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSNFGTQTY 201 TCNVDHKPSN TKVDKTVERK CCVECPPCPA PPVAGPSVFL FPPKPKDTLM 251 ISRTPEVTCV VVDVSHEDPE VQFNWYVDGV EVHNAKTKPR EEQFNSTFRV 301 VSVLTVVHQD WLNGKEYKCK VSNKGLPAPI EKTISKTKGQ PREPQVYTLP 351 PSREEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPMLDSDG 401 SFFLYSKLTV DKSRWQQGNV FSCSVMHEAL 100 WO 2013/023043 PCT/US2012/050124 HNHYTQKSLS LSPGK 3 Light Chain of light PROTEIN I QSALTQPASV SGSPGQSITI SCTGTSSDVG Antibody A heavy SYNVVSWYQQ HPGKAPKLII Antbd A51 YEVSQRPSGV SNRFSGSKSG NTASLTISGL chain QTEDEADYYC CSYAGSSIFV 101L IFGGGTKVTV LGQPKAAPSV TLFPPSSEEL QANKATLVCL VSDFYPGAVT 151 VAWKADGSPV KVGVETTKPS KQSNNKYAAS SYLSLTPEQW KSHRSYSCRV 201 THEGSTVEKT VAPAECS 101

Claims (27)

1. A method of treating advanced stage solid tumors in a human patient comprising administering to the patient an effective amount of (a) an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and 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 second agent, gemcitabine, wherein the method comprises at least one cycle, wherein the cycle is a period of 3 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once per week at a dose of 6, 12, or 20 mg/kg and the gemcitabine is administered at a dose of 800, 1000 or 1250 mg/m2 at day 1 and day 8.

2. A method of treating advanced stage solid tumors in a human patient comprising administering to the patient an effective amount of (a) an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and 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 second agent, carboplatin, wherein the method comprises at least one cycle, wherein the cycle is a period of 3 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once per week at a dose of 6, 12, or 20 mg/kg and the carboplatin is administered at a dose having a target AUC of 5 or 6 mg- min/mL at day 1.

3. A method of treating advanced stage solid tumors in a human patient comprising administering to the patient an effective amount of (a) an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and 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 102 WO 2013/023043 PCT/US2012/050124 second agent, pemetrexed, wherein the method comprises at least one cycle, wherein the cycle is a period of 3 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once per week at a dose of 6, 12, or 20 mg/kg and the pemetrexed is administered at a dose of 375 or 500 mg/m2 at day 1.

4. A method of treating advanced stage solid tumors in a human patient comprising administering to the patient an effective amount of (a) an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and 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 second agent, cabazitaxel, wherein the method comprises at least one cycle, wherein the cycle is a period of 3 weeks, and wherein for each cycle the anti-ErbB3 antibody is administered once per week at a dose of 6, 12, or 20 mg/kg and the cabazitaxel is administered at a dose of 15, 20 or 25 mg/m 2 at day 1.

5. A method of treating cancer in a human patient, said method comprising: administering to the patient, an effective amount of each 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 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 second agent, cetuximab, wherein the method comprises at least one cycle, wherein the cycle is a period of 4 weeks, wherein for each cycle the anti-ErbB3 antibody is administered at a weekly dose of 6, 12, 20, or 40 mg/kg and the cetuximab is administered at a dose of 200 or 250 mg/m 2 once per week, except for week 1 of the first cycle, wherein the cetuximab optionally may be administered at 400 mg/m 2 .

6. The method of claim 5, wherein the antibody and cetuximab are administered according to Dose Schedules -1,1, 2a, 2b, 3a, 3b or 4 as follows: 103 WO 2013/023043 PCT/US2012/050124 Dose Antibody Dose' (mg/kg) Cetuximab Dose (mg/m 2 ) Level -1 6 400 (loading dose) 200 (weekly maintenance dose) 1 12 400 (loading dose) 200 (weekly maintenance dose) 2a 20 400 (loading dose) 200 (weekly maintenance dose) 2b 12 400 (loading dose) 250 (weekly maintenance dose) 3a 40 (loading dose) 400 (loading dose) 20 (weekly maintenance 200 (weekly maintenance dose) dose) 3b 20 400 (loading dose) 250 (weekly maintenance dose) 4 40 (loading dose) 400 (loading dose) 20 (weekly maintenance 250 (weekly maintenance dose). dose)

7. The method of claim 5 or 6, further comprising administering to the patient an effective amount of irinotecan.

8. The method of claim 7, wherein the irinotecan is administered at a dose of 120, 150 or 180 mg/m 2 once every two weeks.

9. The method of any one of claims 1-8, wherein the anti-ErbB3 antibody is administered at a dose of 12, 20 or 40 mg/kg for week 1 of cycle 1.

10. The method of any one of claims 1-9, wherein the anti-ErbB3 antibody is formulated for intravenous administration at a dose of 20 mg/kg.

11. The method of any one of claims 1-5, wherein the second agent is administered immediately after the anti-ErbB3 antibody.

12. The method of any one of claims 5-8, wherein the cetuximab and irinotecan are administered immediately after the anti-ErbB3 antibody. 104 WO 2013/023043 PCT/US2012/050124

13. The method of any one of claims 1-12, wherein the anti-ErbB3 antibody is Antibody A.

14. The method of any one of claims 1-13, wherein the anti-ErbB3 antibody comprises a heavy chain having the amino acid sequence set forth in SEQ ID NO: 12 and a light chain having the amino acid sequence set forth in SEQ ID NO: 13.

15. The method of any one of claims 1-14, 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 metastasic lesions over time, complete response, partial response, stable disease, increase in overall response rate, or a pathologic complete response.

16. The method of claim 6 or 9, wherein the cancer is EGFR dependent.

17. The method of claim 6 or 9 wherein the cancer is selected from the group consisting of: colorectal cancer, squamous cell head and neck cancer, non-small cell lung cancer, and triple negative breast cancer.

18. A 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 the method of any one of claims 1-5.

19. The kit of claim 18, said kit comprising at least 500 mg of the antibody.

20. The kit of claim 19, said kit comprising at least 1 mg of a second agent selected from the group consisting of gemcitabine, carboplatin, pemetrexed, cabazitaxel, cetuximab, and irinotecan. 105 WO 2013/023043 PCT/US2012/050124

21. The kit of claim 20, which comprises one or both of cetuximab and irinotecan.

22. An anti-ErbB3 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 co-administration with cetuximab in at least one cycle, wherein the anti-ErbB3 antibody is administered at a weekly dose of 6, 12, 20, or 40 mg/kg and the cetuximab is administered at a dose of 400, 250 or 200 mg/m 2 once per week.

23. The antibody of claim 22, wherein the antibody is further co-administered with irinotecan.

24. The antibody of claim 23, wherein the irinotecan is administered at a dose of 120, 150 or 180 mg/m 2 once every two weeks.

25. A method of treating cancer in a human patient, said method comprising concomitantly administering to the patient, an effective amount of each of (a) an anti-human ErbB3 antibody that inhibits cellular activation by heregulin, (b) an anti- human-EGFR antibody that inhibits cellular activation by EGF, and (c) a camptothecin topoisomerase I inhibitor.

26. The method of claim 25 wherein the anti-human-ErbB3 antibody is MM-121, the anti- human-EGFR antibody is cetuximab, and the camptothecin topoisomerase I inhibitor is irinotecan.

27. The method of any one of claims 22-26, wherein the anti-ErbB3 antibody is Antibody A. 106