WO2017070456A1

WO2017070456A1 - Methods of treating cancer by administering a bispecific antibody antagonist of igf-ir and erbb3 and a combination of anti-egfr antibodies

Info

Publication number: WO2017070456A1
Application number: PCT/US2016/058089
Authority: WO
Inventors: Biljana BAZDAR-VINOVRSKI; Maria Johanna LAHDENRANTA; Gavin Macbeath; Victor Moyo; Marisa WAINSZELBAUM
Original assignee: Merrimack Pharmaceuticals, Inc.
Priority date: 2015-10-22
Filing date: 2016-10-21
Publication date: 2017-04-27

Abstract

Provided are methods for clinical treatment of cancers (e.g., an Insulin Growth Factor 1 (IGF-1) positive cancer) using a bispecific antibody antagonist of IGF-IR and ErbB3 (e.g., istiratumab) in combination with anti-EGFR antibodies (e.g., MM-151). In one embodiment, the cancer is non- small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), or colorectal cancer (CRC).

Description

METHODS OF TREATING CANCER BY ADMINISTERING A BISPECIFIC ANTIBODY ANTAGONIST OF IGF-IR AND ERBB3

AND A COMBINATION OF ANTI-EGFR ANTIBODIES

RELATED APPLICATIONS

This application claims the benefit of three U.S. Provisional Patent Applications: U.S. Provisional Patent Application Serial No. 62/343,969 filed June 1, 2016, U.S. Provisional Patent Application Serial No. 62/337,012 filed May 16, 2016 and U.S. Provisional Patent Application Serial No. 62/244,981 filed October 22, 2015. The entire contents of the above- referenced patent applications are incorporated herein by these references.

BACKGROUND

Several studies have shown that Epidermal Growth Factor Receptor (EGFR) pathway is a key driver of late-stage colorectal cancer (CRC), squamous cell carcinoma of the head and neck (SCCHN) and non-small cell lung cancer (NSCLC). EGFR inhibitors prolong survival in a large subset of patients, however, not all patients respond and resistance develops in those who respond. Accordingly, it is an object of the present invention to provide improved methods for treating patients with cancers, such as CRC, SCCHN, and NSCLC.

SUMMARY

Provided herein are compositions and methods for treating cancers (e.g., an Insulin Growth Factor 1 (IGF-1) positive cancer) in a human patient, comprising administering to the patient a bispecific antibody antagonist of IGF-IR and ErbB3 and a composition of anti-

EGFR antibodies according to a particular clinical dosage regimen (i.e., at a particular dose amount and according to a specific dosing schedule).

An exemplary bispecific antibody antagonist of IGF-IR and ErbB3 is istiratumab (also known as "MM- 141 " and "P4-G1-M1.3"). In one embodiment, the bispecific antibody is a polyvalent bispecific antibody having two pairs of polypeptide chains, each pair of said two pairs comprising a heavy chain joined to a light chain by at least one heavy-light chain bond, wherein each light chain comprises the amino acid sequence set forth in SEQ ID NO:26 and each heavy chain comprises the amino acid sequence set forth in SEQ ID NO:27. In one embodiment, the bispecific antibody further comprises a linker having the amino acid sequence set forth in SEQ ID NO:28. An exemplary composition of anti-EGFR antibodies is MM- 151. In one embodiment, the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 1, 2, and 3, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 4, 5, and 6,

respectively; (2) a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 7, 8, and 9, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 10, 11, and 12, respectively; and (3) a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 13, 14, and 15, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 16, 17, and 18, respectively.

In another embodiment, the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 29; (2) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 31 and (3) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 33.

In another embodiment, the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a light chain variable region comprising SEQ ID NO: 30; (2) a monoclonal antibody comprising a light chain variable region comprising SEQ ID NO: 32; and (3) a monoclonal antibody comprising a light chain variable region comprising SEQ ID NO: 34.

In another embodiment, the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 29 and a light chain variable region comprising SEQ ID NO: 30; (2) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 31 and a light chain variable region comprising SEQ ID NO: 32; and (3) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 33 and a light chain variable region comprising SEQ ID NO: 34.

In another embodiment, the anti-EGFR antibodies (1), (2), and (3) are in the composition at a molar ratio of 2:2: 1 to each other.

In another embodiment, each of the anti-EGFR antibodies in the composition is a human antibody. In another embodiment, the composition of anti-EGFR antibodies comprises a pharmaceutically acceptable carrier. In another embodiment, the composition is a sterile composition. In one embodiment, the cancer is an Insulin Growth Factor 1 (IGF-1) positive cancer. In one embodiment, the cancer is selected from the group consisting of NSCLC, SCCHN, and CRC.

Accordingly, in one aspect, methods of treating a human patient with a cancer (e.g., an IGF-1 positive cancer) are provided, the methods comprising administering to the patient a bispecific antibody antagonist of IGF-IR and ErbB3 (e.g., istiratumab) and a composition of anti- EGFR antibodies (e.g., MM-151). In one embodiment, the dose of istiratumab is a flat-fixed dose that is fixed irrespective of the weight of the patient. For example, istiratumab may be administered at a fixed dose of 1.96 g, 2.24 g, or 2.8 g without regard to the patient's weight. In certain embodiments, dosage regimens are adjusted to provide the optimum desired response (e.g., an effective response).

In one embodiment, the dose of the composition of anti-EGFR antibodies (e.g., MM- 151) is adjusted to the body-surface area (BSA) of the individual patient. For example, the dose of the composition of anti-EGFR antibodies may be administered at a dose of 9 mg/kg or 10.5 mg/kg.

In one embodiment, the composition of anti-EGFR antibodies is administered during the priming phase, prior to the start of the cycle. For example, in one embodiment, the priming phase is a period of two weeks and the composition of anti-EGFR antibodies is administered on week one of the priming phase at a fixed dose of 225 mg. In another

embodiment, the priming phase is a period of two weeks and the composition of anti-EGFR antibodies is administered on week two of the priming phase at a fixed dose of 450 mg. In another embodiment, the composition of anti-EGFR antibodies is administered on week one of the priming phase at a fixed dose of 225 mg and on week two of the priming phase at a fixed dose of 450 mg.

In another embodiment, methods of treating a human patient with a cancer (e.g., an IGF-1 positive cancer) are provided, wherein the methods comprise administering to the patient:

A. a polyvalent bispecific antibody having two pairs of polypeptide chains, each pair of said two pairs comprising a heavy chain joined to a light chain by at least one heavy- light chain bond, wherein each light chain comprises the amino acid sequence set forth in SEQ ID NO:26 and each heavy chain comprises the amino acid sequence set forth in SEQ ID NO:27; and

B. a composition of anti-EGFR antibodies comprising: 1. a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 1, 2, and 3, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 4, 5, and 6, respectively;

2. a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 7, 8, and 9, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 10, 11, and 12, respectively; and

3. a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 13, 14, and 15, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 16, 17, and 18, respectively, wherein the method comprises a priming phase and a cycle,

wherein the priming phase is a period of two weeks and the composition is administered on week one of the priming phase at a fixed dose of 225 mg and on week two of the priming phase at a fixed dose of 450 mg, and

wherein the cycle is a period of four weeks, wherein:

i. the polyvalent bispecific antibody is administered once every two weeks at a fixed dose of 1.96 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 10.5 mg/kg;

ii. the polyvalent bispecific antibody is administered once every two weeks at a fixed dose of 1.96 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 9 mg/kg;

iii. the polyvalent bispecific antibody is administered once every two weeks at a fixed dose of 2.24 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 10.5 mg/kg;

iv. the polyvalent bispecific antibody is administered once every two weeks at a fixed dose of 2.24 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 9 mg/kg;

v. the polyvalent bispecific antibody is administered once every two weeks at a fixed dose of 2.8 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 10.5 mg/kg; or

vi. the polyvalent bispecific antibody is administered once every two weeks at a fixed dose of 2.8 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 9 mg/kg. In one embodiment, during the cycle the polyvalent bispecific antibody is administered once every two weeks at a fixed dose of 1.96 g and the composition of anti- EGFR antibodies is administered once weekly at a dose of 10.5 mg/kg.

In another embodiment, during the cycle the polyvalent bispecific antibody is administered once every two weeks at a fixed dose of 1.96 g and the composition of anti- EGFR antibodies is administered once weekly at a dose of 9 mg/kg.

In another embodiment, during the cycle the polyvalent bispecific antibody is administered once every two weeks at a fixed dose of 2.24 g and the composition of anti- EGFR antibodies is administered once weekly at a dose of 10.5 mg/kg.

In another embodiment, during the cycle the polyvalent bispecific antibody is administered once every two weeks at a fixed dose of 2.24 g and the composition of anti- EGFR antibodies is administered once weekly at a dose of 9 mg/kg.

In another embodiment, during the cycle the polyvalent bispecific antibody is administered once every two weeks at a fixed dose of 2.8 g and the composition of anti- EGFR antibodies is administered once weekly at a dose of 10.5 mg/kg.

In another embodiment, during the cycle the polyvalent bispecific antibody is administered once every two weeks at a fixed dose of 2.8 g and the composition of anti- EGFR antibodies is administered once weekly at a dose of 9 mg/kg.

A. istiratumab; and

B. a composition of anti-EGFR antibodies comprising:

1. a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3

sequences of SEQ ID NOs: 1, 2, and 3, respectively, and light chain CDR1,

CDR2, and CDR3 sequences of SEQ ID NOs: 4, 5, and 6, respectively;

2. a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 7, 8, and 9, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 10, 11, and 12, respectively; and 3. a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 13, 14, and 15, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 16, 17, and 18, respectively, wherein the method comprises a priming phase and a cycle, wherein the priming phase is a period of two weeks and the composition is administered on week one of the priming phase at a fixed dose of 225 mg and on week two of the priming phase at a fixed dose of 450 mg, and

wherein the cycle is a period of four weeks, wherein:

i. istiratumab is administered once every two weeks at a fixed dose of 1.96 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 10.5 mg/kg;

ii. istiratumab is administered once every two weeks at a fixed dose of 1.96 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 9 mg/kg;

iii. istiratumab is administered once every two weeks at a fixed dose of 2.24 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 10.5 mg/kg;

iv. istiratumab is administered once every two weeks at a fixed dose of 2.24 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 9 mg/kg;

v. istiratumab is administered once every two weeks at a fixed dose of 2.8 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 10.5 mg/kg; or

vi. istiratumab is administered once every two weeks at a fixed dose of 2.8 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 9 mg/kg.

In one embodiment, during the cycle istiratumab is administered once every two weeks at a fixed dose of 1.96 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 10.5 mg/kg.

In another embodiment, during the cycle istiratumab is administered once every two weeks at a fixed dose of 1.96 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 9 mg/kg.

In another embodiment, during the cycle istiratumab is administered once every two weeks at a fixed dose of 2.24 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 10.5 mg/kg.

In another embodiment, during the cycle istiratumab is administered once every two weeks at a fixed dose of 2.24 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 9 mg/kg. In another embodiment, during the cycle istiratumab is administered once every two weeks at a fixed dose of 2.8 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 10.5 mg/kg.

In another embodiment, during the cycle istiratumab is administered once every two weeks at a fixed dose of 2.8 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 9 mg/kg.

On weeks when both the polyvalent bispecific antibody (e.g., istiratumab) and the composition of anti-EGFR antibodies (e.g., MM- 151) are administered, the polyvalent bispecific antibody (e.g., istiratumab) is administered prior to the composition of anti-EGFR antibodies (e.g., MM- 151). For example, on weeks when both istiratumab and MM-151 are administered, istiratumab is administered prior to administration of MM- 151.

The agents described herein can be administered to a patient by any suitable means. In one embodiment, the polyvalent bispecific antibody (e.g., istiratumab) is formulated for intravenous administration. In another embodiment, the composition of anti-EGFR antibodies (e.g., MM- 151) is formulated for intravenous administration.

The efficacy of the treatment methods provided herein can be assessed using any suitable means. In one embodiment, the treatment produces at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in metastasis, complete remission, partial remission, stable disease, increase in overall response rate, or a pathologic complete response. In another embodiment, administration of combination of a bispecific antibody antagonist of IGF-IR and ErbB3 (e.g. , istiratumab) and a composition of anti-EGFR antibodies (such as MM- 151) provides improved efficacy compared to treatment with a bispecific antibody antagonist of IGF-IR and ErbB3 (e.g. , istiratumab) alone or with a composition of anti-EGFR antibodies (such as MM-151) alone. In another embodiment, the combination exhibits therapeutic synergy.

Further provided are kits that include a polyvalent bispecific antibody, such as istiratumab, and a composition of anti-EGFR antibodies, such as MM- 151, in a

therapeutically effective amount adapted for use in the methods described herein. In one embodiment, the kit comprises:

A. a dose of a polyvalent bispecific antibody having two pairs of polypeptide chains, each pair of said two pairs comprising a heavy chain joined to a light chain by at least one heavy-light chain bond, wherein each light chain comprises the amino acid sequence set forth in SEQ ID NO:26 and each heavy chain comprises the amino acid sequence set forth in SEQ ID NO:27; B. a dose of a composition of anti-EGFR antibodies comprising: (1) a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 1, 2, and 3, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 4, 5, and 6, respectively; (2) a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 7, 8, and 9, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 10, 11 and 12, respectively; and (3) a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 13, 14, and 15, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 16, 17, and 18, respectively; and

instructions for using the polyvalent bispecific antibody and the composition of anti- EGFR antibodies, in the methods described herein.

Also provided are kits that include a bispecific antibody antagonist of IGF-IR and ErbB3, such as istiratumab, and a composition of anti-EGFR antibodies, such as MM-151, in a therapeutically effective amount adapted for use in the methods described herein. In one embodiment, the kit comprises:

A. a dose of istiratumab;

B. a dose of a composition of anti-EGFR antibodies comprising: (1) a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 1, 2, and 3, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 4, 5, and 6, respectively; (2) a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 7, 8, and 9, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 10, 11 and 12, respectively; and (3) a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 13, 14, and 15, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 16, 17, and 18, respectively; and

C. instructions for using istiratumab and the composition of anti-EGFR antibodies, in the methods described herein. BRIEF DESCRIPTION OF THE DRAWINGS

Figures 1A-1B are heat maps. Specifically, Figure 1A is a heat map that shows the conditional probability of 29 colorectal cancer cells to respond (increase in viability) to one ligand and also respond to a second one. Figure IB is a response heat map that shows the effect of treatment with MM- 151, MM- 141 or the combination of both in 29 colorectal cancer cells in the presence of EGF and IGF- 1. Figures 2A-F are graphs showing the effect of treatment with each of MM- 151,

seribantumab ("MM- 121"), and istiratumab ("MM- 141") alone or combinations thereof on tumor volume (y-axis, mm ) over time (x-axis, days) in cancer cell derived xenografts. Data shown are for cancer cell lines DLD- 1 (Figure 2A), LoVo (Figure 2B), Liml215 (Figure 2C), LS411N (Figure 2D), LS 174T (Figure 2E) and Liml215 (Figure 2F).

Figure 3 is a schematic depicting the design of the study.

Figure 4 is a schematic depicting the design of the Biomarker-Selected, Multi-Arm Basket Trial.

DETAILED DESCRIPTION

I. Definitions

As used herein, the term "subject" or "patient" is a human patient (e.g., a patient having an IGF- 1 positive cancer).

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. Effective treatment may refer to alleviation of at least one symptom of cancer.

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. An effective amount can be administered in one or more administrations. As used herein, the term "priming phase" refers to the phase preceding the first cycle of the clinical trial (e.g., wherein the composition of anti-EGFR antibodies is administered).

As used herein, the term "cycle" refers to the treatment phase of the clinical trial. In certain embodiments, treatment is continued as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs.

As used herein, the terms "fixed dose", "flat dose" and "flat-fixed dose" are used interchangeably and refer to a dose that is administered to a patient without regard for the weight or body surface area (BSA) of the patient. The fixed or flat dose is therefore not provided as a mg/kg dose, but rather as an absolute amount of the agent.

As used herein, a "body surface area (BSA)-based dose" refers to a dose of the agent that is adjusted to the body-surface area (BSA) of the individual patient. A BSA-based dose may be provided as mg/kg body weight. Various calculations have been published to arrive at the BSA without direct measurement, the most widely used of which is the Du Bois formula (see Du Bois D, Du Bois EF (Jun 1916) Archives of Internal Medicine 17 (6): 863- 71; and Verbraecken, J. et al. (Apr 2006). Metabolism— Clinical and Experimental 55 (4): 515-24). Other exemplary BSA formulas include the Mosteller formula (Mosteller RD. N Engl J Med., 1987; 317: 1098), the Haycock formula (Haycock GB, et al., Pediatr 1978, 93:62-66), the Gehan and George formula (Gehan EA, George SL, Cancer Chemother Rep 1970, 54:225-235), the Boyd formula (Current, JD (1998), The Internet Journal of

Anesthesiology 2 (2); and Boyd, Edith (1935), University of Minnesota. The Institute of Child Welfare, Monograph Series, No. x. London: Oxford University Press), the Fujimoto formula (Fujimoto S, et al., Nippon Eiseigaku Zasshi 1968;5:443-50), the Takahira formula (Fujimoto S, et al., Nippon Eiseigaku Zasshi 1968;5:443-50), and the Schlich formula (Schlich E, et al., Ernahrungs Umschau 2010;57: 178-183).

The term "inhibition" as used herein, refers to any statistically significant decrease in biological activity, including full blocking of the activity. For example, "inhibition" can refer to a statistically significant decrease of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 100% in biological activity.

The phrase "inhibition of cell growth," as used herein, refers to the ability of an antibody or antibody mixture to statistically significantly decrease the growth of a cell relative to the growth of the cell or cells in the absence of the antibody (control) either in vivo or in vitro. In one embodiment, the growth of a cell (e.g., a cancer cell) may be decreased by at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or about 100% when the cells are contacted with the combination disclosed herein, relative to the growth measured in the absence of the combination (control) or when the cells are contacted with a single species of monoclonal antibody. Cellular growth can be assayed using art recognized techniques which measure the rate of cell division, the fraction of cells within a cell population undergoing cell division, and/or the rate of cell loss from a cell population due to terminal differentiation or cell death (e.g., using a CellTiter-Glo® or similar assay).

The terms "treat," "treating," and "treatment," as used herein, refer to therapeutic or preventative measures described herein. The methods of "treatment" employ administration to a subject, the combination disclosed herein in order to prevent, cure, delay, reduce the severity of, or ameliorate one or more symptoms of the disease or disorder or recurring disease or disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.

The term "sample" refers to tissue, body fluid, or a cell (or a fraction of any of the foregoing) taken from a patient. Normally, the tissue or cell will be removed from the patient, but in vivo diagnosis is also contemplated. In the case of a solid tumor, a tissue sample can be taken from a surgically removed tumor and prepared for testing by

conventional techniques. In the case of lymphomas and leukemias, lymphocytes, leukemic cells, or lymph tissues can be obtained (e.g. , leukemic cells from blood) and appropriately prepared. Other samples, including urine, tears, serum, plasma, cerebrospinal fluid, feces, sputum, cell extracts, etc. can also be useful for particular cancers.

The term "antibody" describes polypeptides comprising at least one antibody derived antigen binding site (e.g., VH/VL region or Fv, or CDR). Antibodies include known forms of antibodies. For example, the antibody can be a human antibody, a humanized antibody, a bispecific antibody, or a chimeric antibody. The antibody also can be a Fab, Fab'2, ScFv, SMIP, Affibody®, nanobody, or a domain antibody. The antibody also can be of any of the following isotypes: IgGl , IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgAsec, IgD, and IgE. The antibody may be a naturally occurring antibody or may be an antibody that has been altered by a protein engineering technique (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 or engineered polypeptide constructs which comprise at least one antibody-derived antigen binding site.

Methods for determining whether an antibody binds to a protein antigen and/or the affinity for an antibody to a protein antigen are known in the art. For example, the binding of an antibody to a protein antigen can be detected and/or quantified using a variety of techniques such as, but not limited to, Western blot, dot blot, surface plasmon resonance (SPR) method (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.), or enzyme-linked immunosorbent assay (ELISA). See, e.g., Benny K. C. Lo (2004) "Antibody Engineering: Methods and Protocols," Humana Press (ISBN:

1588290921); Johne et al. (1993) J Immunol Meth 160: 191-198; Jonsson et al. (1993) Ann Biol Clin 51: 19-26; and Jonsson et al. (1991) Biotechniques 11:620-627.

As used herein, the term "k_a" refers to the rate constant for association of an antibody to an antigen. The term refers to the rate constant for dissociation of an antibody from the antibody/antigen complex. And the term "K_D" refers to the equilibrium dissociation constant of an antibody- antigen interaction. The equilibrium dissociation constant is deduced from the ratio of the kinetic rate constants, K_D = k_a/k_d.

In one embodiment, the antibody competes for binding with, and/or binds to the same epitope on a target antigen as, the antibodies described herein. The term "binds to the same epitope" with reference to two or more antibodies means that the antibodies bind to the same segment of amino acid residues, as determined by a given method. Techniques for determining whether antibodies bind to the "same epitope" with the antibodies described herein include, for example, epitope mapping methods, such as, x-ray analyses of crystals of antigen: antibody complexes which provides atomic resolution of the epitope and

hydrogen/deuterium exchange mass spectrometry (HDX-MS). Other methods monitor the binding of the antibody to peptide antigen fragments or mutated variations of the antigen where loss of binding due to a modification of an amino acid residue within the antigen sequence is often considered an indication of an epitope component. In addition,

computational combinatorial methods for epitope mapping can also be used. These methods rely on the ability of the antibody of interest to affinity isolate specific short peptides from combinatorial phage display peptide libraries. Antibodies having the same VH and VL or the same CDR1, 2 and 3 sequences are expected to bind to the same epitope.

Antibodies that "compete with another antibody for binding to a target" refer to antibodies that inhibit (partially or completely) the binding of the other antibody to the target. Whether two antibodies compete with each other for binding to a target, i.e., whether and to what extent one antibody inhibits the binding of the other antibody to a target, may be determined using known competition experiments. In certain embodiments, an antibody competes with, and inhibits binding of another antibody to a target by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%. The level of inhibition or competition may be different depending on which antibody is the "blocking antibody" (i.e., the cold antibody that is incubated first with the target). Competing antibodies bind to the same epitope, an overlapping epitope or to adjacent epitopes (e.g., as evidenced by steric hindrance).

Antibodies, or antigen-binding fragments thereof described herein, used in the methods described herein can be generated using a variety of art-recognized techniques. Monoclonal antibodies may be obtained by various techniques familiar to those skilled in the art. Briefly, spleen cells from an animal immunized with a desired antigen are immortalized, commonly by fusion with a myeloma cell (see, Kohler & Milstein, Eur. J. Immunol. 6: 511- 519 (1976)). Alternative methods of immortalization include transformation with Epstein Barr Virus, oncogenes, or retroviruses, or other methods well known in the art. Colonies arising from single immortalized cells are screened for production of antibodies of the desired specificity and affinity for the antigen, and yield of the monoclonal antibodies produced by such cells may be enhanced by various techniques, including injection into the peritoneal cavity of a vertebrate host. Alternatively, one may isolate DNA sequences which encode a monoclonal antibody or a binding fragment thereof by screening a DNA library from human B cells according to the general protocol outlined by Huse, et ah, Science 246: 1275-1281 (1989).

The term "heregulin" (HRG) refers to an ErbB3 ligand that activates ErbB3, thereby initiating intracellular signaling in tumor cells. This may occur in an autocrine fashion, in which the HRG produced by a cell activates the same cell, or it may occur in a paracrine fashion, in which HRG produced by one cell (e.g., a stromal cell in a tumor) activates neighboring cells (e.g., tumor cells). Data suggest that ErbB3 and its ligand, heregulin, promote clinically significant resistance to targeted agents and chemotherapy.

The term "IGF-1R" or "IGF1R" refers to the receptor for insulin-like growth factor 1 (IGF-1, formerly known as somatomedin C). IGF-1R also binds to, and is activated by, insulin-like growth factor 2 (IGF-2). IGF1-R is a receptor tyrosine kinase, which upon activation by IGF- 1 or IGF-2 is auto-phosphorylated. The amino acid sequence of human

IGF-1R precursor is provided at Genbank Accession No. NP 000866 and is assigned Gene

ID: 3480. A "an IGF-1 positive cancer" is a cancer which expresses IGF-1. IGF- 1 can be detected, for example, using immunohistochemistry. In one embodiment, a patient tumor biopsy is taken and formalin fixed and paraffin embedded. IGF-1 may be detected, for example using the Gi l clone detection antibody (cat# 790-4346, Ventana). Free (unbound) IGF-1 may also be detected in serum by, e.g, by an ELISA assay.

The terms "EGFR," and "EGF receptor" are used interchangeably herein to refer to human EGFR protein (also referred to as ErbB l or HER1); see UniProtKB/Swiss-Prot entry P00533. The EGFR extracellular domain, or EGFR-ECD, is the portion of the EGFR protein that extends beyond the cell surface in vivo, and is thus accessible to antibodies on the exterior of the cell. The wild-type EGFR-ECD protein sequence is SEQ ID NO:25. As used herein, an "EGFR-ECD mutation" or a "mutation in the extracellular domain of EGFR" may refer to an EGFR-ECD protein sequence with a difference in at least one amino acid residue as compared to the wild type sequence; an "EGFR-ECD mutation" may also refer to a change in that portion of the DNA or RNA coding sequence that corresponds to a change in the protein sequence of the extracellular domain of EGFR. In some embodiments, the change in the DNA or RNA coding sequence occurs in exon 12 of the EGFR gene or transcript. In other embodiments, the EGFR-ECD mutation is a change in the protein sequence

corresponding to Domain III of the extracellular domain of EGFR.

"ErbB3 " and "HER3 " refer to ErbB3 protein, as described in U.S. Pat. No. 5,480,968. The human ErbB3 protein sequence is shown in FIG. 4 and SEQ ID NO:4 of U.S. Pat. No. 5,480,968, wherein the first 19 amino acids correspond to the leader sequence that is cleaved from the mature protein. ErbB3 is a member of the ErbB family of receptors, other members of which include ErbB l (EGFR), ErbB2 (HER2/Neu) and ErbB4. While ErbB3 itself lacks tyrosine kinase activity, but is itself phosphorylated upon dimerization of ErbB3 with another ErbB family receptor, e.g., ErbB l, ErbB2 and ErbB4, which are receptor tyrosine kinases. Ligands for the ErbB family include heregulin (HRG), betacellulin (BTC), epidermal growth factor (EGF), heparin-binding epidermal growth factor (HB-EGF), transforming growth factor alpha (TGF-. alpha.), amphiregulin (AR), epigen (EPG) and epiregulin (EPR). The amino acid sequence of human ErbB3 is provided at Genbank Accession No. NP 001973.2 (receptor tyro sine-protein kinase erbB-3 isoform 1 precursor) and is assigned Gene ID: 2065.

II. Istiratumab

An exemplary bispecific antibody antagonist of IGF-IR and ErbB 3 is istiratumab (also known as "MM- 141 " and "P4-G1-M1.3"). Istiratumab is described as "P4-G1-M1.3 " in WO/2012/145507 (PCT/US2012/034244), WO/2013/152034 (PCT/US2013/035013), WO/2015/130554 (PCT/US2015/016672), and US Patent No: 8,476,409, the teachings of all of which are expressly incorporated herein by reference. Istiratumab binds to IGF-1R with a K_D of 0.3 nM and ErbB3 with a K_D of 0.9 nM. Istiratumab has two pairs of polypeptide chains, each pair of said two pairs comprising a heavy chain joined to a light chain by at least one heavy-light chain bond, wherein each light chain comprises the amino acid sequence set forth in SEQ ID NO:26 and each heavy chain comprises the amino acid sequence set forth in SEQ ID NO:27. SEQ ID NOs: 26 and 27 correspond to SEQ ID NOs: 204 and 226, respectively, as set forth in U.S. Patent No. 8,476,409 (which is herein incorporated by reference in its entirety). In one embodiment, istiratumab comprises a linker having the amino acid sequence set forth in SEQ ID NO:28. SEQ ID NO:28 corresponds to SEQ ID NO: 53 as set forth in PCT/US2010/052712 (which is herein incorporated by reference in its entirety).

IGF-IR and ErbB3 complexes both activate a major signaling pathway that allows tumor cells to grow and develop resistance to chemotherapy. Istiratumab acts as a tetravalent inhibitor of PI3K/AKT/mTOR, which is a major pro-survival pathway tumor cells use as a resistance mechanism to anticancer therapies (see, e.g., Jonathan B. Fitzgerald, et al., Mol. Cancer. Ther; 13(2) February 2014). Istiratumab is designed to interfere with the

PI3K/AKT/mTOR pathway in various cancers by blocking ligand-induced signaling through the IGF-IR and ErbB3 receptors. Istiratumab prevents activation of both IGF-IR and ErbB3 by blocking ligand binding and decreasing receptor levels, which leads to the inhibition of AKT and mTOR. Inhibition of AKT and mTOR triggers resistance mediated by decreased degradation of IRS-1 and FoxO-mediated transcriptional upregulation of IGF-IR and ErbB3. Istiratumab abrogates these feedback mechanisms by disrupting the recruitment of IRS-1 to existing and newly formed IGF-IR/Insulin receptor through depletion of receptors.

Istiratumab represents a novel optimally designed biologic therapeutic agent capable of proactive blockade of tumor survival pathways and control of the resistance mechanisms commonly evoked by cancer cells.

III. Composition of Anti-EGFR Antibodies

Compositions of anti-EGFR antibodies (or VH/VL domains derived therefrom) suitable for use in the invention can be generated using methods well known in the art.

Alternatively, compositions comprising art recognized anti-EGFR antibodies, such as Syi 004 (Symphogen), can be used. Antibodies that compete with any of these art-recognized antibodies for binding to EGFR also can be used.

An exemplary composition of anti-EGFR antibodies suitable for use in the invention is "MM-151 ". MM- 151 is an oligoclonal therapeutic consisting of a mixture of three fully human IgGl monoclonal antibodies designed to bind and inhibit signaling of the Epidermal Growth Factor Receptor (EGFR). MM- 151 is a mixture of three independent antibodies (P1X + P2X + P3X), which bind to three non-overlapping sites on EGFR to maximize inhibition of ligand-dependent and independent signaling (see, e.g., WO 2013/006547, the teachings of which are expressly incorporated herein by reference) with a K_D <1 nM. The P1X, P2X and P3X monoclonal antibodies are affinity matured antibodies of parental antibodies referred to as ca, cd and ch, respectively, disclosed in WO 2011/140254, the teachings of which are expressly incorporated herein by reference. The CDR amino acid sequences of P1X, P2X and P3X are shown below in Table 1 : Table 1: CDR amino acid sequences of P1X, P2X and P3X

The full-length VH and VL amino sequences (including leader sequences) for P1X are shown in SEQ ID NO: 19 and SEQ ID NO: 20, respectively. The full-length V_H and V_L amino sequences (including leader sequences) for P2X are shown in SEQ ID NO: 21 and SEQ ID NO: 22, respectively. The full-length VH and VL amino sequences (including leader sequences) for P3X are shown in SEQ ID NO: 23 and SEQ ID NO: 24, respectively.

Additionally, the V_H and V_L CDR segments as presented herein are arranged, e.g., in the amino to carboxy terminal order of CDR1, CDR2 and CDR3. The mature full-length V_H and V_L amino acid sequences for P1X are shown in SEQ ID NO: 29 and SEQ ID NO: 30, respectively. The mature full-length V_H and V_L amino acid sequences for P2X are shown in SEQ ID NO: 31 and SEQ ID NO: 32, respectively. The mature full-length V_H and V_L amino acid sequences for P3X are shown in SEQ ID NO: 33 and SEQ ID NO: 34, respectively. It is well known in the art, that mature heavy and light chain variable region sequences do not include leader sequences, since the leader sequences are ultimately cleaved from the mature variable regions sequences. The mature heavy and light chain variable regions sequences are inherent regions within the precursor sequences that can readily be identified using well established rules and art-recognized techniques. Based on known CDR and consensus sequences, one of ordinary skill in the art can identify the residues corresponding to the beginning and end of the variable regions (and thus, also the mature portion), as taught, for example, by Roguska et al. (Proc. Nati. Acad. Sci. USA, Vol. 91, pp. 969-973, February 1994).

In one embodiment, the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 1, 2, and3, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 4, 5, and 6, respectively; (2) a monoclonal antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 7, 8, and 9, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 10, 11, and 12, respectively; and (3) a monoclonal antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 13, 14, and 15, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 16, 17, and 18, respectively.

Moreover, the exact boundaries of CDRs can be defined differently according to different methods. In some embodiments, the positions of the CDRs or framework regions within a light or heavy chain variable domain can be as defined by Kabat et al. [(1991) "Sequences of Proteins of Immunological Interest." NIH Publication No. 91-3242, U.S. Department of Health and Human Services, Bethesda, MD]. In such cases, the CDRs can be referred to as "Kabat CDRs" (e.g., "Kabat LCDR2" or "Kabat HCDR1"). In other embodiments, the positions of the CDRs of a light or heavy chain variable region can be as defined by Chothia et al. (1989) Nature 342:877-883. Accordingly, these regions can be referred to as "Chothia CDRs" (e.g., "Chothia LCDR2" or "Chothia HCDR3"). In other embodiments, the positions of the CDRs of the light and heavy chain variable regions can be as defined by a Kabat-Chothia combined definition. In such embodiments, these regions can be referred to as "combined Kabat-Chothia CDRs". Thomas et al. [(1996) Mol Immunol 33(17/18): 1389-14011 exemplifies the identification of CDR boundaries according to Kabat and Chothia definitions. In other embodiments, the positions of the CDRs or framework regions within a light or heavy chain variable domain can be as defined by the international ImMunoGeneTics database (IMGT) standard. Marie-Paule Lefranc et al. [(2003)

Developmental & Comparative Immunology 27(l):55-77] exemplifies the identification of and CDR boundaries according to IMGT standard. Accordingly, these regions can be referred to as "IMGT CDRs" {e.g., "IMGT-LCDR2" or "IMGT-HCDR3").

Accordingly, in another embodiment, the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising the CDRl, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 29, and the CDRl, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 30; (2) a monoclonal antibody comprising the CDRl, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 31, and the CDRl, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 32; and (3) a monoclonal antibody comprising the CDRl, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 33, and the CDRl, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 34.

In another embodiment, the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 29 and a light chain variable region comprising SEQ ID NO: 30; (2) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 31 and a light chain variable region comprising SEQ ID NO: 32; and (3) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 33 and a light chain variable region comprising SEQ ID NO: 34. In another embodiment, the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising the mature portion of the heavy chain variable region comprising SEQ ID NO: 19 and the mature portion of the light chain variable region comprising SEQ ID NO: 20; (2) a monoclonal antibody comprising the mature portion of the heavy chain variable region comprising SEQ ID NO: 21 and the mature portion of the light chain variable region comprising SEQ ID NO: 22; and (3) a monoclonal antibody comprising the mature portion of the heavy chain variable region comprising SEQ ID NO: 23 and the mature portion of the light chain variable region comprising SEQ ID NO: 24.

In another embodiment, the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising residues 20-140 of the heavy chain variable region SEQ ID NO: 19 and residues 21-127 of the light chain variable region comprising SEQ ID NO: 20; (2) a monoclonal antibody comprising residues 20-138 of the heavy chain variable region comprising SEQ ID NO: 21 and residues 21-133 of the light chain variable region comprising SEQ ID NO: 22; and (3) a monoclonal antibody comprising residues 20-142 of the heavy chain variable region comprising SEQ ID NO: 23 and residues 21-128 of the light chain variable region comprising SEQ ID NO: 24.

In another embodiment, the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a heavy chain comprising SEQ ID NO: 35 and a light chain comprising SEQ ID NO: 36; (2) a monoclonal antibody comprising a heavy chain comprising SEQ ID NO: 37 and a light chain comprising SEQ ID NO: 38; and (3) a monoclonal antibody comprising a heavy chain comprising SEQ ID NO: 39 and a light chain comprising SEQ ID NO: 40.

IV. Compositions The agents (e.g., anti-EGFR antibodies and bispecific antibodies) described herein can be formulated as pharmaceutical solutions, e.g., for administration to a subject for the treatment of cancer. The pharmaceutical compositions will generally include a

pharmaceutically acceptable carrier. As used herein, a "pharmaceutically acceptable carrier" refers to, and includes, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are

physiologically compatible. The compositions can include a pharmaceutically acceptable salt, e.g., an acid addition salt or a base addition salt, sugars, carbohydrates, polyols and/or tonicity modifiers.

The compositions can be formulated according to standard methods. Pharmaceutical formulation is a well-established art, and is further described in, e.g., Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20^th Edition, Lippincott, Williams & Wilkins (ISBN: 0683306472); Ansel et al. (1999) "Pharmaceutical Dosage Forms and Drug Delivery Systems," 7^th Edition, Lippincott Williams & Wilkins Publishers (ISBN:

0683305727); and Kibbe (2000) "Handbook of Pharmaceutical Excipients American Pharmaceutical Association," 3^rd Edition (ISBN: 091733096X).

The pharmaceutical compositions can be in a variety of forms. These forms include, e.g., liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form depends, in part, on the intended mode of administration and therapeutic application. For example, compositions containing a composition intended for systemic or local delivery can be in the form of injectable or infusible solutions.

Accordingly, the compositions can be formulated for administration by a parenteral mode (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection). "Parenteral administration," "administered parenterally," and other grammatically equivalent phrases, as used herein, refer to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intranasal, intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid and intrasternal injection and infusion.

In one embodiment, the bispecific antibody (e.g., istiratumab) is formulated for intravenous administration. In another embodiment, the composition of anti-EGFR antibodies (e.g., MM- 151) is formulated for intravenous administration. V. Outcomes

Provided herein are methods for treating a cancer (e.g., an IGF-1 positive cancer) in a human patient comprising administering to the patient a bispecific antibody antagonist of IGF-IR and ErbB3 (e.g., istiratumab) and a composition of anti-EGFR antibodies (e.g., MM- 151) .

Treatment outcomes can be evaluated using standard measures for tumor response. Target lesion (tumor) responses to therapy are classified as:

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); and

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.

Non-target lesion responses to therapy are classified as:

Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker levels. 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; and

Progressive Disease (PD): Either or both of appearance of one or more new lesions and unequivocal progression of existing non-target lesions. In this context, unequivocal progression must be representative of overall disease status change, not a single lesion increase.

Patients treated according to the methods disclosed herein preferably experience improvement in at least one sign of cancer. For example, the treatment may produce at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in metastasis, complete remission, partial remission, stable disease, increase in overall response rate, or a pathologic complete response. Response may also be measured by a reduction in the quantity and/or size of measurable tumor lesions. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter is to be recorded) as >10 mm by CT scan (CT scan slice thickness no greater than 5 mm), 10 mm caliper measurement by clinical exam or >20 mm by chest X-ray. The size of non-target lesions, e.g., pathological lymph nodes can also be measured for improvement. Lesions can be measured using, e.g., x-ray, CT, or MRI images. Microscopy, cytology or histology can be also used to evaluate responsiveness to a therapy. An effusion that appears or worsens during treatment when a measurable tumor has otherwise met criteria for response or stable disease can be considered to indicate tumor progression, but only if there is cytological confirmation of the neoplastic origin of the effusion.

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, tumor cell proliferation is reduced or inhibited. Alternately, one or more of the following can indicate a beneficial response to treatment: the number of cancer cells can be reduced; tumor size can be reduced; cancer cell infiltration into peripheral organs can be inhibited, retarded, slowed, or stopped; tumor metastasis can be slowed or inhibited; tumor growth can be inhibited;

recurrence of tumor can be prevented or delayed; one or more of the symptoms associated with cancer can be relieved to some extent. Other indications of a favorable response include reduction in the quantity and/or size of measurable tumor lesions or of non-target lesions.

As described herein, co-administration of a bispecific antibody antagonist of IGF-IR and ErbB3 (e.g., istiratumab) and a composition of anti-EGFR antibodies (e.g., MM- 151), provides improved efficacy compared to treatment with istiratumab alone or with a composition of anti-EGFR antibodies (such as MM- 151) alone. Preferably, the combination exhibits therapeutic synergy.

"Therapeutic synergy" refers to a phenomenon where treatment of patients with a combination of therapeutic agents manifests a therapeutically superior outcome to the outcome achieved by each individual constituent of the combination used at its optimum dose (T. H. Corbett et ah, 1982, Cancer Treatment Reports, 66, 1187). In this context a therapeutically superior outcome is one in which the patients either a) exhibit fewer

incidences of adverse events while receiving a therapeutic benefit that is equal to or greater than that where individual constituents of the combination are each administered as

monotherapy at the same dose as in the combination, or b) do not exhibit dose-limiting toxicities while receiving a therapeutic benefit that is greater than that of treatment with each individual constituent of the combination when each constituent is administered in at the same doses in the combination(s) as is administered as individual components. In xenograft models, a combination, used at its maximum tolerated dose, in which each of the constituents will be present at a dose generally not exceeding its individual maximum tolerated dose, manifests therapeutic synergy when decrease in tumor growth achieved by administration of the combination is greater than the value of the decrease in tumor growth of the best constituent when the constituent is administered alone.

Thus, in combination, the components of such combinations have an additive or superadditive effect on suppressing tumor growth, as compared to monotherapy with a bispecific antibody antagonist of IGF-IR and ErbB3 (such as istiratumab) or a composition of anti-EGFR antibodies (such as MM- 151). By "additive" is meant a result that is greater in extent {e.g., in the degree of reduction of tumor mitotic index or of tumor growth or in the degree of tumor shrinkage or the frequency and/or duration of symptom-free or symptom- reduced periods) than the best separate result achieved by monotherapy with each individual component, while "superadditive" is used to indicate a result that exceeds in extent the sum of such separate results. In one embodiment, the additive effect is measured as slowing or stopping of tumor growth. The additive effect can also be measured as, e.g., reduction in size of a pancreatic tumor, reduction of tumor mitotic index, reduction in number of metastatic lesions over time, increase in overall response rate, or increase in median or overall survival.

VI. Kits and Unit Dosage Forms

Also provided herein are kits which include a dose of a bispecific antibody antagonist of IGF-IR and ErbB3 (such as istiratumab) and a dose of a composition of anti-EGFR antibodies (such as MM- 151), in a therapeutically effective amount adapted for use in the preceding methods. The kits optionally also can include instructions, e.g., comprising administration schedules, to allow a practitioner {e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient having cancer. The kit also can include a syringe. Instruments or devices necessary for administering the pharmaceutical composition(s) also may be included in the kits.

In one embodiment, the present invention provides a kit comprising:

A. a dose of a polyvalent bispecific antibody having two pairs of polypeptide chains, each pair of said two pairs comprising a heavy chain joined to a light chain by at least one heavy-light chain bond, wherein each light chain comprises the amino acid sequence set forth in SEQ ID NO:26 and each heavy chain comprises the amino acid sequence set forth in SEQ ID NO:27;

B. a dose of a composition of anti-EGFR antibodies comprising: (1) a monoclonal antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 1, 2, and 3, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 4, 5, and 6, respectively; (2) a monoclonal antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 7, 8, and 9, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 10, 11 and 12, respectively; and (3) a monoclonal antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 13, 14, and 15, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 16, 17, and 18, respectively; and

In another embodiment, the present invention provides a kit comprising:

A. a dose of istiratumab;

C. instructions for using istiratumab and the composition of anti-EGFR antibodies , in the method of any one of the preceding claims. In one embodiment, the cancer is an Insulin Growth Factor 1 (IGF-1) positive cancer. In another embodiment, the cancer is selected from the group consisting of NSCLC, SCCHN, and CRC.

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.

The contents of all references, Genbank entries, patents and published patent

applications cited throughout this application are expressly incorporated herein by reference.

EXAMPLES EXAMPLE 1: In Vitro Data

29 colorectal cell lines were seeded at 5,000 cells per well in low-binding Nanoculture 96-well plates (Scivax Corporation) and grown in the appropriated medium supplemented with 4% fetal bovine serum and Pen-Strep at 37 °C. Forty eight (48) hours later, after which time spheroids had formed, cells were incubated with ligands: EGF 5nM, HRG 5nM, IGF-1 50 nM or HGF InM for 96 h at 37 °C. Relative live cell densities were then determined by luminescence using the CellTiter Glo reagent (Promega).

Figure 1A shows the conditional probability of 29 colorectal cancer cells to respond (increase in viability) to one ligand and also respond to a second one. Entry (row i, column j) corresponds to the probability that cells that respond to ligand i also respond to ligand j. For example, the black square in the second row (row 2) and first column (column 1) represents the probability that cells that respond to IGF-1 also respond to EGF. Response is defined as >=15% stimulation by the ligand compared to controls. Euclidean distance is used as the distance metric for clustering. As shown in Figure 1A, there is 50% chance that a cell that responds to EGF also responds to IGF- 1.

29 colorectal cell lines were seeded at 5,000 cells per well in low-binding Nanoculture

96-well plates (Scivax Corporation) and grown in the appropriated medium supplemented with 4% fetal bovine serum and Pen-Strep at 37 °C. 48 h later, after which time spheroids had formed, cells were incubated with ligands and/or drugs for 96 h at 37 °C. Relative live cell densities were then determined by luminescence using the CellTiter Glo reagent (Promega). Cells were treated with ligands (EGF and IGF-1, 5 nM each), with ligands plus MM-151 or MM-141 (1 μΜ each) or with ligands plus both MM-151 and MM-141.

Figure IB shows the effect of treatment with MM-151, MM-141 or the combination of both in 29 colorectal cancer cells in the presence of EGF and IGF- 1. Colors correspond to the CTG response of each cell line to combination therapy (top row) or monotherapies

(second and third rows) in the presence of both ligands. CTG response in the presence of inhibitor(s) + ligands is normalized to CTG response in the presence of ligands alone. The cell lines with asterisks below them correspond to cell lines that respond at least 15% better to the combination therapies compared to the best monotherapy. As shown in Figure IB, approximately 50% of the colorectal cancer cells benefit (measured as a decrease in cell viability) from the combination of MM-151+MM-141 when both ligands (EGF and IGF-1) are present.

In sum, the results indicate that the combination of MM-151 and MM-141 is better than either agent alone in approximately 50% of responsive cell lines.

EXAMPLE 2: In Vivo Data

Tumor xenografts were established by subcutaneous injection of 200μί of a cell suspension consisting of 2.5-5 x 10⁶ of DLD-1 (ATCC® CCL-221™), LoVo (ATCC® CCL- 229™), Liml215 (cat # 10092301-1VL, Sigma), LS411N (ATCC® CRL-2159™), or LS 174T (ATCC® CL-188™) colon cancer-derived cells, diluted 1: 1 in Matrigel® (BD Biosciences), into single sites on flank of recipient 4-5 week old female nu/nu mice. Tumor formation was monitored twice weekly and tumor volumes were calculated following caliper measurement according to the formula (7T/6*(length x width x width). Once the average measured tumor volume had reached 210 - 310mm , mice were randomized into groups of 10 and treatment was initiated. Overall, the average tumor volume per group was equivalent across all groups at the beginning of the treatments. Treatment of DLD-lwas initiated on day 9 after tumor implantation, treatment of LoVo was initiated on day 12 after tumor implantation, treatment of Liml215 was initiated on day 14 after tumor implantation, treatment of LS41 IN was initiated on day 7 after tumor implantation, and treatment of LS 174T was initiated on day 8 after tumor implantation. Seribantumab ("MM-121 ") was administered intraperitoneally twice a week (q3/d or q4d;

600μg/mouse), istiratumab ("MM-141 ") was administered intraperitoneally twice a week (q3/d or q4d; 30 mg/kg) and MM-151 tool compound (labeled "MM-151 " in graphs; consisting of 25E+P2X+P3X) was administered as follows in DLD-1, LoVo, LS411N and LS 174T xenograft bearing mice: 25E (12.5 mg/kg) and P3X (6.25 mg/kg) were administered intraperitoneally q7d. In addition to P2X (17.5 mg/kg) being co-administered intraperitoneally with the q7d dosing of 25E and P3X, mice in the study received two additional weekly doses of P2X. The MM-151 tool compound was administered as follows in Liml215 xenograft bearing mice: 25E (1.125 mg/kg) and P3X (0.625 mg/kg) were administered intraperitoneally q7d. In addition to P2X (1.875 mg/kg) being co-administered intraperitoneally with the q7d dosing of 25E and P3X, mice in the study received two additional weekly doses of P2X. (25E is a surrogate for PIX that engages the same epitope as PIX but does not cross-react with murine EGFR.)

Table 2: Ligand Expression Profile from the Xenograft Tumors

n/d: no transcript amplification was detected

+: transcript is present in the sample.

Hs: assay detects only human transcripts

Mm: assay detects only murine transcripts

Hs & Mm: assay detects both human and murine transcripts.

Description of the profiling: Untreated tumors were excised from mice (n=3/model) and total RNA was isolated using RNeasy® Plus mini -kit (Qiagen). 2μg of total RNA was used for reverse transcription using Superscript® VILO™ cDNA Synthesis Kit (Invitrogen) and qPCR of the samples was performed using an NT cycler and TaqMan® Assays in

OpenArray® format (ThermoFisher Scientific). Assay IDs are listed in Table 2, above.

ACTB (Hs03023943_gl, Hs01060665_gl), B2M (Hs00984230_ml), GAPDH

(Hs03929097_gl), GUSB (Hs03929099_ml), TBP (Mm00446973_ml) and HMBS

(Mm00660260_ml) were used as endogenous controls. Based on the analysis, human tumor cells provide mainly EGFR ligands (EGF, HBEGF, AREG, EREG) for autocrine signaling, whereas murine stromal cells provide resistance ligands NRG1, IGF1, IGF2 and INS 1. As shown in Figures 2A-C, combination treatments in mice bearing DLD-1, LoVo, and Liml215 xenografts resulted in significantly more growth inhibition than any of the single agents alone. Additionally, in the Liml215 xenograft model the addition of istiratumab/MM-151 combination treatment to either control group (on Day 37) or istiratumab monotherapy group (on Day 28) and the addition of seribantumab/MM-151 combination treatment to seribantumab monotherapy group (on Day 28) led to rapid decrease in tumor volumes. Accordingly, combination treatments were required for maximum treatment efficacy in Liml215, DLD-1 and LoVo xenografts in vivo. As shown in Figures 2D-E, MM-151 monotherapy is the driver of the anti-tumor response in the LS41 IN and LS 174t models, since combinations of MM- 151 with seribantumab or istiratumab do not yield any additional anti-tumor activity. Specifically, MM-151 dominated the LS411N and LS 174t and Liml215 response to combination treatments.

EXAMPLE 3: Phase I Trial in Patients

A two-part Phase 1, non-randomized, open-label study is conducted in patients having

NSCSL, SCCHN or CRC cancer.

A. Objectives

The primary objective is to determine the Maximum Tolerated Dose (MTD) or recommended Phase 2 dose (R2PD) as determined by the observed safety and tolerability of:

· MM-151 plus MM-121 in patients with advanced, HRG-positive NSCSL, SCCHN and CRC cancers;

• MM-151 plus MM-141 in patients with advanced IGF- 1 -positive NSCSL, SCCHN, and CRC cancers;

• MM-151 plus trametinib in patients with either advanced KRAS mutant or N-RAS- mutant NSCSL, SCCHN, and CRC cancers; and

• MM-151 plus trametinib in double wild type (KRAS, N-RAS) and IGF-1 negative and HRG negative SCCHN, NSCLC or CRC cancers.

Secondary objectives in SCCHN, NSCLC or CRC patients with advanced HRG- positive treated with MM-151 plus MM-121, or IGF-1 positive treated with MM-151 plus MM-141, or KRAS/N-RAs-mutant treated with MM-151 plus trametinib, or double wild type (KRAS, NRAS,) and IGF-1 negative and HRG negative treated with MM-151 plus trametinib, are: • To describe the dose limiting toxicities (DLTs);

• To characterize the adverse event profile of MM- 121 and MM- 151 when

administered in combination;

• To characterize the adverse event profile of MM-151 and MM- 141 when

administered in combination;

• To characterize the adverse event profile of MM-151 and trametinib when

administered in combination;

• To determine the pharmacokinetic parameters;

• To determine the immunogenicity parameters;

• To assess the 8, 16 and 24 week disease control rates (SD, PR, or CR);

• To assess Progression Free Survival (PFS) based on RECIST 1.1;

• To describe any objective response based on RECIST v 1.1 ;

• To assess ErbB, IGF-1R and Insulin receptor pathway biomarkers in pre-treatment tumor biopsies and archived tissue samples;

• To assess the pharmacodynamic effects of treatment on heregulin and IGF- 1/2 mRNA and on ErbB and IGF-1R pathway activation via pre- and on-treatment tumor biopsies; and

• To explore the relationship between clinical activity (and/or toxicity) and changes in blood and additional tissue biomarkers.

B. Trial Design

This is a two-part Phase 1, non-randomized, open-label study of:

• MM-151 plus MM-121 in patients with advanced, HRG-positive NSCSL, SCCHN and CRC cancers;

• MM-151 plus MM-141 in patients with advanced IGF-1 -positive NSCSL, SCCHN, and CRC cancers;

Following signing informed consent and evaluation of initial eligibility criteria, all patients provide a tumor sample to a central lab facility for HRG and IGF-1 testing. Recent tumor tissue is used for the HRG and IGF-1 assessment if it was collected in the last 6 months. Otherwise, a fresh biopsy (2 adequate passes) is collected. If a fresh biopsy is collected, investigators are asked to choose an easily accessible tumor lesion to minimize any possible risk associated with the collection of the tissue. As a general guideline, if the selected procedural location has an established serious complication rate of >2% at the institution completing the procedure, this is considered a high-risk procedure and should be avoided.

The central lab analyzes the tumor sample for HRG and IGF-1 mRNA levels utilizing RNA in-situ hybridization (RNA-ISH). For patients that rely on recent tumor tissue to assess HRG and IGF-1 status, a fresh pre-treatment core biopsy (2 adequate passes) is required for additional exploratory analyses. For patients that use a fresh biopsy to assess HRG and IGF- 1, no additional pre-treatment biopsy is required.

Part 1 is a dose escalation to determine the safety, tolerability and MTD/RP2D of:

· MM-151 plus MM-141 in patients with advanced IGF-1 -positive NSCSL, SCCHN, and CRC cancers;

In this part of the study, cohorts of 3 or 4 patients are enrolled in a 3 + 3 design to assess the safety and pharmacokinetic properties and to establish the MTD or RP2D of the MM-121 plus MM-151 combination, MM-151 plus MM-141 combination, and MM-151 plus trametinib combination.

Once the MTD is defined in Part 1, enrollment into the Part 2 Expansion Cohort proceeds. In this phase of the study, only Cetuximab-resistant CRC patients that are:

• KRAS or NRAS wild-type and HRG-positive are enrolled in the MM-151 plus MM- 121 group;

• KRAS or NRAS wild-type and IGF-1 -positive are enrolled in the MM- 151 plus MM-141 group;

• KRAS or N-RAS -mutant are enrolled in the MM-151 plus trametinib group; and

• Double wild type (KRAS, N-RAS) and IGF-1 -negative and HRG-negative are

enrolled in the MM-151 plus trametinib group. C. General Study Scheme

This is a two-part Phase 1, non-randomized, open-label study of MM-151 plus trametinib, MM- 151 plus MM- 141, and MM- 151 plus MM-121 in patients with advanced NSCSL, SCCHN and CRC cancers. First, patients are evaluated for KRAS and NRAS status. Patients who are either KRAS mutant or NRAS mutant are assigned to MM- 151 plus trametinib study arm. Patients who are KRAS wild type and NRAS wild type are evaluated for IGF-1 and Heregulin (HRG) status next. Patients who are IGF-1 positive are assigned to MM-151 plus MM-141 study arm and patients who are IGF- 1 negative, but HRG positive, are assigned to MM-151 plus MM- 121 study arm. Patients who are KRAS wild type, NRAS wild type, IGF- 1 negative, and HRG negative are assigned to MM- 151 plus trametinib study arm. The general study scheme is depicted in Figure 3. Each arm has its own study schema as described in further detail below.

The number of patients enrolled in Part 1 of the study depends is between 6 and 20 per study arm. In part 2 of the study, 14 patients per study arm are enrolled.

1. MM-151 and MM-121

The dose levels for MM- 151 and MM-121 during Part 1 of the study are summarized the table below:

Table 3: MM-151 and MM-121 Dose Escalation Schedule

Dose levels -1A or -IB are only enrolled in the event that dose levels 1A and IB result in observed toxicity which limits further dosing. Dose levels 1B-3B are only enrolled if observed toxicity limits further dosing in dose levels 1A-3A (e.g., if a DLT is observed in dose level 2A the next cohort enrolled is dose level 2B) Intermediate MM-151 and MM-121 doses or alternate dosing schedules are explored. 2

MM- 121 is administered prior to MM- 151 administration on weeks when they are administered together.

The first two doses of MM- 151 are priming doses of 225 mg and 450 mg. The third dose starts Cycle 1 Week 1 at the dose levels listed.

Dosing begins at Dose Level 1A. A 6-week DLT evaluation window is comprised of a 2 week priming phase for MM-151 and a full Cycle 1 (4 weeks). If no DLT is observed in a cohort of 3 patients, escalation proceeds to Level 2A and then Level 3A. If a DLT is observed in the first 3 patients enrolled into an "A" cohort, a total of 6 patients are enrolled in the current cohort and assessed for safety and tolerability. If there is no more than 1 DLT in a cohort of 6 patients in a given dose level, enrollment commences to the next "A" dose level. If there is more than 1 DLT observed in a cohort of 3-6 patients, no further patients are enrolled into the "A" cohorts, but instead the dose of MM-151 is de-escalated and enrollment resumes in the same numerical dose level "B" (e.g., if there are more than 2 DLTs observed in dose level 2A, the next cohort to enroll is dose level 2B).

2. MM-151 and MM-141

The dose levels for MM- 151 and MM-141 during Part 1 of the study are summarized in the table below:

Table 4: MM-151 and MM-141 Dose Escalation Schedule

Dose levels -1A or -IB are only enrolled in the event that dose levels 1A and IB result in observed toxicity which limits further dosing. Dose levels 1B-2B are only enrolled if observed toxicity limits further dosing in dose levels 1A-2A. (e.g., if a DLT is observed in dose level 2A the next cohort to be enrolled is dose level 2B). Intermediate MM-151 and

MM-141 doses or alternate dosing schedules are explored upon agreement.

MM-141 is administered prior to MM- 151 administration on weeks when they

administered together. The first two doses of MM- 151 are priming doses of 225 mg and 450 mg. The third dose starts Cycle 1 Week 1 at the dose levels listed.

Dosing begins at Dose Level 1A. A 6-week DLT evaluation window is comprised of a 2 week priming phase for MM-151 and a full Cycle 1 (4 weeks). If no DLT is observed in a cohort of 3 patients, escalation proceeds to Level 2A. If a DLT is observed in the first 3 patients enrolled into an "A" cohort, a total of 6 patients are enrolled in the current cohort and assessed for safety and tolerability. If there is no more than 1 DLT in a cohort of 6 patients in a given dose level, enrollment commences to the next "A" dose level. If there is more than 1 DLT observed in a cohort of 3-6 patients, no further patients are enrolled into the "A" cohorts, but instead the dose of MM- 151 is de-escalated and enrollment resumes in the same numerical dose level "B" (e.g., if there are more than 2 DLTs observed in dose level 2A, the next cohort to enroll is dose level 2B).

3. MM-151 and Trametinib

The dose levels for MM- 151 and trametinib during Part 1 of the study are summarized in the table below:

Table 5: MM-151 and Trametinib Dose Escalation Schedule

Dose combinations which are empty are not enrolled

2

Single letters preceded by a "-" are dose de-escalation cohorts

The first two doses of MM-151 are priming doses of 225 mg and 450 mg. The third dose starts Cycle 1 Week 1 at the dose levels listed. Dosing begins with Cohort LL. Upon successful completion of Cohort LL, enrollment into Cohort LM proceeds next. Upon successful completion of Cohort LM, sponsor evaluates data and determines which cohort opens next. Based on the safety data, sponsor may choose to open Cohort MM and Cohort MH simultaneously or one cohort at a time. At the completion of each cohort, the sponsor evaluates data collected thus far and makes a determination as to which cohort opens next. The suggested path is to start enrollment with Cohort LL, upon completion open Cohort LM. Upon successful completion of Cohort LM, the plan is to open Cohort MM and Cohort MH in parallel. Upon successful completion of these cohorts, the next cohorts to open are Cohort HM and Cohort HH.

Patients are re-assessed for evidence of disease progression in accordance with current RECIST vl. l criteria 6 weeks from the date of first dose and then every 8 weeks thereafter or sooner if the Investigator suspects progression has occurred based on clinical signs and symptoms. To support the secondary endpoints, all patients submit samples from archived tissues (if available) and a pre-treatment core tumor biopsy for biomarker studies. Pretreatment biopsies, recent tumor tissue, and archived samples are evaluated for heregulin mPvNA levels and other pathway biomarkers. An on-treatment biopsy is also requested to assess changes in heregulin mRNA and in markers of pathway activation over the course of treatment. Blood samples are taken at various time points during the study to determine the PK of MM- 151 and MM- 121 when administered in combination as well as related pathway biomarkers.

Cycles are repeated every 4 weeks until disease progression, intolerable toxicity or other reason for study termination. Local radiologist and/or PI assessment is accepted for efficacy evaluation.

D. Inclusion Criteria

The general inclusion criteria for all arms are as follows. To be eligible for inclusion into the study patients must have/be:

Measureable disease in accordance with RECIST vl.l;

Availability of a cancerous lesion amenable to biopsy and willing to undergo a pre- treatment and on-treatment biopsy;

Willing to provide archived FFPE tumor block (or slides) if available, and recent tumor tissue, if available to assess heregulin and IGF-1 mRNA, levels and other pathway biomarkers. Fresh tumor biopsy is used to assess heregulin and IGF-1 if recent tissue is not available;

• Adequate bone marrow reserves as evidenced by:

o ANC > 1,500/μ1 (unsupported by growth factors)

o Platelet count > 100,000/μ1

o Hemoglobin > 9 g/dL;

• Adequate hepatic function as evidenced by:

o Serum total bilirubin < 1.5 x ULN

o Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and

Alkaline Phosphatase < 2.5 x ULN (< 5 x ULN is acceptable if bone or liver metastases are present);

• Serum electrolytes (potassium, magnesium, calcium and phosphate) within

institutional limits of normal;

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

• Adequate cardiac function as determined by:

o An LVEF within institutional limits of normal or > 50%

o ECG without clinically significant abnormalities including prolonged QTc interval < 450 msecs; Abnormal ECG is acceptable if investigator confirms it is not clinically significant;

• ECOG Performance Score (PS) of 0 or 1;

• Recovered from the effects of any prior surgery, radiotherapy or other antineoplastic therapy to CTCAE v4.0 grade 1, baseline or less.;

• 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 any study therapy). This applies to women of childbearing potential as well as fertile men and their partners;

• At least 18 years of age; and

• Provide informed consent.

1. Specific Inclusion Criteria for Part 1 of the Study Only for MM- 151 plus MM-121 Combination:

In addition to meeting the general inclusion criteria above, patients in Part 1 of the study must also have/be: Pathologically documented, definitively diagnosed, locally advanced (not amenable to curative treatment) solid cancer that is refractory to standard treatment, or for which no standard treatment is available, or the patient refuses or is intolerant to standard therapy.

A positive ISH test for heregulin with a score of >1+ .

One of the following tumor types in which EGFR and/or ErbB3 is thought to promote tumorigenesis:

o Colorectal Cancer (CRC)

o Squamous Cell Carcinoma of the Head and Neck (SCCHN)

o Non-Small Cell Lung Cancer (NSCLC).

2. Specific Inclusion Criteria for Part 1 of the Study Only for MM- 151 plus MM- 141 Combination:

In addition to meeting the general inclusion criteria above, patients in Part 1 of the study must also have/be:

• Pathologically documented, definitively diagnosed, locally advanced (not amenable to curative treatment) solid cancer that is refractory to standard treatment, or for which no standard treatment is available, or the patient refuses or is intolerant to standard therapy.

· A positive ISH test for IGF-1 with a score of >1+.

• One of the following tumor types in which EGFR and/or IGF-1R is thought to

promote tumorigenesis:

o Colorectal Cancer (CRC)

o Squamous Cell Carcinoma of the Head and Neck (SCCHN)

o Non-Small Cell Lung Cancer (NSCLC).

3. Specific Inclusion Criteria for Part 1 of the Study Only for MM- 151 plus Trametinib Combination:

KRAS mutant OR double wild-type (KRAS, N-RAS) plus IGF- 1 -negative plus HRG- negative.

One of the following tumor types in which EGFR and/or other downstream pathway intermediates s thought to promote tumorigenesis:

o Colorectal Cancer (CRC)

o Squamous Cell Carcinoma of the Head and Neck (SCCHN)

o Non-Small Cell Lung Cancer (NSCLC).

4. Specific Inclusion Criteria for Part 2 of the Study Only for MM- 151 plus MM-121 combination and for MM-151 plus MM- 141 combination:

In addition to meeting the general inclusion criteria above, patients in Part 2 of the must also have/be:

Pathologically documented, definitively diagnosed, colorectal adenocarcinoma that is locally advanced or metastatic and surgically unresectable.

Evidence for recurrent or persistent disease following treatment for locally advanced or metastatic disease.

KRAS and N-RAS wild type, in tumor tissue. Documentation of previously existing mutational status from an accredited laboratory is accepted.

Prior treatment with cetuximab or panitumumab and documentation of progression or intolerance to these therapies.

5. Specific Inclusion Criteria for Part 2 of the Study Only for MM-151 plus Trametinib combination:

Evidence for recurrent or persistent disease following treatment for locally advanced or metastatic disease. Mutant KRAS or NRAS gene in tumor tissue. Documentation of previously existing mutational status from an accredited laboratory is accepted, plus IGF- 1 -negative plus HRG-negative.

Exclusion Criteria

The general exclusion criteria for all study arms are as follows. Patients must meet all usion criteria listed above and none of the following exclusion criteria:

Pregnant or lactating.

Presentation of an active infection or with an unexplained fever > 38.5°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 study outcome. If the fever and active infection have resolved prior to enrollment, the patient is eligible. At the discretion of the investigator, patients with tumor fever are enrolled.

Untreated (primary) or symptomatic CNS (primary or metastatic) malignancies;

patients with CNS metastases who have undergone surgery or radiotherapy or who have been on a stable dose of corticosteroids (e.g. 8 mg dexamethasone) for at least 2 weeks and whose disease is stable prior to the first scheduled day of dosing are eligible for the trial.

History of severe allergic reactions to cetuximab, panitumumab or other monoclonal antibodies or any of their excipients.

Known hypersensitivity to any of the components of MM- 151.

Presence of any other contraindications for cetuximab or panitumumab.

Any prior exposure to MM- 151.

Received other recent antitumor therapy including any standard chemotherapy or radiation within 14 days (and having passed the time of any actual or anticipated toxicities) prior to the first scheduled dose of the study treatment.

Clinically significant cardiac disease, including: NYHA Class III or IV congestive heart failure, unstable angina, acute myocardial infarction within six months of planned first dose, arrhythmia requiring therapy (including torsades de pointes, with the exception of extra systoles, minor conduction abnormalities, or controlled and well treated chronic atrial fibrillation).

• Subjects with a recent (within 1 year) cerebral vascular accident (CVA).

• Ongoing skin rash CTC AE grade > 1.

· Ongoing diarrhea CTCAE grade > 2.

• Subjects with clinically significant gastrointestinal abnormalities.

• Known HIV, active or chronic hepatitis B or C infection.

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

1. Specific Exclusion Criteria for MM-151 plus MM-121 combination:

• Known hypersensitivity to any of the components of MM-121

• Any prior exposure to MM-121 or other ErbB3 antibody.

2. Specific Exclusion Criteria for MM-151 plus MM-141 combination:

• Known hypersensitivity to any of the components of MM-141

• Any prior exposure to MM-141 or other IGF-1R antibody 3. Specific Exclusion Criteria for MM-151 plus Trametinib combination:

• Known hypersensitivity to any of the components of trametinib

• Any prior exposure to trametinib

• History of serous retinopathy, retinal vein occlusion, and serious cardiac

comorbidities

F. Investigational Product: MM-121

MM-121 is a clear liquid, supplied in sterile, single-use vials containing 10.1 ml of MM-121 at a concentration of 25 mg/mL in 20 mM histidine, 150 mM sodium chloride, pH 6.5. MM-121 is stored at 2-8°C. MM-121 is administered Q2W as an IV infusion according to the dose levels outlined above. On weeks when MM-121 and MM-151 are given together, MM-121 is administered prior to MM-151.

G. Investigational Product: MM-151 MM-151 is a clear liquid that is supplied in sterile, single-use vials containing 10 niL of MM-151 (with an extractable volume of 9.5 mL) at a total protein concentration of 25 mg/mL in 20 mM histidine, 10% sucrose, 0.02% polysorbate 80, pH 6.0. MM-151 is stored at 2-8°C. MM-151 is administered QW as an IV infusion. The first two doses of Cycle 1 are priming doses and the dose levels are 225 mg for priming dose 1 and 450 mg for priming dose 2. Subsequent doses of MM-151 are administered according to the dose levels outlined above. MM-151 is not administered as a bolus or a push. On weeks when MM- 121 or MM- 141 and MM-151 are given together, MM- 121 or MM-141 is administered prior to MM-151.

H. Investigational Product: MM-141

MM-141 is a colorless liquid that is supplied in sterile, single-use vials containing 47.6mL of MM-141 (with extractable volume of 46.7mL containing 280mg of MM-141) at a total protein concentration of 6.0 mg/mL in 20mM histidine, 3% sucrose, lOOmM arginine- HC1, 0.005% Tween 80, pH 5.5. MM-141 Drug Product is stored at 2-8°C. MM-141 is administered Q2W as an IV infusion at the dose level outlined above. On weeks when MM- 141 and MM-151 are given together, MM-141 is administered prior to MM-151.

I. MEK Inhibitor: Trametinib

Trametinib is supplied as 0.5 mg, 1 mg, and 2 mg tablets for oral administration. Trametinib is protected from light and moisture and stored at 2-8°C. Trametinib tablets are dispensed in the original bottle. Trametinib is taken once a day, at least 1 hour before or 2 hours after a meal.

J. Statistics

Categorical variables are summarized by frequency distributions (number and percentages of patients) and continuous variables will be summarized by descriptive statistics (mean, standard deviation, median, minimum, maximum). Safety and preliminary efficacy analyses are performed using all patients who received at least one infusion of study drug.

1. Demographics and Baseline Characteristics:

The demographic and baseline data are summarized by dose levels. No formal statistical analysis is performed on these data.

2. Preliminary Efficacy Analyses: 8, 16 and 24 week disease control rate, progression free survival (PFS) and tumor response based on RECIST vl.l are descriptively summarized.

3. Safety Analyses:

Treatment emergent adverse events are presented by treatment cohort, by patient, by

NCI CTCAE v4.0 Grade and by MedDRA system organ class. Separate listings are presented for total adverse events, serious adverse events, and adverse events related to therapy. Grade 3-4 adverse events are also summarized. Listings of clinically significant safety data are reviewed.

Laboratory data is presented by dose cohort and by visit. Abnormal laboratory values are assessed according to NCI CTCAE v4.0 Grade, where possible. Evaluation of QTc is based upon Fridericia's correction method. CTCAE criteria is applied to the QTcF.

All the safety analyses are performed by treatment cycle and week, where appropriate. 4. Pharmacokinetic Analyses:

Serum concentrations are used to determine the PK parameters using standard non- compartmental techniques. PK parameters (C_max, T_max, AUQ, AUC, clearance, volume of distribution at steady state (Vdss), and the terminal elimination half-life are summarized using descriptive statistics, including the median, mean and 95% confidence intervals around parameter estimates by dose level.

EXAMPLE 4: Leading-edge Biomarker-Selected, Multi-Arm Basket Trial that Matches Patients with Most Appropriate Combination Regimens; A Phase 1 Biomarker-directed Study Evaluating the Co-Administration of MM-151 with MM-121, MM-141, or Trametinib in EGFR-Driven Cancers

Brief Title: Phase 1 Combination Study of MM-151 With MM-121, MM-141, and Trametinib.

Official Title: A Phase 1 Multi Arm Study Evaluating the Safety, Pharmacology and Preliminary Activity of the Co-Administration of MM-151 With Seribantumab (MM-121), Istiratumab (MM-141), or Trametinib in Biomarker- selected Cancer Patients.

The Epidermal Growth Factor Receptor (EGFR) is a key driver of tumor growth in colorectal cancer (CRC), squamous cell carcinoma of the head and neck (SCCHN), and non- small cell lung cancer (NSCLC). Although EGFR inhibitors prolong overall survival in many patients, resistance inevitably develops. Resistance usually arises through alterations in the EGFR pathway itself or through upregulation of alternative signaling pathways. In CRC in particular, mutations in KRAS and NRAS are strong predictors of resistance to EGFR inhibitors. Such resistance may potentially be overcome by combining MM- 151, a potent EGFR inhibitor, with trametinib, a MEK inhibitor. In KRAS/NRAS wild-type tumors, resistance may arise through activation of parallel signaling pathways. Emerging data suggest that heregulin (HRG)-driven signaling through ErbB3 and insulin-like growth factor- 1 (IGF-l)-driven signaling through IGF-1R may confer resistance to EGFR inhibitors by activating pro-survival signaling through the PI3K/Akt pathway. If HRG-mediated signaling is active, resistance may potentially be overcome through the combined administration of MM-151 and the ErbB 3 -targeting antibody MM-121. Similarly, if IGF- 1 -mediated signaling is active, resistance may be overcome by combining MM-151 with the IGF-lR-targeting antibody MM- 141. The rationale underlying this trial is that mechanisms of resistance may be identified through biomarker analyses, allowing patients to be prospectively assigned to an appropriate investigational regimen.

MM-151 is an oligoclonal therapeutic mixture consisting of three fully-human monoclonal antibodies designed to bind and inhibit signaling of the epidermal growth factor receptor (EGFR). EGFR-mediated signaling promotes the growth and survival of cancer cells and has long been recognized as an important drug target in several types of cancer, including colon, lung, breast, pancreatic, and head and neck cancers. MM-151 has previously been tested in a Phase 1 dose-escalation clinical trial in patients with advanced solid tumors.

Istiratumab is a tetravalent bispecific antibody designed to block tumor survival signals by inhibiting IGF-1R and ErbB3 (HER3) signaling. IGF-1R and ErbB3 complexes activate major signaling pathways that allow tumor cells to grow and develop resistance to chemotherapy. Currently, istiratumab is in Phase 2 testing in patients with metastatic pancreatic cancer that have a pre-defined IGF-1 biomarker profile.

Seribantumab is Merrimack's wholly owned, fully human monoclonal antibody that targets ErbB3, a cell surface receptor that is activated by the ligand heregulin. Heregulin- driven ErbB 3 signaling has been implicated as a mechanism of tumor growth and resistance to targeted, cytotoxic and anti-endocrine therapies. When used in the combination setting, seribantumab is designed to block ErbB3 signaling in order to enhance the anti-tumor effect of a combination therapy partner. Seribantumab has been investigated in multiple Phase 2 and Phase 1 clinical trials covering a broad spectrum of patient populations and drug

combinations. Primary Objectives: To determine the Maximum Tolerated Dose (MTD) or recommended Phase 2 dose (RP2D) in the respective study arms as determined by the observed safety and tolerability of:

• MM-151 plus seribantumab (MM-121) (Arm A)

• MM-151 plus trametinib (Arm B and Arm D)

• MM-151 plus istiratumab (MM-141) (Arm C)

Secondary Objectives: To describe the safety and tolerability of MM-151 when given in combination with seribantumab (Arm A), trametinib (Arms B and D) or istiratumab (Arm C).

Additionally:

• To determine pharmacokinetic parameters and assess drug-drug interactions

• To determine immunogenicity parameters

• To assess disease control rates (SD, PR, or CR)

• To assess Progression Free Survival (PFS) based on RECIST v 1.1

• To assess objective response rates (ORR) based on RECIST v 1.1

Exploratory Objectives:

• To assess ErbB receptors, IGF-1R, Insulin receptor, Met, and other bimarkers in pre- and on-treatment tumor biopsies, archived tissue samples, and blood

• To explore the relationship between clinical activity (and/or toxicity) and changes in biomarkers in blood and tissue.

METHODS: This is a Phase 1, biomarker-directed open-label study evaluating the safety, pharmacology and preliminary activity of MM-151 in combination with trametinib, MM-121, or MM-141. Patients are evaluated for KRAS/NRAS status and tumoral expression of HRG and IGF-1 and are then assigned to the study arm matching their biomarker profile. A modified "3 + 3" design is used to establish a recommended Phase 2 dose. Expansion cohorts in CRC and SCCHN will then be opened to further evaluate safety and obtain preliminary signs of efficacy. Key exploratory analyses include evaluations of PK, PD, and biomarkers of additional resistance pathways.

Brief Summary: This is a Phase 1 open-label, dose-escalation trial using "3+3" design, evaluating MM-151 co-administration with MM-121, MM-141, and trametinib at varying dose levels.

Detailed Description: This is a two-part Phase 1, non-randomized, open-label study of MM-151 plus MM-121, MM-141, or trametinib in patients with advanced, heregulin-positive lung, head and neck, and colorectal cancers. In part 1 of the study cohorts of 3 or more patients will be treated at escalating doses of MM-151 in combination with MM-121, MM- 141, and trametinib until a maximum tolerated combination dose for each combination is identified. In part 2 of the study, patients will be treated with combination dose identified in part 1 of the study. Conditions include: Colorectal Cancer, Non-small Cell Lung Cancer, and Squamous Cell Carcinoma of the Head and Neck.

Experimental Arms Include:

• Experimental: MM-151+MM-121 Dose Escalation: MM-151 and MM-121 dose escalation in lung, head and neck, and colorectal cancers.

• Experimental: MM-151+ trametinib Dose Escalation: MM-151 and trametinib dose escalation in lung, head and neck, and colorectal cancers. There are two MM-151 + trametinib arms.

• Experimental: MM-151+MM-141 Dose Escalation: MM-151 and MM-141 dose escalation in lung, head and neck, and colorectal cancers.

• Experimental: MM-151+trametinib Dose Escalation: MM-151 and trametinib dose escalation in lung, head and neck, and colorectal cancers. There are two MM-151 + trametinib arms.

All patients enrolling in the study will provide a core needle biopsy, which will be tested for KRAS and NRAS mutations and for expression of two resistance ligands - heregulin (HRG) and insulin-like growth factor 1 (IGF-1). Patients will receive Merrimack's oligoclonal EGFR (epidermal growth factor receptor) inhibitor, MM-151, in combination with another agent that is intended to target their cancer' s mechanism of resistance to EGFR inhibition. The general study scheme is depicted in Figure 4. Assignment to one of the four trial arms will be based on the following criteria:

• Patients that test positive for HRG will be assigned to Group A and receive MM-151 in combination with seribantumab (MM-121), a fully human antibody designed to block heregulin-driven ErbB3 pro-survival signaling.

• Patients that test negative for HRG and positive for activating mutations in either KRAS or NRAS will be assigned to Group B and receive MM-151 in combination with trametinib, a MEK inhibitor (Novartis). This regimen is designed to block signaling both upstream and downstream of RAS mutations.

• Patients that test negative for HRG, wild-type for KRAS and NRAS, and positive for IGF-1 will be assigned to Group C and receive MM-151 in combination with istiratumab (MM- 141), a bispecific antibody designed to block IGF-1R and ErbB3 pro-survival signaling.

Patients that test negative for both HRG and IGF-1 and wild-type for KRAS and NRAS will be assigned to Group D and receive MM-151 in combination with trametinib. This regimen is designed to block signaling from alternative receptors and to delay potential acquisition of KRAS and NRAS mutations.

Patients diagnosed with CRC, SCCHN or NSCLC are eligible to participate in the study. Patients must have/be:

• For wild type KRAS and NRAS colorectal patients, prior treatment

with cetuximab or panitumumab

• Measureable disease in accordance with RECIST vl. l

• Willingness to provide tumor biopsy to assess KRAS, NRAS, and

BRAF status and to assess HRG and IGF-1 expression (mRNA)

• Arm A: patients must be positive for HRG (RNA-ISH score >1+)

· Arm B: patients must be mutant for KRAS or NRAS and negative

for HRG

• Arm C: patients must be positive for IGF-1 (RNA-ISH score >1+),

negative for HRG, and wild-type for KRAS and NRAS

• Arm D: patients must be: wild-type for KRAS and NRAS and

negative for both IGF- 1 and HRG

Only CRC and SCCHN patients will be enrolled in Part 2 of the study.

Outcome Measures:

Primary Outcome Measure:

1. Phase II dose of MM-151 in combination with MM-121, MM-141, and trametinib based on maximum tolerated dose (MTD) in patients with lung, head and neck, and colorectal cancers. [Time Frame: 1.5 years] [Safety Issue: Yes].

Secondary Outcome Measure:

2. Number of dose limiting toxicities (DLTs) within a cohort [Time Frame: 1.5 years] [Safety Issue: Yes].

3. Adverse event profile of MM-151 in combination with MM-121, MM-141, and trametinib [Time Frame: 1.5 years] [Safety Issue: Yes].

4. Objective response to MM-151 in combination with MM-121, MM-141, and trametinib based on RECIST [Time Frame: 1.5 years] [Safety Issue: No].

Inclusion Criteria include, but are not limited to: Patients must have either heregulin-positive cancer, cancer with RAS mutation, IGF-1 positive cancer, or RAS wild type cancer.

Exclusion Criteria include, but are not limited to:

Patients with untreated (primary) or symptomatic CNS (primary or metastatic) malignancies; patients with CNS metastases who have undergone surgery or

radiotherapy or who have been on a stable dose of corticosteroids for at least 2

weeks and whose disease is stable prior to the first scheduled day of dosing will be eligible for the trial.

Patients who have received other recent antitumor therapy including any standard chemotherapy or radiation within 14 days (and having passed the time of any

actual or anticipated toxicities) prior to the first scheduled dose of the study

treatment.

SEQUENCE SUMMARY

SEQ ID DESIGNATION SEQUENCE NO:

20 P1X V_L MGTPAQLLFLLLLWLPDTTG Protein - with DIQMTQSPST LSASVGDRVT leader sequence rrCRASQSISSWWAWYQQKP

GKAPKLLIYD AS S LES GVPS RFS GS GS GTEFTLTIS S LQP DDFATYYCQQYHAHPTTFGG GTKVEIK

21 P2X V_H MGFGLSWLFLVAILKGVQC

Protein - with QVQLVQS G AE VKKPGS S VKV leader sequence SC KAS GGTFGS Y AIS W VRQ A

PGQGLEWMGSIIPIFGAANP AQKS QGR VTIT ADES TS T A Y MELS S LRS EDT A V Y YC AKMG RGKVAFDIWGQGTMVTVSS

22 P2X V_L MGTPAQLLFLLLLWLPDTTG Protein - with DIVMTQSPDSLAVSLGERAT leader sequence INC KS S QS VLYS PNNKN YLA

W YQQKPGQPPKLLIY W AS TR ES G VPDRFS GS GS GTDFTLT IS S LQAED VA VYYCQQYYGS PITFGGGTKVEIK

23 P3X V_H MGFGLSWLFLVAILKGVQC

Protein - with QVQLVQSGAEVKKPGASVKV leader sequence SCKASGYAFTSYGINWVRQA

PGQGLEWMGWISAYNGNTYY

AQKLRGR VTMTTDTS TS T A Y

MELRS LRS DDT A V Y YC ARDL

GGYGSGSVPFDPWGQGTLVTVSS

24 P3X V_L MGTPAQLLFLLLLWLPDTTG Protein - with EIVMTQS P ATLS VS PGERAT leader sequence LS CRAS QS VS S NLA W YQQKP

GQ APRLLIYG AS TRATGIP A RFS GS GS GTEFTLTIS S LQS EDFAVYYCQDYRTWPRRVFG GGTKVEIK

SEQ ID DESIGNATION SEQUENCE

NO:

25 EGFR ECD MRPS GT AGAALLALLAALCP

Protein ASRALEEKKVCQGTSNKLTQ

LGTFEDHFLSLQRMFNNCEV VLGNLEIT Y VQRN YDLS FLK TIQEVAGYVLIALNTVERIP LENLQIIRGNM Y YENS Y ALA

VLSNYDANKTGLKELPMRNLQEILHGAVRFSNNPALCN

VES IQWRDIVS S DFLS NMS MDFQNHLGS CQKCDPS CPN

GS C WG AGEENC QKLTKIIC AQQC S GRCRGKS PS DCCHN

QCAAGCTGPRESDCLVCRKFRDEATCKDTCPPLMLYNP

TTYQMDVNPEGKYSFGATCVKKCPRNYVVTDHGSCVR

ACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFK

DS LS INATNIKHFKNCTSIS GDLHILP VAFRGDSFTHTPPL

DPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIR

GRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNK

NLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQV

CHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLE

GEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQC

AHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCH

LCHPNCTYGCTGPGLEGCPTNGPKIPSHHHHHH

26 Light Chain of DIQMTQS PS S LS AS LGDR VTITCRAS QGIS S YLA W YQQK polyvalent PGKAPKLLIY AKS TLQS G VPS RFS GS GS GTDFTLTIS S LQ bispecific PEDS AT Y YC QQ YWTFPLTFGGGTKVEIKRT V A APS VFIF antibody PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ

P4-G1-M1.3 SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYA

(MM-141) CE VTHQGLS S P VTKS FNRGEC

[Recited as SEQ

ID NO: 204 in US

Patent No.:

US 8476409]

Protein

SEQ ID DESIGNATION SEQUENCE

NO:

27 Heavy Chain of E VQLLQS GGGLVQPGGS LRLS C A AS GFMFS RYPMHW V polyvalent RQ APGKGLE W VGS IS GS GG ATP Y ADS VKGRFTIS RDNS bispecific KNTLYLQMNSLRAEDTAVYYCAKDFYQILTGNAFDYW antibody GQGTT VT VS S AS TKGPS VFPLAPS S KS TS GGT A ALGCLV

P4-G1-M1.3 KD YFPEPVT VS WNS GALTS GVHTFPA VLQS S GLYS LS S V

(MM-141) VTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT

HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV

[Recited as SEQ VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY ID NO: 226 in US RV VS VLT VLHQD WLNGKE YKC KVS NKALP APIEKTIS K Patent No.: AKGQPREPQ V YTLPPS REEMTKNQ VS LTCL VKGF YPS DI US 8476409] AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS

RWQQGN VFS CS VMHE ALHNH YTQKS LSLSPGGGGGSG

Protein GGGS GGGGS QVQLVQS GGGLVQPGGS LRLSC AAS GFTF

DDYAMHWVRQAPGKGLEWVAGISWDSGSTGYADSVK GRFTIS RDN AKNS LYLQMNS LRAEDT ALY YC ARDLG A YQW VEGFD YWGQGTLVT VS SASTGGGGSGGGGSGGG GSGGGGSSYELTQDPAVSVALGQTVRITCQGDSLRSYY AS W YQQKPGQAPVLVIYGKNNRPS GIPDRFS GSTS GNS ASLTITGAQAEDEADYYCNSRDSPGNQWVFGGGTKVT VLG

28 Linker EPKS CDKTHTCPPCP APELLGGPS VFLFPPKPKDTLMIS R

[Recited as SEQ TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR ID NO: 53 in EEQ YNS T YRV VS VLT VLHQD WLNGKE YKC KVS NKALP PCT/US2010/052 APIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL 712] VKGF YPS DIAVEWES NGQPENN YKTTPP VLDS DGS FFL

YS KLT VDKS RWQQGN VFS CS VMHE ALHNH YTQKS LS L

Protein SPGGGGGSGGGGSGGGGS

29 P1X V_H - without QVQLVQS G AE VKKPGS S VKV

leader sequence SCKASGGTFSSYAISWVRQA

PGQGLEWMGSIIPIFGTVNY AQKFQGR VTIT ADES TS T A Y MELS S LRS EDT A V Y YC ARDP SVNLYWYFDLWGRGTLVTVSS

30 P1X V_L - without DIQMTQSPST LSASVGDRVT

leader sequence rrCRASQSISSWWAWYQQKP

GKAPKLLIYD AS S LES GVPS RFS GS GS GTEFTLTIS S LQP DDFATYYCQQYHAHPTTFGG GTKVEIK

31 P2X V_H - without QVQLVQS GAE VKKPGS S VKV

leader sequence SC KAS GGTFGS Y AIS W VRQ A

PGQGLEWMGSIIPIFGAANP AQKS QGR VTIT ADES TS T AY MELS S LRS EDT A V Y YC AKMG RGKVAFDIWGQGTMVTVSS SEQ ID DESIGNATION SEQUENCE

NO:

32 I P2X V_L - without DIVMTQSPDSLAVSLGERAT

leader sequence INC KS S QS VLYS PNNKN YLA

P3X V_H - without QVQLVQS G AE VKKPG AS VKV leader sequence SCKASGYAFTSYGINWVRQA

PGQGLEWMGWISAYNGNTYY AQKLRGR VTMTTDTS TS T A Y MELRS LRS DDT A V Y YC ARDL GGYGSGSVPFDPWGQGTLVTVSS

34 I P3X V_L - without EIVMTQS P ATLS VS PGERAT

leader sequence LS CRAS QS VS S NLA W YQQKP

35 P1X Heavy Chain QVQLVQSGAE VKKPGSSVKV SCKASGGTFS

SYAISWVRQA PGQGLEWMGS IIPIFGTVNY AQKFQGRVTI TADESTSTAY MELSSLRSED TAVYYCARDP SVNLYWYFDL WGRGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ TYICNVNHKP SNTKVDKKVE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK PKDTLMI SRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP QVYTLPPSRE EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG

K

36 P1X Light Chain DIQMTQSPST LSASVGDRVT ITCRASQSIS

SWWAWYQQKP GKAPKLLIYD ASSLESGVPS RFSGSGSGTE FTLTISSLQP DDFATYYCQQ YHAHPTTFGG GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC SEQ ID DESIGNATION SEQUENCE

NO:

37 P2X Heavy Chain QVQLVQSGAE VKKPGSSVKV SCKASGGTFG

SYAISWVRQA PGQGLEWMGS IIPIFGAANP

AQKSQGRVTI TADESTSTAY MELSSLRSED

TAVYYCAKMG RGKVAFDIWG QGTMVTVSSA

STKGPSVFPL APSSKSTSGG TAALGCLVKD

YFPEPVTVSW NSGALTSGVH TFPAVLQSSG

LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN

TKVDKKVEPK SCDKTHTCPP CPAPELLGGP

SVFLFPPKPK DTLMI SRTPE VTCVVVDVSH

EDPEVKFNWY VDGVEVHNAK TKPREEQYNS

TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL

PAPIEKTISK AKGQPREPQV YTLPPSREEM

TKNQVSLTCL VKGFYPSDIA VEWESNGQPE

NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ

QGNVFSCSVM HEALHNHYTQ KSLSLSPGK

38 P2X Light Chain DIVMTQSPDS LAVSLGERAT INCKSSQSVL

YSPNNKNYLA WYQQKPGQPP KLLIYWASTR

ESGVPDRFSG SGSGTDFTLT ISSLQAEDVA

VYYCQQYYGS PITFGGGTKV EIKRTVAAPS

VFIFPPSDEQ LKSGTASVVC LLNNFYPREA

KVQWKVDNAL QSGNSQESVT EQDSKDSTYS

LSSTLTLSKA DYEKHKVYAC EVTHQGLSSP

VTKSFNRGEC

39 P3X Heavy Chain QVQLVQSGAE VKKPGASVKV SCKASGYAFT

SYGINWVRQA PGQGLEWMGW I SAYNGNTYY

AQKLRGRVTM TTDTSTSTAY MELRSLRSDD

TAVYYCARDL GGYGSGSVPF DPWGQGTLVT

VSSASTKGPS VFPLAPSSKS TSGGTAALGC

LVKDYFPEPV TVSWNSGALT SGVHTFPAVL

QSSGLYSLSS VVTVPSSSLG TQTYICNVNH

KPSNTKVDKK VEPKSCDKTH TCPPCPAPEL

LGGPSVFLFP PKPKDTLMIS RTPEVTCVVV

DVSHEDPEVK FNWYVDGVEV HNAKTKPREE

QYNSTYRVVS VLTVLHQDWL NGKEYKCKVS

NKALPAP IEK TISKAKGQPR EPQVYTLPPS

REEMTKNQVS LTCLVKGFYP SDIAVEWESN

GQPENNYKTT PPVLDSDGSF FLYSKLTVDK

SRWQQGNVFS CSVMHEALHN HYTQKSLSLS

PGK

40 P3X Light Chain EIVMTQSPAT LSVSPGERAT LSCRASQSVS

SNLAWYQQKP GQAPRLLIYG ASTRATGIPA

RFSGSGSGTE FTLTISSLQS EDFAVYYCQD

YRTWPRRVFG GGTKVEIKRT VAAPSVFIFP

PSDEQLKSGT ASVVCLLNNF YPREAKVQWK

VDNALQSGNS QESVTEQDSK DSTYSLSSTL

TLSKADYEKH KVYACEVTHQ GLSSPVTKSF

NRGEC

Claims

CLAIMS What is claimed is:

1. A method of treating cancer in a human patient comprising administering to the patient an effective amount of:

A. istiratumab; and

B. a composition of anti-EGFR antibodies comprising:

1. a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 1, 2, and 3, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 4, 5, and 6, respectively;

3. a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 13, 14, and 15, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 16, 17, and 18, respectively,

wherein the method comprises a priming phase and a cycle,

wherein the cycle is a period of four weeks, wherein:

iii. istiratumab is administered once every two weeks at a fixed dose of 2.24 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 10.5 mg/kg; iv. istiratumab is administered once every two weeks at a fixed dose of 2.24 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 9 mg/kg;

2. The method of claim 1, wherein during the cycle istiratumab is administered once every two weeks at a fixed dose of 1.96 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 10.5 mg/kg. 3. The method of claim 1, wherein during the cycle istiratumab is administered once every two weeks at a fixed dose of 1.96 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 9 mg/kg.

4. The method of claim 1, wherein during the cycle istiratumab is administered once every two weeks at a fixed dose of 2.24 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 10.5 mg/kg.

5. The method of claim 1, wherein during the cycle istiratumab is administered once every two weeks at a fixed dose of 2.24 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 9 mg/kg.

6. The method of claim 1, wherein during the cycle istiratumab is administered once every two weeks at a fixed dose of 2.8 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 10.5 mg/kg.

7. The method of claim 1, wherein during the cycle istiratumab is administered once every two weeks at a fixed dose of 2.8 g and the composition of anti-EGFR antibodies is administered once weekly at a dose of 9 mg/kg.

8. The method of any one of the preceding claims, wherein the composition of anti- EGFR antibodies comprises:

1. a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 29 and a light chain variable region comprising SEQ ID NO: 30;

2. a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 31 and a light chain variable region comprising SEQ ID NO: 32; and

3. a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 33 and a light chain variable region comprising SEQ ID NO: 34.

9. The method of any one of the preceding claims, wherein anti-EGFR antibodies (1), (2), and (3) are in the composition at a molar ratio of 2:2: 1 to each other.

10. The method of any one of the preceding claims, wherein each of the anti-EGFR antibodies in the composition is a human antibody.

11. The method of any one of the preceding claims, wherein the composition further comprises a pharmaceutically acceptable carrier.

12. The method of any one of the preceding claims, wherein the composition is a sterile composition.

13. The method of any one of the preceding claims, wherein the cancer is non-small-cell lung cancer (NSCLC).

14. The method of any one of the preceding claims, wherein the cancer is squamous cell carcinoma of the head and neck (SCCHN).

15. The method of any one of the preceding claims, wherein the cancer is colorectal cancer (CRC).

16. The method of any one of the preceding claims, wherein the cancer is an Insulin Growth Factor 1 (IGF-1) positive cancer.

17. The method of any one of the preceding claims, wherein istiratumab is administered intravenously.

18. The method of any one of the preceding claims, wherein the composition of anti- EGFR antibodies is administered intravenously.

19. The method of any one of the preceding claims, wherein istiratumab is administered prior to the composition of anti-EGFR antibodies on weeks when istiratumab and the composition of anti-EGFR antibodies are administered together.

20. The method of any one of the preceding claims, wherein the treatment produces at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in metastasis, complete remission, partial remission, stable disease, increase in overall response rate, or a pathologic complete response.

21. A kit for treating a cancer in a human patient, the kit comprising:

A. a dose of istiratumab;

B. a dose of a composition of anti-EGFR antibodies comprising: (1) a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID

NOs: 1, 2, and 3, respectively, and light chain CDR1, CDR2, and CDR3 sequences of

SEQ ID NOs: 4, 5, and 6, respectively; (2) a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 7, 8, and 9, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 10, 11 and 12, respectively; and (3) a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 13, 14, and 15, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 16, 17, and 18, respectively; and

instructions for using istiratumab and the composition of anti-EGFR antibodies method of any one of the preceding claims.

22. The kit of claim 21, wherein the cancer is an Insulin Growth Factor 1 (IGF-1) positive cancer.

23. The kit of claim 21, wherein the cancer is non- small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), or colorectal cancer (CRC).