WO2017035482A1

WO2017035482A1 - Combination therapies for treatment of heregulin positive cancers

Info

Publication number: WO2017035482A1
Application number: PCT/US2016/049027
Authority: WO
Inventors: Akos CZIBERE; Gavin Macbeath; James Murray; Rachel C. NERING; Beni B. WOLF; Olga BURENKOVA; William Kubasek; Marisa WAINSZELBAUM
Original assignee: Merrimack Pharmaceuticals Inc
Current assignee: Merrimack Pharmaceuticals Inc
Priority date: 2015-08-27
Filing date: 2016-08-26
Publication date: 2017-03-02
Anticipated expiration: 2018-02-27

Abstract

Provided are methods for clinical treatment of heregulin positive cancers using anti-ErbB3 antibodies in combination with anti-EGFR antibodies.

Description

COMBINATION THERAPIES FOR TREATMENT

OF HEREGULIN POSITIVE CANCERS

BACKGROUND

This application claims the benefit of two U.S. Provisional Patent Applications

U.S. Provisional Patent Application Serial No. 62/210,838 filed August 27, 2015 and U.S. Provisional Patent Application Serial No. 62/337,019 filed May 16, 2016. The entire contents of the above-referenced patent applications are incorporated herein by these references.

The ErbB network consists of four receptor tyrosine kinases (RTKs): epidermal growth factor receptor (EGFR or ErbB 1), ErbB2 (HER2), ErbB3 (HER3) and ErbB4

(HER4), multiple ErbB ligands, and downstream signaling molecules that mediate cell proliferation, survival and anti-apoptosis (see, e.g., Chong, C. R. & Janne, P., Nat. Med. 19, 1389-400 (2013); Tebbutt, N., et al., Nat. Rev. Cancer 13, 663-73 (2013); and Arteaga, C. L. & Engelman, J. A, Cancer Cell 25, 282-303 (2014)). The ErbB network is essential for growth and development of normal epithelial tissues. Deregulated ErbB signaling, however, occurs frequently in solid tumors and this enhances both aberrant tumor growth and drug resistance. EGFR and ErbB2 are valid therapeutic targets with antagonists having well proven clinical activity, particularly in biomarker-defined patient populations. These include KRAS wild-type colorectal cancer (CRC), EGFR-mutant non-small cell lung cancer

(NSCLC), and ErbB 2- amplified breast and gastric cancer. Less is known about ErbB3 and ErbB4. Emerging data, however, indicate that ErbB3 and its ligand, heregulin (HRG), promote clinically significant resistance to both targeted agents and chemotherapy. Despite the clinical success with EGFR and ErbB2 inhibition, de novo and acquired resistance limit clinical benefit for many patients. Accordingly, it is an object of the present invention to provide improved methods for treating patients with heregulin positive cancers.

SUMMARY

Provided herein are compositions and methods for treating heregulin positive cancers {e.g., non- small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), or colorectal cancer (CRC)) in a human patient, comprising administering to the patient an anti-ErbB3 antibody and a composition of anti-EGFR antibodies according to a particular clinical dosage regimen {i.e., at a particular dose amount and according to a specific dosing schedule). An exemplary anti-ErbB3 antibody is seribantumab (also known as "MM- 121 " or "Ab #6") or antigen binding fragments and variants thereof. In one embodiment, the anti-ErbB3 antibody comprises the heavy and light chain CDRs or variable regions of seribantumab. In one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of seribantumab having the sequence set forth in SEQ ID NO: 10 and the CDR1,

CDR2 and CDR3 domains of the VL region of seribantumab having the sequence set forth in SEQ ID NO: 12.

In another embodiment, the antibody comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively. In another embodiment, the antibody comprises VH and/or VL regions having the amino acid sequences set forth in SEQ ID NO: 10 and SEQ ID NO: 12, respectively. In another embodiment, the anti-ErbB3 antibody comprises VH and/or VL regions encoded by the nucleic acid sequences set forth in SEQ ID NOs: 9 and 11, respectively. In another embodiment, the anti-ErbB3 antibody comprises heavy and/or light chains having the amino acid sequences set forth in SEQ ID NO: 7 and SEQ ID NO: 8, respectively.

In another embodiment, an antibody is used that competes for binding with and/or binds to the same epitope on human ErbB3 as the above-mentioned antibodies. In a particular embodiment, the epitope comprises residues 92-104 of human ErbB3 (SEQ ID NO: 13). In another embodiment, the antibody binds all or a portion of residues 92-104 of human ErbB3 (SEQ ID NO: 13). In another embodiment, the epitope is a discontinuous epitope. In another embodiment, the antibody binds all or a portion of a discontinuous epitope comprising residues 92- 104 and 129 of human ErbB3 (SEQ ID: 13). In yet another embodiment, the antibody competes with seribantumab for binding to human ErbB3 and has at least 90% variable region amino acid sequence identity with the above-mentioned anti- ErbB3 antibodies (e.g., at least about 90%, 95% or 99% variable region identity with SEQ ID NO: 10 and SEQ ID NO: 12).

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: 14, 15, and 16 , respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 17, 18, and 19, respectively; (2) a monoclonal antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 20, 21, and 22, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 23, 24, and 25, respectively; and (3) a monoclonal antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 26, 27, and 28, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 29, 30, and 31, respectively.

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: 32, and the CDRl, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 33; (2) a monoclonal antibody

comprising the CDRl, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 34, and the CDRl, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 35; and (3) a monoclonal antibody comprising the CDRl, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 36, and the CDRl, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 37.

In another embodiment, the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 32; (2) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 34 and (3) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 36.

In another embodiment, the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a light chain variable region comprising SEQ ID NO: 33; (2) a monoclonal antibody comprising a light chain variable region comprising SEQ ID NO: 35; and (3) a monoclonal antibody comprising a light chain variable region comprising SEQ ID NO: 37.

In another embodiment, the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 32 and a light chain variable region comprising SEQ ID NO: 33; (2) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 34 and a light chain variable region comprising SEQ ID NO: 35; and (3) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 36 and a light chain variable region comprising SEQ ID NO: 37.

In another embodiment, the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 39; (2) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 41 and (3) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 43.

In another embodiment, the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a light chain variable region comprising SEQ ID NO: 40; (2) a monoclonal antibody comprising a light chain variable region comprising SEQ ID NO: 42; and (3) a monoclonal antibody comprising a light chain variable region comprising SEQ ID NO: 44.

In another embodiment, the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 39 and a light chain variable region comprising SEQ ID NO: 40; (2) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 41 and a light chain variable region comprising SEQ ID NO: 42; and (3) a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 43 and a light chain variable region comprising SEQ ID NO: 44.

In another embodiment, the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a heavy chain comprising SEG ID NO: 45 and a light chain comprising SEQ ID NO: 46; (2) a monoclonal antibody comprising a heavy chain comprising SEG ID NO: 47 and a light chain comprising SEQ ID NO: 48; and (3) a monoclonal antibody comprising a heavy chain comprising SEG ID NO: 49 and a light chain comprising SEQ ID NO: 50.

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. Accordingly, in one aspect, methods of treating a human patient with a heregulin positive cancer (e.g., NSCLC, SCCHN, or CRC) are provided, the methods comprising administering to the patient an anti-ErbB3 antibody and a composition of anti-EGFR antibodies. In one embodiment, the dose of the anti-ErbB3 antibody, or antigen binding fragment thereof, is a flat- fixed dose that is fixed irrespective of the weight of the patient. For example, the anti-ErbB3 antibody, or antigen binding fragment thereof, may be administered at a fixed dose of 0.75 g, 1.0 g, 1.5 g, or 2.0 g without regard to the patient's weight. 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 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, methods of treating a human patient with a heregulin positive cancer (e.g., NSCLC, SCCHN, or CRC) are provided, wherein the methods comprise administering to the patient:

A. an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences

comprising the amino acid sequences set forth in SEQ ID NO: 1 (CDRH1) SEQ ID NO: 2 (CDRH2) and SEQ ID NO: 3 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 4 (CDRL1) SEQ ID NO: 5 (CDRL2) and SEQ ID NO: 6 (CDRL3); 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: 14, 15, and 16, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 17, 18, and 19, respectively;

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

sequences of SEQ ID NOs: 20, 21, and 22, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 23, 24, and 25, respectively; and 3. a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 26, 27, and 28, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 29, 30, and 31, 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 anti-ErbB3 antibody is administered once weekly at a fixed dose of 0.75 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg;

ii. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 0.75 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg;

iii. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg;

iv. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg;

v. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.5 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg;

vi. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.5 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg;

vii. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 2.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg; or

viii. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 2.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg. 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.

A. an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences

B. a composition of anti-EGFR antibodies comprising:

1. a monoclonal antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 32, and the CDR1, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 33;

2. a monoclonal antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 34, and the CDR1, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 35; and

3. a monoclonal antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 36, and the CDR1, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 37,

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:

ix. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 0.75 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg;

x. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 0.75 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg;

xi. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg;

xii. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg;

xiii. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.5 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg;

xiv. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.5 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg;

xv. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 2.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg; or

xvi. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 2.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg.

In one embodiment, during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 0.75 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg.

In another embodiment, during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 0.75 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg. In another embodiment, during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg. In another embodiment, the anti-ErbB3 antibody is administered on week one of the priming phase at a fixed dose selected from the group consisting of 0.75 g, 1.0 g, 1.5 g, and 2.0 g.

In another embodiment, during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg.

In another embodiment, the anti-ErbB3 antibody is administered

once weekly at a fixed dose of 1.5 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg.

In another embodiment, during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.5 g and the composition is administered every two weeks at a dose of 10.5 mg/kg.

In another embodiment, during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 2.0 g and the composition is administered every two weeks at a dose of 9 mg/kg.

In another embodiment, during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 2.0 g and the composition is administered every two weeks at a dose of 10.5 mg/kg.

On weeks when both the anti-ErbB3 antibody and composition of anti-EGFR antibodies are administered, the anti-ErbB3 antibody is administered prior to the composition of anti-EGFR antibodies. In one embodiment, acetaminophen, diphenhydramine, or methylprednisone (SOLUMEDROL) is administered prior to administration of the anti-ErbB3 antibody. In another embodiment, acetaminophen is administered at a dose of 650 mg by mouth or intravenously, diphenhydramine is administered at a dose of 25-50 mg by mouth or intravenously, or methylprednisone (SOLUMEDROL) is administered at a dose of 125 mg intravenously, prior to administration of the anti-ErbB3 antibody. In a further embodiment, acetaminophen, diphenhydramine, or methylprednisone (SOLUMEDROL) is administered 30 - 90 minutes prior to administration of the anti-ErbB3 antibody. In a further embodiment, on days when the anti-ErbB3 antibody is not administered, acetaminophen, diphenhydramine, or methylprednisone is administered prior to administration of the composition of anti-EGFR antibodies (e.g., 30-90 minutes prior to the administration of the composition of anti-EGFR antibodies) in a dose described above. In a further embodiment, an H2 antagonist (e.g., cimetidine, ranitidine, famotidine, or nizatidine) is administered prior to the anti-ErbB3 antibody or the composition of anti-EGFR antibodies (on weeks when the anti-ErbB3 antibody is not administered).

The antibodies, or antigen binding fragments thereof, and compositions described herein can be administered to a patient by any suitable means. In one embodiment, the anti- Erb3 antibody and composition of anti-EGFR antibodies are formulated for intravenous administration. In one embodiment, the anti-ErbB3 antibody is intravenously infused over 60 minutes. In one embodiment, a first intravenous administration of the composition of anti- EGFR antibodies is infused at a rate of 25 mg/hr over 30 minutes, 50 mg/hr over 30 minutes, or 100 mg/hr until completion. In another embodiment, a second intravenous administration of the composition of anti-EGFR antibodies is infused at a rate of 25 mg/hr over 30 minutes, 50 mg/hr over 30 minutes, 100 mg/hr over 30 minutes, or 200 mg/hr until completion. In another embodiment, a third intravenous administration of the composition of anti-EGFR antibodies is infused at a rate of 50 mg/hr over 30 minutes, 100 mg/hr over 30 minutes, or 200 mg/hr over 30 minutes, or 400 mg/hr until completion. In another embodiment, fourth and subsequent intravenous administrations of the composition of anti-EGFR antibodies are infused at a rate of 100 mg/hr and advanced as tolerated.

Uses of seribantumab for the treatment of a heregulin-positive cancer, characterized in that the seribantumab is co-administered with MM- 151 are also contemplated.

The efficacy of the treatment methods or uses 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.

Further provided are kits that include an anti-ErbB3 antibody, or antigen binding fragment thereof, such as seribantumab, and a pharmaceutically-acceptable carrier, and a composition of anti-EGFR antibodies, such as MM- 151, in a therapeutically effective amount adapted for use in the methods described herein. In one embodiment, the kit comprises:

A. a dose of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3

sequences comprising the amino acid sequences set forth in SEQ ID NO: 1 (CDRH1) SEQ ID NO: 2 (CDRH2) and SEQ ID NO: 37 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 4 (CDRL1) SEQ ID NO: 5 (CDRL2) and SEQ ID NO: 6 (CDRL3);

B. a dose of a composition of anti-EGFR antibodies comprising: (1) a monoclonal

antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 14, 15, and 16, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 17, 18, and 19, respectively; (2) a monoclonal antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 20, 21, and 22, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 23, 24 and 25, respectively; and (3) a monoclonal antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 26, 27, and 28, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 29, 30, and 31, respectively; and

C. instructions for using the anti-ErbB3 antibody and composition of anti-EGFR

antibodies, in the methods described herein.

In another embodiment, the kit comprises:

A. a dose of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3

B. a dose of a composition of anti-EGFR antibodies comprising: (1) a monoclonal

antibody comprising the CDRl, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 32, and the CDRl, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 33; (2) a monoclonal antibody comprising the CDRl, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 34, and the CDRl, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 35; and (3) a monoclonal antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 36, and the CDR1, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 37; and

C. instructions for using the anti-ErbB3 antibody and composition of anti-EGFR

antibodies, in the methods described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

Figures 1A and IB depict the effect of MM- 121 in combination with cetuximab in two head and neck cell lines in xenograft models.

Figure 2 depicts the results of treatment of Liml215 CRC xenograft tumors with 25Etrio (MM- 151), MM- 121, and 25Etrio plus MM- 121.

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

Figure 4 is a schematic depicting the dose adjustment for skin reactions related to MM- 151 treatment.

Figure 5 is the schedule of assessments.

Figure 6 is a timeline for completing all procedures during normal business hours.

DETAILED DESCRIPTION

I. Definitions

As used herein, the term "subject" or "patient" is a human patient (e.g., a patient having a heregulin 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 terms "ErbB3," "HER3," "ErbB3 receptor," and "HER3 receptor," as used interchangeably herein, refer human ErbB3 protein, as described in U.S. Pat. No. 5,480,968 and Plowman et al, Proc. Natl. Acad. Sci. USA, 87:4905-4909 (1990); see, also, Kani et al, Biochemistry 44: 15842-857 (2005), Cho and Leahy, Science 297: 1330-1333 (2002)). The protein sequence of human ErbB3 is set forth in SEQ ID NO: 13. The term "heregulin" (HRG) refers to an ErbB3 ligand that activates ErbB3, thereby initiating intracellular signaling in tumor cells. 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.

A "heregulin positive cancer" is a cancer which expresses heregulin. Heregulin can be detected, for example, using a chromogenic RNA-In Situ Hybridization Assay (RNA- ISH), e.g., as described in WO 2015/100459, the teachings of which are expressly incorporated herein by reference.

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:38. 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. II. Anti-ErbB3 Antibodies

Anti-ErB3 antibodies (or VH/VL domains derived therefrom) suitable for use in the invention can be generated using methods well known in the art. Alternatively, art recognized anti-ErbB3 antibodies can be used. Antibodies that compete with any of these art-recognized antibodies for binding to ErbB3 also can be used.

An exemplary anti-ErbB3 antibody is seribantumab (also known as "MM- 121 " or "Ab

#6") or antigen binding fragments and variants thereof. Seribantumab is a human

monoclonal anti-ErbB3 IgG2 (see, e.g., U.S. Patent Nos. 7,846,440; 8,691,771 and 8,961,966; 8,895,001, U.S. Patent Publication Nos., 20110027291, 20140127238,

20140134170, and 20140248280), as well as international publication Nos.

WO/2013/023043, WO/2013/138371, WO/2012/103341, and US Provisional Patent

Application serial No. 62/090,780, the teachings of which are expressly incorporated herein by reference).

In one embodiment, the anti-ErbB3 antibody comprises the heavy and light chain CDRs or variable regions of seribantumab. Accordingly, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of seribantumab having the sequence set forth in SEQ ID NO: 10 and the CDR1, CDR2 and CDR3 domains of the VL region of seribantumab having the sequence set forth in SEQ ID NO: 12. In another embodiment, the antibody comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively. In another embodiment, the antibody comprises VH and/or VL regions having the amino acid sequences set forth in SEQ ID NO: 10 and SEQ ID NO: 12, respectively. In another embodiment, the anti-ErbB3 antibody comprises VH and/or VL regions encoded by the nucleic acid sequences set forth in SEQ ID NOs: 9 and 11, respectively. In another embodiment, the anti-ErbB3 antibody comprises heavy and/or light chains having the amino acid sequences set forth in SEQ ID NO: 7 and SEQ ID NO: 8, respectively. In another embodiment, an antibody is used that competes for binding with and/or binds to the same epitope on human ErbB3 as the above-mentioned antibodies. In a particular embodiment, the epitope comprises residues 92-104 of human ErbB3 (SEQ ID NO: 13). In another embodiment, the antibody competes with seribantumab for binding to human ErbB3 and has at least 90% variable region amino acid sequence identity with the above-mentioned anti- ErbB3 antibodies (see, e.g., US Patent No. 7,846,440 and US Patent Publication No.

20100266584).

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 monoclonal antibodies designed to bind and inhibit signaling of the Epidermal Growth Factor Receptor (EGFR). MM- 151 is a mixture of three independent antibodies (PIX + P2X + P3X), which to three non-overlapping sites on EGFR to maximize inhibition of ligand-dependent and independent signaling (see, e.g., WO 2013/006547 and Kearns et al., 2015, Mol. Cancer Ther., 14: 1625-36, the teachings of both of which are expressly incorporated herein by reference). PIX, P2X, and P3X correspond to CAS Registry Numbers 1509928-01- 1, 1509928-02-2, and 1509928-03-3, respectively. The PIX, P2X and P3X monoclonal antibodies are affinity matured antibodies of parental antibodies referred to as ca, cd and ch, respectively, disclosed in WO 2011/140254, the teachings of which are expressly incorporated herein by reference. The CDR amino acid sequences of PIX, P2X and P3X are shown below:

The full-length V_H and V_L amino acid sequences (including leader sequences) for PIX are shown in SEQ ID NO: 32 and SEQ ID NO: 33, respectively. The full-length V_H and VL amino acid sequences (including leader sequences) for P2X are shown in SEQ ID NO: 34 and SEQ ID NO:35, respectively. The full-length V_H and V_L amino acid sequences

(including leader sequences) for P3X are shown in SEQ ID NO: 36 and SEQ ID NO: 37, respectively. Additionally, the VH and VL CDR segments as presented herein are arranged, e.g., in the amino to carboxy terminal order of CDR1 , CDR2 and CDR3. The mature full-length V_H and V_L amino acid sequences for P1X are shown in SEQ ID NO: 39 and SEQ ID NO: 40, respectively. The mature full-length V_H and V_L amino acid sequences for P2X are shown in SEQ ID NO: 41 and SEQ ID NO: 42, respectively. The mature full-length V_H and V_L amino acid sequences for P3X are shown in SEQ ID NO: 43 and SEQ ID NO: 44, respectively. 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: 14, 15, and 16, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 17, 18, and 19, respectively; (2) a monoclonal antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 20, 21, and 22, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 23, 24, and 25, respectively; and (3) a monoclonal antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 26, 27, and 28, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 29, 30, and 31, respectively.

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: 32, and the CDRl, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 33; (2) a monoclonal antibody comprising the CDRl, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 34, and the CDRl, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 35; and (3) a monoclonal antibody comprising the CDRl, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 36, and the CDRl, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 37.

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: 32 and the mature portion of the light chain variable region comprising SEQ ID NO: 33; (2) a monoclonal antibody comprising the mature portion of the heavy chain variable region comprising SEQ ID NO: 34 and the mature portion of the light chain variable region comprising SEQ ID NO: 35; and (3) a monoclonal antibody comprising the mature portion of the heavy chain variable region comprising SEQ ID NO: 36 and the mature portion of the light chain variable region comprising SEQ ID NO: 37.

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: 32 and residues 21-127 of the light chain variable region comprising SEQ ID NO: 33; (2) a monoclonal antibody comprising residues 20-138 of the heavy chain variable region comprising SEQ ID NO: 34 and residues 21-133 of the light chain variable region comprising SEQ ID NO: 35; and (3) a monoclonal antibody comprising residues 20-142 of the heavy chain variable region comprising SEQ ID NO: 36 and residues 21-128 of the light chain variable region comprising SEQ ID NO: 37.

In another embodiment, the composition of anti-EGFR antibodies comprises: (1) a monoclonal antibody comprising a heavy chain comprising SEQ ID NO: 45 and a light chain comprising SEQ ID NO: 46; (2) a monoclonal antibody comprising a heavy chain comprising SEQ ID NO: 47 and a light chain comprising SEQ ID NO: 48; and (3) a monoclonal antibody comprising a heavy chain comprising SEQ ID NO: 49 and a light chain comprising SEQ ID NO: 50.

IV. Compositions

The anti-ErbB3 antibodies and/or anti-EGFR antibodies can be formulated as pharmaceutical solutions, e.g., for administration to a subject for the treatment of cancer. The pharmaceutical compositions will generally include a pharmaceutically acceptable carrier. 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.

V. Outcomes

Provided herein are methods for treating a heregulin positive cancer in a human patient comprising administering to the patient an anti-ErbB3 antibody and a composition of anti-EGFR antibodies. 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.

VI. Kits and Unit Dosage Forms

Also provided herein are kits which include a dose of an anti-ErbB3 antibody (such as seribantumab), or an antigen binding fragment thereof, and a dose of a composition of anti-EGFR antibodies (such as MM- 151), in a therapeutically effective amount adapted for use in the preceding methods. The kits optionally also can include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient having cancer. The kit also can include a syringe. Instruments or devices necessary for administering the

pharmaceutical composition(s) also may be included in the kits.

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

A. a dose of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3

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: 14, 15, and 16, respectively, and light chain CDRl, CDR2, and CDR3

sequences of SEQ ID NOs: 17, 18, and 19, respectively; (2) a monoclonal antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 20, 21, and 22, respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 23, 24 and 25, respectively; and (3) a monoclonal antibody comprising heavy chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 26, 27, and 28,

respectively, and light chain CDRl, CDR2, and CDR3 sequences of SEQ ID NOs: 29, 30, and 31, respectively; and

C. instructions for using the anti-ErbB3 antibody and composition of anti-EGFR

antibodies, in the method of any one of the preceding claims.

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

A. a dose of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3

sequences comprising the amino acid sequences set forth in SEQ ID NO: 1 (CDRH1) SEQ ID NO: 2 (CDRH2) and SEQ ID NO: 37 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 4 (CDRL1) SEQ ID NO: 5 (CDRL2) and SEQ ID NO: 6 (CDRL3); B. a dose of a composition of anti-EGFR antibodies comprising: (1) a monoclonal antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 32, and the CDR1, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 33; (2) a monoclonal antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 34, and the CDR1, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 35; and (3) a monoclonal antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 36, and the CDR1, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 37; and

C. instructions for using the anti-ErbB3 antibody and composition of anti-EGFR

antibodies, in the methods described herein.

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:

Pre- Clinical Data

MM-121 in combination with cetuximab was explored in two head and neck cell lines in xenograft models. Mice were treated with PBS control, cetuximab, MM-121 at low (LD) and high (HD) doses, or the combinations. Tumor volumes were measured three times a week (Figure 1A) and tumors were harvested and weighed after treatment (Figure IB). For the Tu212 xenograft model, a similar result was found with both cetuximab and MM-121 monotherapies showing intermediate effects and the combination having great potency. The SCC47 xenograft model was found to be highly sensitivity to MM-121 and this drug alone was enough to halt tumor growth.

The combination of MM-151 plus MM-121 was also explored in vivo. MM-151 has poor pharmacokinetics in mice due to cross-reactivity with mouse EGFR. A non-cross reactive variant of one of the antibody components of MM- 151, called 25E, was therefore used for mouse xenograft studies. The equivalent tri-clonal mixture used in place of MM- 151 is referred to as "25Etrio". Figure 2 shows the steady growth of untreated Liml215 tumors (PBS) and slowed tumor growth with 25Etrio or MM- 121 monotherapies. The 25Etrio plus MM-121 appeared to halt tumor growth and cause some tumor regression. Interestingly, when MM-121 was added to a monotherapy of the 25Etrio (dashed after day 28) or when the 25Etrio was added to MM-121(after day 35), tumor regression was observed. The combination of MM- 151 plus MM-121 is thus more effective than either monotherapy alone. EXAMPLE 2:

A Phase 1 Study Evaluating the Safety, Pharmacology and Preliminary Activity of Co- Administration of MM-151 and MM-121 in Heregulin Positive Cancer Patients

A two-part Phase 1, non-randomized, open-label study of MM-151 plus MM-121 is conducted in patients with advanced, heregulin -positive cancers.

1. Objectives

The primary aim of the dose escalation is to define the safety, tolerability, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), pharmacokinetic (PK), potential immunogenicity, and ErbB biomarker levels for the MM-151 plus MM-121 combination in advanced colorectal cancer (CRC), squamous cell carcinoma of the head and neck (SCCHN) and non-small cell lung cancer (NSCLC).

The primary aim of the dose expansion is to further characterize safety, biomarker levels and to assess the preliminary clinical activity of the MM-151 plus MM-121 combination when administered at the maximum tolerated dose in CRC patients that are KRAS wild-type.

Secondary objectives for cancer patients with heregulin -positive SCCHN, NSCLC or

CRC treated with MM-151 plus MM-121 include: describing the dose limiting toxicities (DLTs), characterizing the adverse event profile, determining the pharmacokinetic parameters, determining the immunogenicity parameters, assessing the 8, 16 and 24 week disease control rates (RECIST stable disease (SD), RECIST partial response (PR), or RECIST complete remission (CR)), assessing Progression Free Survival (PFS) based on RECIST 1.1, describing any objective response based on RECIST vl.l, assessing ErbB pathway biomarkers in pre-treatment tumor biopsies and archived tissue samples, assessing the pharmacodynamic effects of treatment on heregulin mRNA and on ErbB pathway activation via pre- and on-treatment tumor biopsies, and exploring the relationship between clinical activity (and/or toxicity) and changes in blood and additional tissue biomarkers.

2. Study Design

The overall study design is depicted in Figure 3. The study is a two-part Phase 1, non-randomized, open-label study of MM- 151 plus MM- 121 in patients with advanced, heregulin -positive cancers.

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

The central lab analyzes the tumor sample for heregulin levels utilizing in-situ hybridization (ISH). For patients that relied on recent tumor tissue to assess heregulin status, a fresh pre-treatment biopsy (2 passes) is required for additional exploratory analyses. For patients that used a fresh biopsy to assess heregulin, no additional pre-treatment biopsy is required.

Part 1 is a dose escalation to determine the safety, tolerability and maximum tolerated dose/recommended Phase 2 dose of MM-151 plus MM-121 in heregulin -positive SCCHN, NSCLC or CRC cancers. In this phase 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 maximum tolerated dose or recommended Phase 2 dose of the MM-121 plus MM-151 combination.

Once the maximum tolerated dose is defined in Part 1, enrollment into the Part 2 Expansion Cohort proceeds. In this phase of the study, only CRC patients that are cetuximab refractory, KRAS wild-type and heregulin-positive are enrolled.

Pretreatment biopsies, recent tumor tissue, and archived samples are evaluated for heregulin mRNA levels and other pathway biomarkers. The MM-121 program has demonstrated in multiple indications (breast, ovarian, lung), that elevated heregulin expression in tumor tissue may predict response to MM-121 (see, e.g., Liu, Joyce, et al, J. Clin. Oncol. 32:5s, 2014 (suppl; abstr 5519) (2014), Cleary, JM, et al, J. Clin. Oncol 32:5s, 2014 (suppl; abstr 3076) (2014), Higgins, M, et al, J. Clin. Oncol. 32:5s, 2014 (suppl; abstr 587) (2014), Sequist, LV, et al, J. Clin. Oncol. 32:5s, 2014 (suppl; abstr 8051) (2014)). 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.

3. Enrollment and Treatment

Three or four patients are enrolled initially into each dose escalation cohort of the study. After the third patient enrolled in a cohort has completed the 6 week dose limiting toxicity window, the data is evaluated. If the safety profile is acceptable, enrollment proceeds to the next cohort.

MM-151 is dosed once weekly (QW) and MM-121 is dosed every two weeks (Q2W).

On weeks when both are administered on the same day, MM-121 is administered first. It is intended that patients are treated until disease progression or intolerable toxicity. The safety profile in the 6 week dose limiting toxicity window, which begins from the date of first dose of study drug, is used to inform decisions about dose escalations for the next cohort. A patient must receive at least three of his/her planned doses of the combination to be considered evaluable for a dose escalation decision.

During the dose escalation, if a patient discontinues study treatment after receiving fewer than two doses of MM-121 and four doses of MM-151, for reasons that are clearly not related to study drug, that patient is replaced by a new patient at that same dose level.

Patients that experience a dose limiting toxicity (as a dose limiting toxicity is by definition related to study drug), are not be replaced and the current dose level cohort is expanded (even if the dose limiting toxicity occurs within the priming phase of the study).

If multiple study sites are open and actively participating in the study, ideally each dose level includes at least one patient enrolled from each site. However, the goal is to enroll all patients in a cohort within a two-week period. If a site does not anticipate identifying a patient within these two weeks, one or more additional patient may come from any site.

a. Dose Levels for Part 1 ( Dose Escalation Phase )

The dosing levels of MM-121 and MM-151 in the dose escalation phase of the study are summarized in Table 1 below.

Table 1: Dose Levels of MM-151 and MM-121 for Part 1 (Dose Escalation)

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

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

Dosing begins at Dose Level 1A. A 6-week dose limiting toxicity evaluation window that includes a 2 week priming phase for MM-151 and a four week cycle 1 is used for dose escalation decisions. If no dose limiting toxicity is observed in a cohort of 3 patients, escalation proceeds to Level 2A and then Level 3A. If a dose limiting toxicity is observed in the first 3 patients enrolled into an "A" cohort, a total of 6 patients are enrolled in the current cohort and assessed for safety and tolerability. If there is no more than 1 patient with a dose limiting toxicity in a cohort of 6 patients in a given dose level, enrollment commences to the next "A" dose level. If there is more than 1 dose limiting toxicity 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 dose limiting toxicities observed in dose level 2A, the next cohort to enroll is dose level 2B).

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

A 6 week dose limiting toxicity evaluation window, that includes a two week priming phase for MM- 151 plus a four week cycle 1, is employed for dose escalation decisions in Part 1 of the study.

Decisions to escalate the dose to a new cohort of patients can be made by mutual agreement during a dose escalation meeting. These meetings serve as a forum for the review of safety and other relevant data that is needed to assess the safety profile of the patients who have completed the 6 week dose limiting toxicity window. Decisions to escalate to the next dose are documented along, with a summary of the information supporting the decision.

Decisions to escalate the dose for a new cohort of patients are made after the third patient in a cohort has completed the 6 week dose limiting toxicity window and the criteria for maximum tolerated dose have not been met. Available data from a potential fourth patient can be considered. Escalation decisions are based on safety data for the dose cohort under evaluation. Immunogenicity and pharmacokinetic data can be evaluated, but is not be required for decisions on dose escalation. In addition, safety data from ongoing patients in previous cohorts can be included in such dose escalation reviews. This includes data regarding serious adverse events or CTCAE 4.02 grade 3-4 drug-related events. Patients that are discontinued from the study for reasons that were not due to drug related toxicities, and received less than four doses of MM-151 and two doses of MM-121, are replaced for purposes of assessing safety for a dose escalation decision.

4. Definition and Management of Dose Limiting Toxicity (DLT)

For MM- 151 and MM- 121 administered in combination, the following adverse events are considered dose limiting if they occur within six weeks of the date of first dose of study drug, and the relatedness is possible, probable or definite with regards to the combination:

1. Any related grade 4 non-hematologic or hematological toxicity; 2. > CTCAE Grade 3 hyponatremia, hypokalemia, hypomagnesemia, hypophosphatemia that persists > 5 days despite maximal medical management;

3. Any related grade 3 non-hematologic toxicity (except fatigue/asthenia < 2 weeks in duration, grade 3 rash which persists despite optimal management and persists for > 7 days, or alkaline phosphatase changes; vomiting or diarrhea are only considered dose limiting if they last > 48 hours and were treated with an optimal anti-emetic or anti- diarrheal regimen respectively);

4. Any grade > 3 thrombocytopenia and/or neutropenia;

5. A grade 4 infusion related reaction after the first MM-151 administration;

6. Grade 3 or 4 infusion reactions which occur despite optimal medical management and premedication with glucocorticoid, antihistamine and acetaminophen therapy and despite adherence to the outlined infusion schedule; or

7. Any related toxicity that delays treatment by > 28 days.

Ordinarily a patient who experiences a dose-limiting toxicity does not receive additional doses of MM-151 or MM-121 and is removed from the study. If there is evidence that a patient who experiences a dose limiting toxicity has also derived clinical benefit from treatment with the MM-151 and MM-121, then the specifics of the case are reviewed. Such a patient may continue on study at a lower dose level if the consensus judgment is that continued treatment is in the patient' s best interest. Patients should have recovered from toxicity to baseline (except alopecia) prior to re-treatment.

The maximum tolerated dose is defined as the highest dose level at which a dose limiting toxicity is experienced by fewer than 2 patients in a cohort of 3 to 6 patients. If a patient experiences a treatment-related toxicity that qualifies as a dose limiting toxicity, up to 3 additional patients are enrolled at that dose level, for no more than 6 total patients. If no additional dose limiting toxicities are observed, the dose escalation resumes. If a second patient experiences a treatment-related toxicity that qualifies as a dose limiting toxicity at that dose, that dose is considered the toxic dose. The maximum tolerated dose is then defined as the next lower dose level and an additional 3 patients are enrolled (for a total of 6) to ensure that < 1 patient out of 6 experienced a treatment-related toxicity that qualifies as a dose limiting toxicity. If a maximum tolerated dose is not declared, a recommended Phase 2 dose is determined by assessing the overall safety and tolerability, pharmacokinetic,

pharmacodynamic and preliminary clinical activity.

5. Patient selection and Discontinuation

a. Inclusion and Exclusion Criteria

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 post-treatment biopsy

• Willing to provide recent tumor tissue block (or slides) to assess heregulin mRNA levels and other pathway biomarkers

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

• 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:

• Serum total bilirubin < 1.5 x ULN

• Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and Alkaline Phosphatase < 2.5 x ULN (< 5 x ULN is acceptable if 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:

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

• ECG without clinically significant abnormalities including prolonged QTc interval < 450 msecs.; Abnormal ECG is acceptable if principle 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 (e.g. double barrier method). This applies to women of childbearing potential as well as fertile men and their partners.

• At least 18 years of age

• Able to provide informed consent, or have a legal representative able and willing to do so.

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

• Pathologically documented, definitively diagnosed, advanced solid tumor that is refractory to standard treatment, for which no standard treatment is available or the patient refuses standard therapy.

• 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)

In addition to meeting the above criteria, patients in Part 2 of the study 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

• Wild type KRAS gene 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 Patients must meet all the inclusion 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. At the discretion of the investigator, patients with tumor fever can be 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 is 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 or MM- 121.

• Presence of any other contraindications for cetuximab or panitumumab.

• Any prior exposure to MM-151, MM-121 or other ErbB3 antibody.

• 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 CTCAE 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 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

b. Assessing Heregulin Status in Tumor Specimens

In both parts of the study, only patients that are heregulin positive are enrolled. A patient's tumor heregulin status is analyzed at a central CLIA certified lab using a qualified RNA in situ hybridization (RNA-ISH) assay. To be considered heregulin positive, patients must be > 1+ by ISH.

c. Description ofHRG RNA-ISH Assay

RNA-ISH is a test in which oligonucleotide target probes are hybridized to the RNA in formalin-fixed, paraffin-embedded (FFPE) tissue samples. The signal on the target RNA molecule is detected by using a chromogenic substrate reaction. This approach enables mRNA molecules to be visualized and scored by pathologists in a manner similar to a standard immunohistochemistry assay.

The heregulin RNA-ISH assay can measure mRNA expression on tissue slides obtained from recent tumor tissue blocks, core biopsies or fine needle aspirates. Any of these methods of collection are therefore acceptable for testing, as long as the patient did not receive intervening systemic therapy between the time of tissue collection and screening for this study. Clinical trial specimens are submitted directly by clinical sites to a certified facility, in 70% ethanol.

The facility processes the samples and provides the stained slides to a trained pathologist to assess tumor content and percentage of tumor cells expressing heregulin mRNA. The pathologist assigns scores of 0, 1+, 2+ or 3+ based on heregulin mRNA staining. Samples scored at > 1+ are considered heregulin positive, and samples scored at 0 are considered heregulin negative. The results are communicated back to the investigative site within 7 days of site shipment date.

d. Patient Discontinuation

Patients can withdraw from the study at any time and for any reason. Some possible reasons for early withdrawal include, but are not limited to the following:

· Progressive neoplastic disease;

• The patient experiences a dose-limiting toxicity; The patient experiences a non-dose limiting adverse event which precludes further participation in the trial;

Development of an intercurrent medical condition or need for concomitant treatment which precludes further participation in the trial;

Patient withdraws consent to continue participation;

The Investigator removes the patient from the trial in the best interests of the patient;

Study termination by the Sponsor;

Use of prohibited concomitant medications; or

Patient is lost to follow up;

If a patient withdraws from the trial, attempts should be made to contact the patient to determine the reason(s) for discontinuation. All procedures and evaluations required by the 30 day follow up visit are completed when a patient is discontinued. All patients who discontinue the trial as a result of an adverse event are followed until resolution or

stabilization of the adverse event.

6. Investigational Products and Study Treatment

Investigators and Pharmacy staff reference the study Pharmacy Manual for comprehensive instructions regarding required storage, accountability, dosing preparation and administration of the study drugs. The information in the Pharmacy Manual is summarized in the following sections.

a. MM-121

MM-121 is supplied in sterile, single-use vials containing 10.1 mL of MM-121 at a concentration of 25 mg/ml in 20 mM histidine, 150 mM sodium chloride, and pH 6.5. MM- 121 appears as a colorless liquid solution and may contain a small amount of visible, white, amorphous, MM-121 particulates.

MM-121 is stored refrigerated (2 to 8°C, 35.6 to 46.4°F) with protection from light. Light protection is not required during infusion. MM-121 is not frozen. The pharmacy is provided with expiration dates for stored MM-121. Stability data are generated on a continual basis and the expiration date is continually updated by notification to the pharmacy.

Twenty vials of MM-121 are packaged in a cardboard container. The individual vials, as well as the outside of the cardboard container, are labeled in accordance with local regulatory requirements. MM-121 is administered as an intravenous infusion once every 2 weeks as a fixed dose. Administration of MM-121 requires multiple vials, all of which come from the same lot number. MM-121 is brought to room temperature prior to mixing with saline. Vials of MM- 121 are not shaken. The appropriate quantity of study drug is removed from the vial, diluted in 250 mL of 0.9% normal saline and administered over 60 minutes (+15 minutes) for all infusions, in the absence of infusion reactions, using a low protein binding 0.22 micrometer in-line filter. The line is flushed before and after the study drug infusion. Study drug is not administered as a bolus or a push.

On weeks when MM-121 and MM-151 are dosed together, MM-121 is dosed first, followed by MM-151.

b. MM-151

MM-151 is stored refrigerated (2 to 8°C, 35.6 to 46.4°F) and protected from light. MM-151 diluted in saline can be held at room temperature for up to 4 hours before infusion. MM-151 is not frozen. The pharmacy is provided with expiration dates for stored MM-151. Stability data are generated on a continual basis and the expiration date is continually updated by notification to the pharmacy. Vials of MM-151 are not used beyond their date of stability.

Twenty vials of MM-151 are packaged in a cardboard container. The individual vials, as well as the outside of the cardboard container, are labeled in accordance with local regulatory requirements.

30-90 minutes prior to the MM-121 infusion, patients are administered their MM-151 premedication (on days when MM-121 is not administered, MM-151 premedication is administered 30-90 minutes prior to MM-151 infusion) with one of the following:

· acetaminophen 650 mg PO or IV

• diphenhydramine 25-50 mg PO or IV or

• methylprednisolone (SOLUMEDROL) 125 mg IV

If the patient is tolerating MM-151 infusion well, investigators consider the possibility of tapering or discontinuing premedications.

The first two doses of MM-151 are administered during a two week priming phase.

The first priming dose is given as a fixed dose of 225 mg in week 1 and the second priming dose is given as a fixed dose of 450 mg in week 2 (Table 2). Subsequent dose levels are given as per the dose level defined for Cycle 1.

Table 2: MM-151 Administration Schedule

Priming Phase precedes Cycle 1 only and doses are given as fixed doses.

mpk: Note cycle 1 and subsequent weekly doses of MM-151 are the mg/kg dose level of the current cohort.

The MM-151 infusion rate are increased over time as outlined in Table 3 below.

Table 3: MM-151 Administration Rates

Regardless of whether the infusion schedule contains a priming phase

MM-151 is brought to room temperature prior to administration. Vials of MM-151 are not shaken. The appropriate quantity of MM-151 is removed from the vial, diluted to a final concentration of 2 mg/ml in 0.9% normal saline and administered according to the infusion rate in Table 4. MM-151 is administered using a low protein binding 0.22 micrometer in-line filter. The line is flushed before and after MM- 151 infusion. MM- 151 is not administered as a bolus or a push.

A patient' s body weight at the start of a cycle (or Priming Phase), at a minimum, is used to calculate the dose used throughout the cycle. If site-specific policies advise more frequent measurement of a patient's body weight to calculate dose, that is acceptable. Should a patient' s body weight change by 10%, as compared to Day 1 of the current cycle, a new total dose is calculated to reflect this change.

Patients are monitored for 1 hour following MM- 151 infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., Epinephrine, corticosteroids, intravenous antihistamines, bronchodilators and oxygen). Longer monitoring is required to confirm resolution of the event in patients requiring treatment for infusion reactions.

7. Management of Infusion Reactions and Other Toxicities

Infusion reactions are defined according to the National Cancer Institute CTCAE, Version 4.0 (Table 4).

Table 4: NCI CTCAE Grading for Infusion Reactions

Study site policies or the following treatment guidelines are used for the management of infusion reactions.

1

Maintain infusion rate unless progression of symptoms to > Grade 2; if symptoms worsen, refer to guidelines below

Consider additional medication with diphenhydramine 25-50 mg by mouth (PO) or prn, methylprednisolone 125 mg (or equivalent ) IV prn • Monitor patient every 15 minutes for worsening of condition

Grade 2

• Interrupt infusion and per investigator's discretion, disconnect infusion tubing from subject

· Administer additional medication with diphenhydramine 25-50 mg by mouth (PO) or

IV prn, methylprednisolone 125 mg (or equivalent ) IV prn

• Monitor patient every 15 minutes for worsening of condition

• After recovery from symptoms, resume infusion rate at 50% of the previous rate and if no further symptoms appear, gradually increase rate until infusion is completed · If grade 2 symptoms recur, disconnect infusion tubing from patient and do not restart infusion

• If all symptoms have resolved after 7 days, the patient may be rechallenged with MM- 151 and MM- 121

• If symptoms worsen to > grade 3 at any time, follow guidelines below

Grade 3

• Interrupt infusion and disconnect infusion tubing from subject

• Administer diphenhydramine 25-50 mg IV

• Administer normal saline, epinephrine (0.2-0.5 mL of a 1: 1000 dilution (0.2-0.5 mg) SQ or EVI and bronchodilators (nebulized albuterol 2.5-5 mg in 3 mL of saline) as medically indicated

• Consider additional medication with methylprednisolone 125 mg (or equivalent ) IV prn

• Monitor patient every 15 minutes for worsening of condition

• Report as Adverse Event of Special Interest (AESI)

· If the patients symptoms improve and they are discharged, advise patient to seek

emergency treatment and notify investigator/clinic if the infusion reaction symptoms recur after discharge from the clinic

Depending on the severity and persistence of the reaction, investigators can consider re- treatment of MM- 151 + MM- 121.

Grade 4

• Interrupt infusion and disconnect infusion tubing from subject • Administer diphenhydramine 50 mg IV

• Consider additional medication with methylprednisolone (or equivalent ) IV up to 0.5 mg/kg Q 6h) to prevent recurrent or ongoing reactions

• Monitor patient every 15 minutes for worsening of condition

• Consider hospital admission for observation

• Report as Serious Adverse Event

Do not re-administer MM-151 or MM-121 and remove patient from study.

For all patients who experience an infusion reaction, anti-MM-151 and anti-MM-121 antibody assays are obtained within 24 hours following the event. Patients experiencing severe Grade 4 hypersensitivity reactions to MM-151 or MM-121, despite the use of premedication, are not re-challenged. Such reactions, including hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema or generalized urticaria, require immediate discontinuation of MM-151/MM-121 and aggressive symptomatic therapy, in accordance with institutional practice and investigator discretion.

a. Management of Other Toxicities

Serum electrolytes from a recent pre-study collection, including magnesium, potassium and calcium, are checked on the day of infusion and repleted as necessary.

Electrolyte monitoring is continued per the Schedule of Assessments. Electrolytes are replaced as necessary. Isolated, clinically non- significant electrolyte abnormalities do not require dose reduction.

Investigators should follow Institutional policies or the following guidelines for the management of hypomagnesemia (see, e.g., M. Fakih et al., Curr. Oncol., Jul, (Suppl 1): S 18-S30 (2010); and Saif, M. W. Management of Hypomagnesemia in Cancer Patients Receiving Chemotherapy. J Support Oncol 6, 243-248 (2008)).

• Grade 1: Monitor electrolytes per schedule of assessments and if hypomagnesemia worsens, follow guidelines below.

• Grade 2: Weekly IV replacement (4g of Mg Sulfate) is recommended. • Grade > 3: At a minimum of twice per week, IV replacement is administered with 6 to lOg of Mg Sulfate. MM- 151 is held until improvement and the investigator should consider a dose reduction when dosing is resumed.

b. EGFR-Related Toxicity

Acneiform rash and other dermatologic toxicities (skin drying, paronychial inflammation, keratitis) are common toxicities of EGFR-targeted treatment. Patients are monitored throughout the course of therapy for skin and soft tissue toxicities and

inflammatory or infectious sequelae. Patients are advised to limit sun exposure during treatment and up to two months following treatment. Investigators follow institutional policies or the general guidelines provided below for dermatologic care during anti-EGFR therapy.

For severe (> Gr 3) dermatologic toxicity, investigators consult with an experienced dermatologist.

c. General Recommendations for Dermatologic Care for Patients

Receiving Anti-EGFR Therapy

General recommendations for dermatologic care for patients receiving anti-EGFR therapy are described by by Lacouture, M. E. et al. (Support. Care Cancer 19, 1079-95 (2011)), Potthoff, K. et al. (Ann. Oncol. 22, 524-35 (2011)), and Abdullah, S. E., Haigentz, M. & Piperdi, B. (Chemother. Res. Pract. 2012, 351210 (2012)) and summarized in brief below.

Gentle soaps and shampoos are used for personal hygiene. Only clean and smooth towels are used to diminish risk of skin infection. Manicuring is done (e.g. nail-cutting) with care and cuticle cutting is avoided to decrease the risk of nail bed infection. Sunscreen is applied daily to exposed areas regardless of season. Hypoallergenic sunscreens with high SPF (at least SPF30, PABA-free, UVA/UVB protection) are used. Sun is avoided, protective clothing is worn, and head cover is used. The skin is moisturizedas anti-EGFR therapy is initiated. Hypoallergenic moisturizing creams, ointments, and emollients are used once daily to smooth skin, and to prevent and alleviate dryness. To prevent paronychia, Patients keep their hands dry and out of water as much as possible. Pressure or friction on the nail fold is avoided, as well as picking or manipulating the nail. Topical application of petrolatum is recommended around the nails due to lubricant and smoothing effects on the skin. d. General Recommendations for Treatment of Dermatologic Toxicities Related to Anti-EGFR Therapy

Tables 5 - 8 summarize treatment guidances for dermatologic toxicities related to anti-EGFR therapies,

able 5: Acneiform Rash Treatment Guidance

Table 6: Dry Skin / Xerosis Treatment Guidance

• Limiting self-care ADL Body: emollient or emollient with urea

BID or salicylic acid 6% cream BID Eczematous areas of body: topical steroid of moderate strength

'able 7: Pruritus Treatment Guidance

Symptoms Treatment

CTCAE Grade 1

• Mild or localized Topical steroid moderate strength BID or

• Topical intervention indicated topical antipruritic BID

CTCAE Grade 2

• Intense or widespread Topical steroid moderate strength BID or

• Intermittent topical antipruritic BID

• Skin changes from scratching (e.g. Oral antihistamine

edema, papulation, excoriation,

lichenification, oozing/crusts)

• Oral intervention indicated

• Limiting instrumental ADL

CTCAE Grade > 3

• Intense or widespread Oral antihistamine

• Limiting self-care ADL or sleep GABA agonist (gabapentin 300 mg or

• Oral corticosteroid or pregabalin 50-75 mg every 8 hours) or immunosuppressive therapy doxepin (25-50 mg every 8 hours) indicated

'able 8: Paronychia Treatment Guidance

Symptoms Treatment

CTCAE Grade 1

• Nail fold edema or erythema Topical antibiotic BID and vinegar soaks

• Disruption of the cuticle

CTCAE Grade 2

• Localized intervention indicated Topical antibiotic BID and vinegar soaks

• Nail fold edema or erythema with Topical silver nitrate weekly

pain

• Associated with discharge or nail

plate separation

• Limiting instrumental activities of

daily living (ADL)

CTCAE Grade > 3

• Surgical intervention or IV Topical antibiotic BID and vinegar soaks antibiotics indicated Topical silver nitrate weekly

• Limiting self-care ADL Consider nail avulsion/removal

Mucositis/Stomatitis Mouth ulcers, stomatitis and oral mucositis have been seen with the treatment of MM- 151 and can occur with the combination of MM-151 and MM- 121. The following is an example of an oral solution to be administered to prevent oral mucositis: a salt and baking soda swish and spit QID, followed by a special mouthwash rinse QID prepared by the local pharmacy (16 oz recipe. - 480 ml: 320 ml Benadryl oral solution, 2 grams tetracycline powder, 80mg hydrocortisone (20mg tablets (4) crushed into solution), 40ml Nystatin suspension, Q.S with water).

The following are guidelines for the management of these toxicities.

• For Grade 1 oral mucositis/mouth ulcers, treat with non-alcoholic mouthwash or salt water several times a day.

• For Grade 2-3 oral mucositis/mouth ulcers, treat with topical analgesic mouth

treatments with or without topical corticosteroids. Agents containing hydrogen peroxide, iodine, and thyme derivatives tend to worsen mouth ulcers and are avoided. Anti-fungal agents are avoided unless a fungal infection is diagnosed, in which case topical antifungal agents are preferred.

• For Grade 4 oral mucositis/mouth ulcers, treatment with MM-151 + MM-121 is

discontinued. If treatment is held for any other grade 3 or 4 toxicity and the time required for recovery from toxicity is more than one Cycle (28 days), a patient's continuation on study is discussed regarding risks and benefits of continued treatment.

Other Toxicities Related to MM-151 and/or MM-121

Following the 6 week dose limiting toxicity window, MM-151 and MM-121 therapy is held for up to 28 days to allow for recovery from toxicity. If a patient does not recover from toxicity within 28 days, the patient's continuation on study is discussed regarding risks and benefits of continuation. During the dose limiting toxicity evaluation window, if a patient experiences a toxicity requiring more than one held doses (e.g. one week off treatment), the patient's continuation is discussed and the event is evaluated for dose limiting toxicity criteria.

In case a patient's MM-151 or MM-121 dose is reduced due to an adverse event, it remains reduced for the remainder of the study. Re-escalation to a previous level is not permitted.

g. Dosing Adjustments as A Result of Toxicity

In the event of intolerable toxicities that are possibly related to MM-151 or MM-121 treatment, Investigators use discretion in deciding whether to continue the current treatment. If treatment is held and the time required for recovery from toxicity is more than 28 days, a patient's continuation on study is discussed regarding risks and benefits of continued treatment. If the patient continues on study, dose reductions of MM-121 and MM-151 are considered. For MM-121, a typical dose reduction schedule is from 2 to 1.5 to 1 to 0.75 to 0.5 g. For MM-151, a typical dose reduction schedule is from 10.5 to 9 to 7.5 to 6 to 3 mg/kg.

For Grade 3-4 toxicities that are possibly related to MM-151 or MM-121 treatment, dosing is held for up to 28 days to allow for recovery of toxicity to < Grade 1 or baseline or less. If the toxicity has not resolved after holding treatment for 28 days, the patient is discontinued from the study.

h. Guidance for MM-151 Dose Adjustment for Acneiform Rash and Other Skin Reactions

In patients with Grade 1 or 2 skin toxicity, treatment continues without dose modification. For dermatologic toxicities that are grade 3 or higher or are considered intolerable, MM-151 is discontinued and the dose modification guidelines in Figure 4 are followed.

8. Concomitant Therapy

All intercurrent medical conditions and complications of the underlying malignancy are treated at the discretion of the Investigator according to acceptable local standards of medical care. Patients receive analgesics, antiemetics, antibiotics, anti-pyretic s, and blood products as necessary. All concomitant medications, including transfusions of blood products, are recorded on the appropriate page of the case report form.

9. Prohibited Therapy

The following therapies are not permitted in this study:

· Other anti-neoplastic therapy, including cytotoxics, targeted agents or other antibodies

(patients on long-term GnRH analogues can continue on these while on study).

Sponsor approval is required for patients receiving denosumab for treatment of bone metastasis.

• Radiotherapy (patients who require a short course of palliative radiotherapy can

continue on the study after discussion between the Investigator and Sponsor)

• Steroids are only be permitted as required per premedication regimens and on a case by case basis requiring approval by the Sponsor prior to initiation of treatment (examples include asthma, COPD), and as part of a premedication regimen for study treatment. Stable doses of corticosteroids e.g. 5 mg of prednisone or equivalent are permitted for the management of CNS metastasis and do not require sponsor approval. Other permitted uses of corticosteroids include topical cutaneous, ophthalmic, nasal and inhalational steroids.)

• Any other investigational therapy is not permitted.

10. Study Procedures

A medical history includes all pertinent prior medical conditions, surgeries or other medical procedures. Vital signs include weight, resting blood pressure, pulse, respiratory rate and temperature.

The ECOG Performance Score is by questioning the patient about their functional capabilities. The ECOG scale is described in Table 9.

Table 9: ECOG Performance Scores

A 12 lead ECG includes a description of the cardiac rate, rhythm, interval durations and an overall impression.

The Fridericia Formula is used to calculate the QTc interval. Fridericia's formula is a clinical correction formula for determining the heart-rate corrected QT interval, where QTF is the QT interval corrected for heart rate, the RR is the interval (in seconds) between QRS complexes, and QT is measured in milliseconds. Fridericia's formula takes the cube root of RR. The Fridericia Formula is as follows:

QT

'^■ F

V "/RR A multiple gated acquisition scan or echocardiogram is performed to determine ejection fraction. The same procedure (MUGA or Echo) is performed during Screening to determine the ejection fraction should be employed at subsequent visits. MUGA or

Echocardiogram is performed post-screening for any study subject who develops symptoms consistent with new onset of congestive heart failure.

Tumor response is evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Eisenhauer, E. et al. (2009). New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European Journal of Cancer (Oxford, England : 1990), 45(2), 228-47. doi: 10.1016/j.ejca.2008.10.026) to establish disease progression by computerized tomography or magnetic resonance imaging (MRI). In addition, other radiographic or scintigraphic procedures (such as radionuclide bone scans), as deemed appropriate by the Investigator, re performed to assess sites of neoplastic

involvement. The same method of assessment is used throughout the study. Investigators select target and non-target lesions in accordance with RECIST vl. l guidelines. Follow up measurements and overall response are in accordance with these guidelines. To assign a status of confirmed PR or CR, changes in tumor measurements are confirmed by repeated assessments that are performed >30 days after the criteria for response are first met.

The extent of disease assessment is completed until it has been determined the patient has progressive disease (in accordance with RECIST vl. l). In the event the patient discontinues study treatment for reasons other than disease progression, an extent of disease assessment is completed as soon as possible relative to the date of study termination to ensure disease progression is not present and to assess overall disease status. In such patients, this assessment occurs no later than the date of the 30 day follow up visit.

A complete blood count (CBC) includes a white blood count (WBC) and differential, hemoglobin, hematocrit and platelet count.

A coagulation profile includes a partial thromboplastin time (PTT) and an

international normalized ratio (INR).

Serum chemistry includes BUN, serum creatinine, glucose, bilirubin, AST, ALT, alkaline phosphatase, LDH, uric acid, total protein, albumin, calcium, magnesium, phosphate and electrolytes. The required screening electrolytes are potassium, magnesium, calcium, and phosphate. During study treatment, the required electrolytes are potassium, calcium, and magnesium. Carcinoembryonic antigen (CEA) is a protein biomarker tested for in blood serum. This protein is typically produced in fetal development and production ends before birth. This biomarker in adults has been associated with some forms of cancer, including CRC, where it is a routine measure of disease burden.

A urinalysis include descriptions of color and clarity; pH; specific gravity; and analyses of hemoglobin, glucose, ketones and total protein. A microscopic examination of the urine, to include WBC, RBC, bacteria and casts is performed if the urinalysis is abnormal.

A urine or serum pregnancy test is obtained for all females of childbearing potential. Exempt female patients include those who have undergone a bilateral oophorectomy or hysterectomy or who are menopausal (defined as absence of a menstrual cycle for at least 12 consecutive months).

Serum samples are collected to assess to determine the presence of an immunologic reaction to MM-151 or MM-121 (i.e. human anti-human antibodies; HAHA).

Pharmacokinetic Assessments: Serum samples are collected to determine the levels of each of the monoclonal antibodies that comprise MM-151 and MM-121 according to Table 10 below. Additional analytes which may impact the pharmacokinetics of MM-151 and MM-121 are also measured from this sample.

Table 10: Summary of PK Time-points

2 Immediately after the end of the infusion of MM-121 and MM-151 w/in 5 mins

Cycle 1, Weeks 4 (Only MM-151 dosed)

Sample Time-point Window

1 Immediately before the infusion of MM-151 -15 mins

Cycle 2, Week 1 (MM-121 and MM-151 both) dosed

Sample Time-point Window

1 Immediately before the infusion of MM-121 -15 mins

2 Immediately after the end of the infusion of MM-121 w/in 5 mins

3 Immediately before the infusion of MM-151 -15 mins

4 Immediately after the end of the infusion of MM-151 ±5 mins

5 +6 hours after the start of the infusion of M M-121 ±60 mins

6 +24 hours after the start of the infusion of MM-121 ±60 mins

7 +72 hours after the start of the infusion of MM-121 ±90 mins

Cycle 2, Week 2 (Only MM-151 dosed)

Sample Time-point Window

1 Immediately before the infusion of MM-151 -15 mins

Additional Cycles, Week 1

Sample Time-point Window

1 Immediately before the infusion of MM-121 -15 mins

2 Immediately after the end of the infusion of MM-121 and MM-151 w/in 5 mins

30 Day Follow Up Visit

Sample Time-point Window

1 Any time during the visit NA

Blood samples are collected to conduct exploratory studies to further characterize and correlate possible biomarkers that may help to predict or evaluate efficacy and/or toxicity. Samples are used to conduct specific biomarker analysis, or, in the event that there is remaining sample available after conducting these analyses, it is stored for future biomarker analysis related to this combination. At the time of informed consent, patients are able to refuse storage of these remaining samples.

Patients also infusion-related reaction (IRR) labs drawn at specified visits. Table 11 below details the labs and their corresponding time points.

Table 11: Time-points for IRR Collection

Patients require two formalin fixed paraffin embedded (FFPE) tumor samples during the study. The first is collected prior to dosing and the second is collected during Cycle 2, Week 1 after both MM- 121 and MM- 151 have been administered. Two passes are collected.

The schedule of assessments is set forth in Figure 5.

On Cycles when MM- 121 and MM- 151 are administered together, the pre-dosing assessments (i.e., labs, ECOG, AEs, etc) is started as early as possible to allow time to collect the last PK time-point (+6 hours after the start of the MM- 121 infusion) during normal business hours. Figure 6 is a timeline of a typical day that would allow for all assessments to be completed during normal business hours.

11. Adverse Event Reporting

An adverse event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign, including abnormal laboratory findings, symptoms, or diseases temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Worsening of a medical condition for which the efficacy of the study drug is being evaluated will not be considered an adverse event.

An unexpected adverse event is one for which the nature or severity of the event is not consistent with the applicable product information, e.g., the Investigator's brochure or Package Insert.

A serious adverse event (SAE) is any untoward medical occurrence that at any dose:

• Results in death

• Is life-threatening (an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe)

• Requires in-patient hospitalization or prolongation of existing hospitalization

• Results in persistent or significant disability/incapacity

• Is a congenital anomaly or birth defect

• Other important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed above. Examples of such events are intensive treatment in an emergency room for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development of drug dependency or drug abuse.

The term "severe" is often used to describe the intensity (severity) of an event; the event itself may be of relatively minor medical significance (such as a severe headache). This is not the same as "serious", which is based on patient/event outcome or action criteria usually associated with events that pose a threat to a patient's life or functioning,

a. Documenting Adverse Events

SAE reporting begins on the date the patient provides informed consent to participate in the study. Treatment-emergent adverse event reporting begins as of the first dose of MM- 121 and MM-151 in the priming phase.

All adverse events, whether serious or not, are recorded in the source documents and the adverse event page of the case report form (except as noted below). All new events, as well as those that worsen in intensity or frequency relative to baseline, which occur after first administration of study drug through 30 days following the last dose of study drug, are recorded. Adverse events are followed through resolution, where possible. Adverse events that are ongoing at the time of treatment discontinuation are followed through the 30 day follow up assessment. Serious adverse events are followed after the 30 day follow up assessment until resolution/stabilization or death. However, new adverse events felt by the Investigator to be related to the investigational therapies, are reported any time the

Investigator becomes aware of such an event, even if this occurrence is more than 30 days after the last dose of study drug.

Laboratory, vital signs, ECG abnormalities, or progressive disease are recorded as Adverse Events only if they are medically relevant: symptomatic, requiring corrective treatment, leading to discontinuation and/or fulfilling a seriousness criterion.

Information reported in the description of each adverse event includes:

• A medical diagnosis of the event (if a medical diagnosis cannot be determined, a description of each sign or symptom characterizing the event should be recorded)

• The date of onset of the event

· The date of resolution of the event

• A determination of whether the event is serious or not • Action taken: none; change in the study drug administration (e.g., temporary interruption in dosing); drug treatment required; non-drug treatment required;

hospitalization or prolongation of hospitalization required (complete serious adverse event page); diagnostic procedure performed; patient discontinued from the study (complete Final Visit Section of the case report form)

• Outcome: resolved without sequelae; resolved with sequelae; event resolving; event ongoing; subject died (notify the Sponsor immediately, and complete the Serious Adverse Event page and the Final Visit section of the case report form).

b. Reporting Serious Adverse Events

All fatal or life-threatening adverse events or adverse event of special interest (AESI; e.g. events meeting the definition of a dose limiting toxicity) are reported to the Sponsor's medical monitor or designee immediately by telephone or e-mail. Within 24 hours of the event, the Serious Adverse Event Form is faxed to the Drug Safety Manager whether full information regarding the event is known or not. Additional follow-up by the Investigator is required if complete information is not known. Source documentation of all examinations, diagnostic procedures, etc., which were completed with respect to the event are included with the SAE form. Care is taken to ensure that the patient's identity is protected and the patient's identifiers (as assigned at the time of study enrollment) are properly mentioned on any copy of source document provided to the Sponsor. For laboratory results, normal ranges are included.

In case of accidental or intentional overdose of MM-151 or MM-121, even if asymptomatic or not fulfilling a seriousness criterion, the overdose is reported to the Sponsor immediately (within 1 working day) using the AE and SAE forms. Overdose of MM-151 or MM-121 is defined as > 133% of planned dose of MM-151 or MM-121.

All other serious adverse events are reported to the Drug Safety Manager within 24 hours by phone, e-mail or fax. The Serious Adverse Event Form is be faxed to the Drug Safety Manager within 24 hours of the event whether full information regarding the event is known or not. Additional follow-up by the Investigator is required if complete information is not known.

The medical monitor is contacted as deemed necessary by the site. Current contact information is maintained at the site within the regulatory binder. All SAEs are evaluated by the Sponsor's medical monitor. If meeting the

requirements for expedited reporting, the Sponsor will report the adverse event to all regulatory authorities with jurisdiction over ongoing trials with the study drug and to all other Investigators involved in clinical trials with the study drug. The Investigator is responsible for reporting all SAEs to the appropriate IRB/EC.

12. Determining the Severity and Relatedness of Adverse Events

Each adverse event wis graded according to the NCI CTCAE V 4.02, which is found at http://ctep.cancer.gov/reporting/ctc.html. For events not listed in the CTCAE, severity is designated as mild, moderate, severe or life threatening or fatal which correspond to Grades 1, 2, 3, 4 and 5, respectively on the NCI CTCAE, with the following definitions:

• Mild: an event not resulting in disability or incapacity and which resolves without intervention;

• Moderate: an event not resulting in disability or incapacity but which requires intervention;

• Severe: an event resulting in temporary disability or incapacity and which requires intervention;

• Life-threatening: an event in which the patient was at risk of death at the time of the event; and

• Fatal: an event that results in the death of the patient.

a. Relatedness to MM- 151 plus MM-121

The Investigator attempts to determine if there exists reasonable possibility that an adverse event is related to the use of one or more study drugs, according to the following guidelines:

The Investigator attempts to determine if an adverse event is in some way related to the use of any study drug. This relationship is described as follows:

• Unrelated: This category is applicable to those AEs that are clearly due to extraneous causes (concurrent drugs, environment, etc.) and/or the clinically plausible temporal sequence is inconsistent with the onset of the event and the administration of the study drug and do not meet the criteria for drug relationship listed under UNLIKELY, POSSIBLY, PROBABLY, DEFINITELY RELATED or UNKNOWN.

• Unlikely: The event is clearly due to causes distinct from the use of the study drug, such as a documented pre-existing condition, the effect of a concomitant medication a new condition which, based on the pathophysiology of the condition, and the pharmacology of the study drug, would be unlikely related to the use of the study drug

• Possible: The event follows a reasonable temporal sequence from administration of the study drug and the event follows a known response pattern to the study drug BUT the event could have been produced by an intercurrent medical condition which, based on the pathophysiology of the condition, and the pharmacology of the study drug, would be unlikely related to the use of the study drug or the event could be the effect of a concomitant medication

• Probable: The event follows a reasonable temporal sequence from administration of the study drug and the event follows a known response pattern to the study drug AND the event cannot have been reasonably explained by an intercurrent medical condition which or the event cannot be the effect of a concomitant medication

• Definite: The event follows a reasonable temporal sequence from administration of the study drug, the event follows a known response pattern to the study drug and based on the known pharmacology of the study drug, the event is clearly related to the effect of the study drug

• Unknown: Based on the evidence available, causality cannot be ascribed

b. Reporting and Follow -Up of Pregnancy

Patients who become pregnant while on study discontinue MM- 151 and MM- 121, and the pregnancy is immediately reported to the medical monitor. Pregnancies occurring up to 90 days after the completion of the study medication are also reported to the Sponsor.

Monitoring of the patient continues until conclusion of the pregnancy.

In the event of a pregnancy occurring in the partner of a male patient participating in the study, the pregnant partner is requested to report the pregnancy to the Sponsor. The partner is informed of the risks of continuing with the pregnancy, the possible effects on the fetus, and is followed until conclusion of the pregnancy.

13. Data Management and Statistical Analysis

All data for the patients recruited for the trial re entered into electronic case report forms supplied by the Sponsor. The data for the patients who screen-failed from the study is not be entered into the database. Only authorized staff enter data onto the case report forms (CRFs). If an entry error is made, the corrections to the CRFs are made according to CRF guidelines by an authorized member of the site staff. Electronic case report forms are checked for correctness against source document data by the Sponsor' s monitor. If any entries into the CRF are incorrect or incomplete, the monitor asks the Investigator or the study site staff to make appropriate corrections, and the corrected CRF is reviewed for completeness and consistency. Any discrepancies are noted in the CRF system by means of electronic data queries. Authorized site staff are asked to respond to all electronic queries according to the CRF guidelines.

a. Sample Size: Dose Escalation Phase (Part 1 )

The total number of patients enrolled in the Dose Escalation Phase depends on the number of dose cohorts required to identify the maximum tolerated dose or recommended Phase 2 dose. Escalation to the next dose cohort depends on the background toxicity rate (i.e., probability of dose limiting toxicity at a given dose). When 1 of 3 patients develops a dose limiting toxicity and the cohort is expanded to 6 subjects, the proposed plan for dose escalation provides a 91% probability that dose escalation proceeds at doses associated with dose limiting toxicity probability of <10%. Table 12 below shows the probability of escalation from cohort to cohort with various toxicity rates.

Table 12: Probability of Escalation to Next Cohort in the Dose Escalation Phase

b. Expansion cohort Phase (Part 2)

In the Expansion Cohort, 14 cetuximab-refractory metastatic colorectal patients that are KRAS wild-type are enrolled. A sample size of 14 patients provides additional safety, PK, and pharmacodynamic information at the selected dose level, as well as provides biomarker data sufficient to provide a population mean and measure of variance that may guide the design of future trials.

If the true dose limiting toxicity rate at the maximum tolerated dose is 10-20%, there is a 77-96% probability of observing at least 1 dose limiting toxicity in the 14 patient expansion cohort (Table 13). If more than 1 dose limiting toxicity is observed and the dose limiting toxicity rate is greater than 33% in the expansion cohort, further enrollment to the cohort is stopped and the safety and PK data is reviewed to determine how further dosing will proceed. If it is decided that a new dose should be investigated, 14 additional patients are enrolled at that dose.

Table 13: Probability of Observing a DLT in the Expansion Cohort

c. Statistical Analysis

Categorical variables are summarized by frequency distributions (number and percentages of patients) and continuous variables are summarized by descriptive statistics (mean, standard deviation, median, minimum, maximum). Both efficacy and safety analyses re performed using all the patients who received at least one infusion of both MM-151 and MM-121.

d. Demographics and Baseline Characteristics

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

e. Efficacy Analysis

Objective response rate and 95% exact confidence intervals are analyzed. Disease control rate (DCR) at 8, 16 and 24 weeks, where DCR = PR + CR + SD, are described using RECISTvl.l. Progression free survival is also analyzed. PFS is defined as the time from randomization to the first documented radiographical progression of disease using RECIST vl.l (based on investigator assessment) or death from any cause, whichever comes first.

f. Safety Analysis

Treatment emergent adverse events are presented by treatment cohort, by patient, by NCI CTCAE version 4.0 grade and by MedDRA system organ class. Separate listings are presented for total adverse events, serious adverse events, adverse events related to MM-151 plus MM-121 and Grade 3/4 adverse events are presented.

Laboratory data is presented by dose cohort and by visit. Abnormal laboratory values are assessed according to NCI CTCAE grade, where possible. Evaluation of QTc are based upon Fridericia's correction method. CTCAE criteria are applied to the QTcF (i.e. Grade 3 = QTc > 500 msec).

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

g. Pharmacokinetics Analysis

Pharmacokinetic parameters derived from the blood PK samples and are analyzed using descriptive statistics, including the median, mean and 95% confidence intervals around parameter estimates by dose level. At each time point, PK analyses are done for each of individual monoclonal antibody components of the oligoclonal mixture of MM- 151 (P1X, P2X and P3X), as well as by adding together the total of all three components, and separately for the monoclonal antibody MM- 121. All PK parameters include Cmax, Tmax, AUC (area under the concentration curve), clearance, volume of distribution at steady state (Vdss), and the terminal elimination half-life. Estimation of the pharmacokinetic parameters is performed using standard non-compartmental methods. All these are done for the individual components of the mixture (MM-151) and also MM-121, as deemed appropriate.

h. Pharmacodynamic and Biomarker Analysis

Archived tumor samples, recent tumor tissue, as well as fresh pre-treatment and post treatment biopsy samples are collected from each patient. Messenger RNA expression of resistance-related ligands is assessed, and may include EGFR ligands, heregulin (the ligand for ErbB3), IGF-1, IGF-2, HGF, and other resistance-related ligands. Additionally, quantitative measurements of staining by immunohistochemistry is obtained and includes an assessment of the following: EGFR (ErbB l), ErbB2 (HER2), ErbB3 (HER3), ErbB4, IGF- 1R, c-Met, and other receptors that mediate resistance. Blood samples are assessed for quantitative measurements of cytokines and other biomarkers related to ErbB and resistance signaling.

Key efficacy endpoints (e.g. disease control rate, PFS, response rate, change in tumor burden and change in blood biomarker levels) as well as safety endpoints (e.g. percent of patients experiencing Grade 3 or higher adverse event) are analyzed.

The endpoint of interest for the pretreatment and on-treatment biopsies, as well as the recent tumor tissue and archived samples, is the level of heregulin. Previous work has suggested that upregulation of heregulin levels following anti-EGFR therapy may correlate with therapeutic resistance (see, e.g.,Yonesaka, K. et al., Sci. Transl. Med. 3, 99ra86 (2011)). Therefore, to further interrogate this hypothesis, pharmacodynamic changes in levels of heregulin as assessed by RNA-ISH between the pre- and on-treatment biopsies are examined. An increase in heregulin levels, as determined by a pathologist-assessed increase in heregulin mRNA staining (or a transition from non-detectable to detectable levels) is considered significant change from baseline. Assuming a total of 14 matched sets are obtained and 50% meet this criteria, a minimum of five heregulin upregulated matched pre- and on-treatment samples is obtained with a probability of 91%. If only 25% of samples are heregulin upregulated, three heregulin positive matched samples are obtained with a probability of 72%. This small sample size still provides an initial glimpse into whether this feedback loop may exist in colorectal cancer in response to MM-151 plus MM-121 and helps determine whether monitoring heregulin pharmacodynamics is valuable in future studies. In addition to testing for heregulin mRNA, additional pharmacodynamic markers, indicative of pathway activation, are assessed in patient-matched pairs of pre- and on-treatment biopsies. These markers are measured by IHC and include p-Erk, p-Akt, p-S6, and other pathway-related proteins.

EXAMPLE 3: Leading-edge Biomarker-Selected, Multi-Arm Basket Trial that Matches Patients with Most Appropriate Combination Regimens; A Phase 1 Biomarker-directed Study Evaluating the Co-Administration of MM-151 with MM-121, MM-141, or Trametinib in EGFR-Driven Cancers;

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 ErbB 3 signaling in order to enhance the anti-tumor effect of a combination therapy partner. Seribantumab has been investigated in multiple Phase 2 and Phase 1 clinical trials covering a broad spectrum of patient populations and drug

combinations.

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, ad 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 with 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. 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.

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:

Heavy Chain of 1 EVQLLESGGG LVQPGGSLRL SCAASGFTFS HYVMAWVRQA

Antibody PGKGLEWVSS

51 ISSSGGWTLY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED Seribantumab TAVYYCTRGL

101 KMATIFDYWG QGTLVTVSSA STKGPSVFPL APCSRSTSES

Protein TAALGCLVKD

151 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSWTV PSSNFGTQTY

20.1 TCNVDHKPSN TKVDKTVERK CCVECPPCPA PPVAGPSVFL FPPKPKDTLM

251 ISRTPEVTCV WDVSHEDPE VQFNWYVDGV EVHNAKTKPR EEQFNSTFRV

301 VSVLTWHQD WLNGKEYKCK VSNKGLPAPI EKTISKTKGQ PREPQVYTLP

351 PSREEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPMLDSDG

401 SFFLYSKLTV DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS LSPGK

Light Chain of 1 QSALTQPASV SGSPGQSITI SCTGTSSDVG SYNWSWYQQ Seribantumab HPGKAPKLI I

51 YEVSQRPSGV SNRFSGSKSG NTASLTISGL QTEDEADYYC CSYAGSSIFV

Protein 101 IFGGGTKVTV LGQPKAAPSV TLFPPSSEEL QANKATLVCL

VSDFYPGAVT

151 VAWKADGSPV KVGVETTKPS KQSNNKYAAS SYLSLTPEQW KSHRSYSCRV

201 THEGSTVEKT VAPAECS

Heavy Chain gaggtgcagc tgctggagag cggcggaggg

Variable Region ctggtccagc caggcggcag cctgaggctg

tcctgcgccg ccagcggctt caccttcagc

(VH) of cactacgtga tggcctgggt gcggcaggcc

Seribantumab ccaggcaagg gcctggaatg ggtgtccagc

atcagcagca gcggcggctg gaccctgtac

DNA gccgacagcg tgaagggcag gttcaccatc

agcagggaca acagcaagaa caccctgtac

ctgcagatga acagcctgag ggccgaggac

accgccgtgt actactgcac caggggcctg

aagatggcca ccatcttcga ctactggggc

cagggcaccc tggtgaccgt gagcagc

Heavy Chain Glu Val Gin Leu Leu Glu Ser Gly Gly Gly

Variable Region Leu Val Gin Pro Gly Gly Ser Leu Arg Leu

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser

(VH) of His Tyr Val Met Ala Trp Val Arg Gin Ala

Seribantumab Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

He Ser Ser Ser Gly Gly Trp Thr Leu Tyr

Protein Ala Asp Ser Val Lys Gly Arg Phe Thr He

Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp

Thr Ala Val Tyr Tyr Cys Thr Arg Gly Leu

Lys Met Ala Thr He Phe Asp Tyr Trp Gly

Gin Gly Thr Leu Val Thr Val Ser Ser SEQ ID DESIGNATION SEQUENCE

NO:

11 I Light Chain cagtccgccc tgacccagcc cgccagcgtg

Variable Region agcggcagcc caggccagag catcaccatc

agctgcaccg gcaccagcag cgacgtgggc

(VL) of agctacaacg tggtgtcctg gtatcagcag

Seribantumab caccccggca aggcccccaa gctgatcatc

tacgaggtgt cccagaggcc cagcggcgtg

DNA agcaacaggt tcagcggcag caagagcggc

aacaccgcca gcctgaccat cagcggcctg cagaccgagg acgaggccga ctactactgc tgcagctacg ccggcagcag catcttcgtg atcttcggcg gagggaccaa ggtgaccgtc

Light Chain Gin Ser Ala Leu Thr Gin Pro Ala Ser Val Variable Region Ser Gly Ser Pro Gly Gin Ser He Thr He

Ser Cys Thr Gly Thr Ser Ser Asp Val Gly (VL) of Ser Tyr Asn Val Val Ser Trp Tyr Gin Gin Seribantumab His Pro Gly Lys Ala Pro Lys Leu He He

Tyr Glu Val Ser Gin Arg Pro Ser Gly Val

Protein Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly

Asn Thr Ala Ser Leu Thr He Ser Gly Leu Gin Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser Ser He Phe Val He Phe Gly Gly Gly Thr Lys Val Thr Val Leu

13 I Human ErbB3 Ser Glu Val Gly Asn Ser Gin Ala Val Cys

Pro Gly Thr Leu Asn Gly Leu Ser Val Thr Gly Asp Ala Glu Asn Gin Tyr Gin Thr Leu Protein Tyr Lys Leu Tyr Glu Arg Cys Glu Val Val

Met Gly Asn Leu Glu He Val Leu Thr Gly His Asn Ala Asp Leu Ser Phe Leu Gin Trp He Arg Glu Val Thr Gly Tyr Val Leu Val Ala Met Asn Glu Phe Ser Thr Leu Pro Leu Pro Asn Leu Arg Val Val Arg Gly Thr Gin Val Tyr Asp Gly Lys Phe Ala He Phe Val Met Leu Asn Tyr Asn Thr Asn Ser Ser His Ala Leu Arg Gin Leu Arg Leu Thr Gin Leu Thr Glu He Leu Ser Gly Gly Val Tyr He Glu Lys Asn Asp Lys Leu Cys His Met Asp Thr He Asp Trp Arg Asp He Val Arg Asp Arg Asp Ala Glu He Val Val Lys Asp Asn Gly Arg Ser Cys Pro Pro Cys His Glu Val Cys Lys Gly Arg Cys Trp Gly Pro Gly Ser Glu Asp Cys Gin Thr Leu Thr Lys Thr He Cys Ala Pro Gin Cys Asn Gly His Cys Phe Gly Pro Asn Pro Asn Gin Cys Cys His Asp Glu Cys Ala Gly Gly Cys Ser Gly Pro Gin Asp Thr Asp Cys Phe Ala Cys Arg His Phe Asn Asp Ser Gly Ala Cys Val Pro Arg Cys Pro Gin Pro Leu Val Tyr Asn Lys Leu Thr Phe Gin Leu Glu Pro Asn Pro His Thr Lys Tyr Gin Tyr Gly Gly Val Cys Val Ala Ser Cys Pro His Asn Phe Val Val Asp Gin Thr Ser Cys Val Arg Ala Cys Pro Pro Asp Lys Met Glu Val Asp Lys Asn Gly Leu Lys Met Cys Glu Pro Cys Gly Gly Leu Cys Pro Lys Ala Cys Glu Gly Thr Gly Ser Gly Ser Arg Phe Gin Thr Val Asp Ser Ser Asn He Asp Gly Phe Val Asn Cys Thr Lys He Leu Gly Asn Leu Asp Phe Leu He Thr Gin Gly Asp SEQ ID DESIGNATION SEQUENCE

NO:

Pro Trp His Lys He Pro Ala Leu Asp Pro Glu Lys Leu Asn Val Phe Arg Thr Val Arg Glu He Thr Gly Tyr Leu Asn He Gin Ser Trp Pro Pro His Met His Asn Phe Ser Val Phe Ser Asn Leu Thr Thr He Gly Gly Arg Ser Leu Tyr Asn Arg Gly Phe Ser Leu Leu He Met Lys Asn Leu Asn Val Thr Ser Leu Gly Phe Arg Ser Leu Lys Glu He Ser Ala Gly Arg He Tyr He Ser Ala Asn Arg Gin Leu Cys Tyr His His Ser Leu Asn Trp Thr Lys Val Leu Arg Gly Pro Thr Glu Glu Arg Leu Asp He Lys His Asn Arg Pro Arg Arg Asp Cys Val Ala Glu Gly Lys Val Cys Asp Pro Leu Cys Ser Ser Gly Gly Cys Trp Gly Pro Gly Pro Gly Gin Cys Leu Ser Cys Arg Asn Tyr Ser Arg Gly Gly Val Cys Val Thr His Cys Asn Phe Leu Asn Gly Glu Pro Arg Glu Phe Ala His Glu Ala Glu Cys Phe Ser Cys His Pro Glu Cys Gin Pro Met Glu Gly Thr Ala Thr Cys Asn Gly Ser Gly Ser Asp Thr Cys Ala Gin Cys Ala His Phe Arg Asp Gly Pro His Cys Val Ser Ser Cys Pro His Gly Val Leu Gly Ala Lys Gly Pro He Tyr Lys Tyr Pro Asp Val Gin Asn Glu Cys Arg Pro Cys His Glu Asn Cys Thr Gin Gly Cys Lys Gly Pro Glu Leu Gin Asp Cys Leu Gly Gin Thr Leu Val Leu He Gly Lys Thr His Leu Thr Met Ala Leu Thr Val He Ala Gly Leu Val Val He Phe Met Met Leu Gly Gly Thr Phe Leu Tyr Trp Arg Gly Arg Arg He Gin Asn Lys Arg Ala Met Arg Arg Tyr Leu Glu Arg Gly Glu Ser He Glu Pro Leu Asp Pro Ser Glu Lys Ala Asn Lys Val Leu Ala Arg He Phe Lys Glu Thr Glu Leu Arg Ser Leu Lys Val Leu Gly Ser Gly Val Phe Gly Thr Val His Lys Gly Val Trp He Pro Glu Gly Glu Ser He Lys He Pro Val Cys He Lys Val He Glu Asp Lys Ser Gly Arg Gin Ser Phe Gin Ala Val Thr Asp His Met Leu Ala He Gly Ser Leu Asp His Ala His He Val Arg Leu Leu Gly Leu Cys Pro Gly Ser Ser Leu Gin Leu Val Thr Gin Tyr Leu Pro Leu Gly Ser Leu Leu Asp His Val Arg Gin His Arg Gly Ala Leu Gly Pro Gin Leu Leu Leu Asn Trp Gly Val Gin He Ala Lys Gly Met Tyr Tyr Leu Glu Glu His Gly Met Val His Arg Asn Leu Ala Ala Arg Asn Val Leu Leu Lys Ser Pro Ser Gin Val Gin Val Ala Asp Phe Gly Val Ala Asp Leu Leu Pro Pro Asp Asp Lys Gin Leu Leu Tyr Ser Glu Ala Lys Thr Pro He Lys Trp Met Ala Leu Glu Ser He His Phe Gly Lys Tyr Thr His Gin Ser Asp Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ala Glu Pro Tyr Ala Gly Leu Arg Leu Ala Glu Val Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Ala Gin Pro Gin He Cys Thr He Asp Val Tyr Met Val Met Val Lys Cys Trp Met He Asp Glu Asn He Arg Pro Thr Phe Lys Glu Leu SEQ ID DESIGNATION SEQUENCE

NO:

Ala Asn Glu Phe Thr Arg Met Ala Arg Asp Pro Pro Arg Tyr Leu Val He Lys Arg Glu Ser Gly Pro Gly He Ala Pro Gly Pro Glu Pro His Gly Leu Thr Asn Lys Lys Leu Glu Glu Val Glu Leu Glu Pro Glu Leu Asp Leu Asp Leu Asp Leu Glu Ala Glu Glu Asp Asn Leu Ala Thr Thr Thr Leu Gly Ser Ala Leu Ser Leu Pro Val Gly Thr Leu Asn Arg Pro Arg Gly Ser Gin Ser Leu Leu Ser Pro Ser Ser Gly Tyr Met Pro Met Asn Gin Gly Asn Leu Gly Glu Ser Cys Gin Glu Ser Ala Val Ser Gly Ser Ser Glu Arg Cys Pro Arg Pro Val Ser Leu His Pro Met Pro Arg Gly Cys Leu Ala Ser Glu Ser Ser Glu Gly His Val Thr Gly Ser Glu Ala Glu Leu Gin Glu Lys Val Ser Met Cys Arg Ser Arg Ser Arg Ser Arg Ser Pro Arg Pro Arg Gly Asp Ser Ala Tyr His Ser Gin Arg His Ser Leu Leu Thr Pro Val Thr Pro Leu Ser Pro Pro Gly Leu Glu Glu Glu Asp Val Asn Gly Tyr Val Met Pro Asp Thr His Leu Lys Gly Thr Pro Ser Ser Arg Glu Gly Thr Leu Ser Ser Val Gly Leu Ser Ser Val Leu Gly Thr Glu Glu Glu Asp Glu Asp Glu Glu Tyr Glu Tyr Met Asn Arg Arg Arg Arg His Ser Pro Pro His Pro Pro Arg Pro Ser Ser Leu Glu Glu Leu Gly Tyr Glu Tyr Met Asp Val Gly Ser Asp Leu Ser Ala Ser Leu Gly Ser Thr Gin Ser Cys Pro Leu His Pro Val Pro He Met Pro Thr Ala Gly Thr Thr Pro Asp Glu Asp Tyr Glu Tyr Met Asn Arg Gin Arg Asp Gly Gly Gly Pro Gly Gly Asp Tyr Ala Ala Met Gly Ala Cys Pro Ala Ser Glu Gin Gly Tyr Glu Glu Met Arg Ala Phe Gin Gly Pro Gly His Gin Ala Pro His Val His Tyr Ala Arg Leu Lys Thr Leu Arg Ser Leu Glu Ala Thr Asp Ser Ala Phe Asp Asn Pro Asp Tyr Trp His Ser Arg Leu Phe Pro Lys Ala Asn Ala Gin Arg Thr

14 P1X V_H CDRl SYAIS

Protein

15 | P1X V_H CDR2 IIPIFGTVNY Protein

16 | P1X V_H CDR3 DPSVNL Protein

P1X V_L CDRl QSISSWWA Protein

18 | P1X V_L CDR2 DASSL Protein SEQ ID DESIGNATION SEQUENCE NO:

19 P1X V_L CDR3 QQYHAHP Protein

20 P2X V_H CDR1 SYAIS Protein

21 P2X V_H CDR2 IIPIFGAANP Protein

22 P2X V_H CDR3 MGRGKV Protein

23 P2X V_L CDR1 QS VLYS PNNKN YLA Protein

24 P2X V_L CDR2 WASTR Protein

25 P2X V_L CDR3 QQYYGSP Protein

26 P3X V_H CDRl SYGIN Protein

27 P3X V_H CDR2 ISAYNGNTYY Protein

28 P3X V_H CDR3 DLGGYGSGS Protein

29 P3X V_L CDRl QSVSSNLA Protein

30 P3X V_L CDR2 GASTR Protein

31 P3X V_L CDR3 QDYRTWPR Protein

32 P1X V_H MGFGLSWLFLVAILKGVQC

QVQLVQSGAEVKKPGSSVKV

Protein SCKASGGTFSSYAISWVRQA

PGQGLEWMGSIIPIFGTVNY

AQKFQGR VTIT ADES TS T A Y

MELSSLRSEDTAVYYCARDP

SVNLYWYFDLWGRGTLVTVSS SEQ ID DESIGNATION SEQUENCE NO:

33 P1X V_L MGTPAQLLFLLLLWLPDTTG

DIQMTQSPST LSASVGDRVT

Protein rrCRASQSISSWWAWYQQKP

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

34 P2X V_H MGFGLSWLFLVAILKGVQC

QVQLVQS G AE VKKPGS S VKV

Protein 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

35 P2X V_L MGTPAQLLFLLLLWLPDTTG

DIVMTQSPDSLAVSLGERAT

Protein INC KS S QS VLYS PNNKN YLA

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

36 P3X V_H MGFGLSWLFLVAILKGVQC

QVQLVQSGAEVKKPGASVKV

Protein SCKASGYAFTSYGINWVRQA

PGQGLEWMGWISAYNGNTYY

AQKLRGR VTMTTDTS TS T A Y

MELRS LRS DDT A V Y YC ARDL

GGYGSGSVPFDPWGQGTLVTVSS

37 P3X V_L MGTPAQLLFLLLLWLPDTTG

EIVMTQS P ATLS VS PGERAT

Protein 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:

38 EGFR ECD 1 MRPSGTAGAA LLALLAALCP ASRALEEKKV CQGTSNKLTQ

LGTFEDHFLS LQRMFNNCEV

61 VLGNLEITYV QRNYDLSFLK TIQEVAGYVL lALNTVERIP Protein LENLQIIRGN MYYENSYALA

121 VLSNYDANKT GLKELPMRNL QEILHGAVRF SNNPALCNVE SIQWRDIVSS DFLSNMSMDF

181 QNHLGSCQKC DPSCPNGSCW GAGEENCQKL TKIICAQQCS GRCRGKSPSD CCHNQCAAGC

241 TGPRESDCLV CRKFRDEATC KDTCPPLMLY NPTTYQMDVN PEGKYSFGAT CVKKCPRNYV

301 VTDHGSCVRA CGADSYEMEE DGVRKCKKCE GPCRKVCNGI GIGEFKDSLS INATNIKHFK

361 NCTSISGDLH ILPVAFRGDS FTHTPPLDPQ ELDILKTVKE ITGFLLIQAW PENRTDLHAF

421 ENLEIIRGRT KQHGQFSLAV VSLNITSLGL RSLKEISDGD VIISGNKNLC YANTINWKKL

481 FGTSGQKTKI ISNRGENSCK ATGQVCHALC SPEGCWGPEP RDCVSCRNVS RGRECVDKCN

541 LLEGEPREFV ENSECIQCHP ECLPQAMNIT CTGRGPDNCI QCAHYIDGPH CVKTCPAGVM

601 GENNTLVWKY ADAGHVCHLC HPNCTYGCTG

PGLEGCPTNG PKIPSHHHHH H

39 Mature P1X QVQLVQSGAEVKKPGSSVKVSCKASGGTFS

Heavy Chain SYAI SWVRQAPGQGLEWMGS I IPIFGTVNY Variable Region AQKFQGRVTITADESTSTAYMELSSLRSED

TAVYYCARDPSVNLYWYFDLWGRGTLVTVS

S

40 Mature P1X Light DIQMTQSPSTLSASVGDRVTITCRASQS I S

Chain Variable SWWAWYQQKPGKAPKLLIYDASSLESGVPS Region RFSGSGSGTEFTLTI SSLQPDDFATYYCQQ

YHAHPTTFGGGTKVEIK

41 Mature P2X QVQLVQSGAEVKKPGSSVKVSCKASGGTFG

Heavy Chain SYAI SWVRQAPGQGLEWMGS I IPIFGAANP Variable Region AQKSQGRVTITADESTSTAYMELSSLRSED

TAVYYCAKMGRGKVAFDIWGQGTMVTVSS

42 Mature P2X Light DIVMTQSPDSLAVSLGERATINCKSSQSVL

Chain Variable YSPNNKNYLAWYQQKPGQPPKLLIYWASTR Region ESGVPDRFSGSGSGTDFTLTISSLQAEDVA

VYYCQQYYGSPITFGGGTKVEIK

43 Mature P3X QVQLVQSGAEVKKPGASVKVSCKASGYAFT

Heavy Chain SYGINWVRQAPGQGLEWMGWI SAYNGNTYY Variable Region AQKLRGRVTMTTDTSTSTAYMELRSLRSDD

TAVYYCARDLGGYGSGSVPFDPWGQGTLVT VSS

44 Mature P3X Light EIVMTQSPATLSVSPGERATLSCRASQSVS

Chain Variable SNLAWYQQKPGQAPRLLIYGASTRATGIPA Region RFSGSGSGTEFTLTI SSLQSEDFAVYYCQD

YRTWPRRVFGGGTKVEIK SEQ ID DESIGNATION SEQUENCE

NO:

45 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

46 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

47 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

48 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 SEQ ID DESIGNATION SEQUENCE

NO:

49 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

NKALPAPIEK TISKAKGQPR EPQVYTLPPS

REEMTKNQVS LTCLVKGFYP SDIAVEWESN

GQPENNYKTT PPVLDSDGSF FLYSKLTVDK

SRWQQGNVFS CSVMHEALHN HYTQKSLSLS

PGK

50 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 a heregulin positive cancer in a human patient comprising administering to the patient an effective amount of:

A. an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences

B. a composition of anti-EGFR antibodies comprising:

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

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

sequences of SEQ ID NOs: 20, 21, and 22, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 23, 24, and 25, respectively; and

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

sequences of SEQ ID NOs: 26, 27, and 28, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 29, 30, and 31, respectively, wherein the method comprises a priming phase and a cycle,

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

ii. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 0.75 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg; iii. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg;

viii. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 2.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg.

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

A. an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences

comprising the amino acid sequences set forth in SEQ ID NO: 1 (CDRH1) SEQ ID NO: 2 (CDRH2) and SEQ ID NO: 3 (CDRH3), and CDRLl, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 4 (CDRLl) SEQ ID NO: 5 (CDRL2) and SEQ ID NO: 6 (CDRL3); and

B. a composition of anti-EGFR antibodies comprising:

3. a monoclonal antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region comprising SEQ ID NO: 36, and the CDR1, CDR2, and CDR3 domains of a light chain variable region comprising SEQ ID NO: 37, wherein the method comprises a priming phase and a cycle,

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

3. The method of claims 1 or 2, wherein the anti-ErbB3 antibody is administered on week one of the priming phase at a fixed dose selected from the group consisting of 0.75 g, 1.0 g, 1.5 g, and 2.0 g.

4. The method of claims 1 or 2, wherein during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 0.75 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg.

5. The method of claims 1 or 2, wherein during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 0.75 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg.

6. The method of claims 1 or 2, wherein during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg.

7. The method of claims 1 or 2, wherein during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg.

8. The method of claims 1 or 2, wherein during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.5 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg.

9. The method of claims 1 or 2, wherein during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.5 g and the composition is administered every two weeks at a dose of 10.5 mg/kg.

10. The method of claims 1 or 2, wherein during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 2.0 g and the composition is administered every two weeks at a dose of 9 mg/kg.

11. The method of claims 1 or 2, wherein during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 2.0 g and the composition is administered every two weeks at a dose of 10.5 mg/kg.

12. The method of any one of the preceding claims, wherein the anti-ErbB3 antibody comprises a heavy chain variable region comprising SEQ ID NO: 10.

13. The method of any one of the preceding claims, wherein the anti-ErbB3 antibody comprises a light chain variable region comprising SEQ ID NO: 12.

14. The method of any one of the preceding claims, wherein the anti-ErbB3 antibody comprises heavy and light chain variable regions comprising SEQ ID NO: 10 and SEQ ID NO: 12, respectively or wherein the anti-ErbB3 antibody is seribantumab.

15. 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: 32 and a light chain variable region comprising SEQ ID NO: 33;

2. a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 34 and a light chain variable region comprising SEQ ID NO: 35; and

3. a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 36 and a light chain variable region comprising SEQ ID NO: 37;

or wherein the composition of anti-EGFR antibodies is MM- 151.

16. The method of any one of claims 1-15, wherein the composition of anti-EGFR

antibodies comprises:

1. a monoclonal antibody comprising the mature portion of a heavy chain variable region comprising SEQ ID NO: 32 and the mature portion of a light chain variable region comprising SEQ ID NO: 33;

2. a monoclonal antibody comprising the mature portion of a heavy chain variable region comprising SEQ ID NO: 34 and the mature portion of a light chain variable region comprising SEQ ID NO: 35; and

3. a monoclonal antibody comprising the mature portion of a heavy chain variable region comprising SEQ ID NO: 36 and the mature portion of a light chain variable region comprising SEQ ID NO: 37.

17. The method of claim 16, wherein the composition of anti-EGFR antibodies comprises:

1. a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 39 and a light chain variable region comprising SEQ ID NO: 40;

2. a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 41 and a light chain variable region comprising SEQ ID NO: 42; and

3. a monoclonal antibody comprising a heavy chain variable region comprising SEQ ID NO: 43 and a light chain variable region comprising SEQ ID NO: 44.

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

1. a monoclonal antibody comprising a heavy chain comprising SEG ID NO: 45 and a light chain comprising SEQ ID NO: 46;

2. a monoclonal antibody comprising a heavy chain comprising SEG ID NO: 47 and a light chain comprising SEQ ID NO: 48; and

3. a monoclonal antibody comprising a heavy chain comprising SEG ID NO: 49 and a light chain comprising SEQ ID NO: 50.

19. 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.

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

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

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

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

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

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

26. The method of any one of the preceding claims, wherein the anti-ErbB3 antibody is administered intravenously.

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

28. The method of claim 27, wherein:

A. a first intravenous administration of the composition of anti-EGFR antibodies is infused at a rate of 25 mg/hr over 30 minutes, 50 mg/hr over 30 minutes, or 100 mg/hr until completion;

B. a second intravenous administration of the composition of anti-EGFR antibodies is infused at a rate of 25 mg/hr over 30 minutes, 50 mg/hr over 30 minutes, 100 mg/hr over 30 minutes, or 200 mg/hr until completion;

C. a third intravenous administration of the composition of anti-EGFR antibodies is infused at a rate of 50 mg/hr over 30 minutes, 100 mg/hr over 30 minutes, or 200 mg/hr over 30 minutes, or 400 mg/hr until completion; and/or

D. fourth and subsequent intravenous administrations of the composition of anti-EGFR antibodies are infused at a rate of 100 mg/hr and advanced as tolerated.

29. The method of claim 27, wherein the anti-ErbB3 antibody is intravenously infused over 60 minutes.

30. The method of any one of the preceding claims, wherein the anti-ErbB3 antibody is administered prior to the composition of anti-EGFR antibodies on weeks when both the anti- ErbB3 antibody and composition of anti-EGFR antibodies are administered.

31. The method of claim 30, wherein acetaminophen, diphenhydramine, or methylprednisone is administered prior to administration of the anti-ErbB3 antibody.

32. The method of claim 31, wherein acetaminophen is administered at a dose of 650 mg by mouth or intravenously, diphenhydramine is administered at a dose of 25-50 mg by mouth or intravenously, or methylprednisone is administered at a dose of 125 mg intravenously, prior to administration of the anti-ErbB3 antibody.

33. The method of claim 31 or 32, wherein acetaminophen, diphenhydramine, or methylprednisone is administered 30-90 minutes prior to administration of the anti-ErbB3 antibody.

34. 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.

35. A kit for treating a heregulin positive cancer in a human patient, the kit comprising:

A. a dose of an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3

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: 14, 15, and 16, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 17, 18, and 19, respectively; (2) a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 20, 21, and 22, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 23, 24 and 25, respectively; and (3) a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 26, 27, and 28, respectively, and light chain CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 29, 30, and 31, respectively; and C. instructions for using the anti-ErbB3 antibody and composition of anti-EGFR antibodies, in the method of any one of the preceding claims.

36. Use of seribantumab for the treatment of a heregulin-positive cancer, characterized in that the seribantumab is co-administered with MM- 151.

37. The use of claim 36, wherein the treatment 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:

vii. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 2.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg; or viii. the anti-ErbB3 antibody is administered once weekly at a fixed dose of 2.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg.

38. The use of claim 37, wherein during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 0.75 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg.

39. The use of claim 37, wherein during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 0.75 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg.

40. The use of claim 37, wherein during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg.

41. The use of claim 37, wherein during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.0 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 10.5 mg/kg.

42. The use of claim 37, wherein during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.5 g and the composition of anti-EGFR antibodies is administered every two weeks at a dose of 9 mg/kg.

43. The use of claim 37, wherein during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 1.5 g and the composition is administered every two weeks at a dose of 10.5 mg/kg.

44. The use of claim 37, wherein during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 2.0 g and the composition is administered every two weeks at a dose of 9 mg/kg.

45. The use of claim 37, wherein during the cycle the anti-ErbB3 antibody is administered once weekly at a fixed dose of 2.0 g and the composition is administered every two weeks at a dose of 10.5 mg/kg.

46. The use of any one of claims 37-45, wherein the heregulin positive cancer is non- small-cell lung cancer (NSCLC).

47. The use of any one of claims 37-46, wherein the heregulin positive cancer is squamous cell carcinoma of the head and neck (SCCHN).

48. The use of any one of claims 37-47, wherein the heregulin positive cancer is colorectal cancer (CRC).

49. The use of any one of claims 37-48, wherein the anti-ErbB3 antibody is administered intravenously.

50. The use of any one of claims 37-49, wherein the composition of anti-EGFR antibodies is administered intravenously.

51. The use of claim 50, wherein:

52. The use of claim 50, wherein the anti-ErbB3 antibody is intravenously infused over 60 minutes.

53. The use of any one of claims 37-52, wherein the anti-ErbB3 antibody is administered prior to the composition of anti-EGFR antibodies on weeks when both the anti-ErbB3 antibody and composition of anti-EGFR antibodies are administered.

54. The use of claim 53, wherein acetaminophen, diphenhydramine, or methylprednisone is administered prior to administration of the anti-ErbB3 antibody.

55. The use of claim 54, wherein acetaminophen is administered at a dose of 650 mg by mouth or intravenously, diphenhydramine is administered at a dose of 25-50 mg by mouth or intravenously, or methylprednisone is administered at a dose of 125 mg intravenously, prior to administration of the anti-ErbB3 antibody.

56. The use of claim 54 or 55, wherein acetaminophen, diphenhydramine, or

methylprednisone is administered 30-90 minutes prior to administration of the anti-ErbB3 antibody.

57. The use of any one of claims 37-56 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.