Clinical trial NCT03241810
Conditions: Metastatic Breast Cancer
Keywords: Breast Cancer, HER2 Negative, Hormone receptor positive
Sponsor: Elevation Oncology
Start date: 2017-08-15; Completion date: 2018-11-30
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a multi-center, randomized, double-blind, placebo-controlled, Phase 2 study in postmenopausal women with heregulin positive, hormone receptor positive, HER2 negative metastatic, unresectable breast cancer.

Detailed description:
This study is a randomized, double-blind, placebo-controlled international phase 2 trial in patients with HRG+, HR+, HER2- metastatic breast cancer that has progressed following treatment with no more than 2 prior therapies, one of which must have been a CDK inhibitor. All patients will be screened for heregulin using central testing, and eligible patients will be randomized to receive either seribantumab + fulvestrant or placebo + fulvestrant. Disease status will be assessed according to RECIST v 1.1 to support the primary endpoint.

Arms: arm 1: Seribantumab

Fulvestrant arm 2: Placebo

Fulvestrant
Interventions: intervention 1: Seribantumab intervention 2: Fulvestrant intervention 3: Placebo
Intervention descriptions: intervention 1: Seribantumab is a human monoclonal antibody that inhibits ErbB3 signalling intervention 2: Fulvestrant is an estrogen receptor antagonist with no agonist effects intervention 3: Placebo

Protocol documents:
Prot_000.pdf: 
 
 
 
SHERBOC: A Double-blind, Placebo-controlled, Phase 2 trial of 
Seribantumab Plus Fulvestrant in Postmenopausal Women with 
Hormone Receptor-positive, Heregulin Positive (HRG+), HER2 
Negative Metastatic Breast Cancer Whose Disease Progressed After 
Prior Systemic Therapy 
Merrimack Pharmaceuticals, Inc. 
 
 
Version 1.2: 28 April 2017 
IND Number: 123522 
EudraCT# 2017-000565-76 
 
 
 
 
 
 
Sponsor: 
 
One Kendall Square 
Suite B7201 
Cambridge, MA 02139 
 
Confidentiality Statement 
This document and the information it contains is confidential and the proprietary property of 
Merrimack Pharmaceuticals.  The information is not to be disclosed or transmitted to any party without 
the express approval of Merrimack Pharmaceuticals, or its agents, and any such unauthorized use or 
disclosure is expressly prohibited. 


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Table of Contents 
List of Figures ................................................................................................................................. 5 
List of Tables .................................................................................................................................. 5 
Abbreviations .................................................................................................................................. 6 
Study Synopsis ................................................................................................................................ 9 
Study Schema................................................................................................................................ 15 
1. 
Introduction ........................................................................................................................... 16 
1.1. 
Breast Cancer ................................................................................................................. 16 
1.2. 
Treatment for ER/PR positive HER2 Negative Advanced Breast Cancer ..................... 16 
1.3. 
Predictive Biomarkers for Response to Treatment ........................................................ 17 
1.4. 
ErbB3 ............................................................................................................................. 18 
1.5. 
Seribantumab .................................................................................................................. 19 
1.5.1. 
Pre-Clinical Experience of Seribantumab in Breast Cancer ................................... 19 
1.5.2. 
Clinical Experience of Seribantumab in Humans ................................................... 25 
1.5.3. 
Potential Toxicities with Seribantumab .................................................................. 26 
1.6. 
Study Rationale .............................................................................................................. 27 
1.6.1. 
Previous Experience in Heregulin Negative Patients ............................................. 29 
1.6.2. 
Summary of Study Rationale .................................................................................. 29 
1.6.3. 
Rationale for Seribantumab Dose Selection ........................................................... 30 
2. 
Objectives .............................................................................................................................. 32 
2.1. 
Primary Objective .......................................................................................................... 32 
2.2. 
Secondary Objectives ..................................................................................................... 32 
2.3. 
Exploratory Objectives ................................................................................................... 32 
3. 
Study Design.......................................................................................................................... 32 
3.1. 
Overview of Study Design ............................................................................................. 32 
4. 
Study Population.................................................................................................................... 34 
4.1. 
Inclusion Criteria ............................................................................................................ 34 
4.2. 
Exclusion Criteria ........................................................................................................... 35 
4.3. 
Assessing Heregulin Status in Breast Cancer Specimens .............................................. 36 
4.3.1. 
Description of HRG RNA-ISH Assay .................................................................... 36 
4.3.2. 
Implementation of HRG RNA-ISH Testing ........................................................... 36 
4.4. 
Patient Discontinuation .................................................................................................. 36 
5. 
Study Treatment .................................................................................................................... 37 
5.1. 
Method of Assigning Patients to Treatment Groups ...................................................... 37 
5.2. 
Seribantumab .................................................................................................................. 37 
5.2.1. 
Seribantumab Formulation, Packaging, and Labeling ............................................ 37 
5.2.2. 
Seribantumab Product Storage and Stability .......................................................... 37 
5.2.3. 
Seribantumab Dosage, Preparation, and Administration ........................................ 38 
5.2.4. 
Management of Infusion Reactions to Seribantumab ............................................. 38 
5.2.5. 
Management of Toxicity Related to Seribantumab ................................................ 39 
5.3. 
Fulvestrant ...................................................................................................................... 40 
5.3.1. 
Fulvestrant Formulation, Packaging, Labeling, and Storage .................................. 40 
5.3.2. 
Fulvestrant Dosage and Administration.................................................................. 40 
5.3.3. 
Fulvestrant Dose Modifications .............................................................................. 40 
5.3.4. 
Potential Toxicities with Fulvestrant ...................................................................... 40 
5.4. 
Rules for Dose Omissions and Modified Treatment Schedules ..................................... 41 


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5.5. 
Concomitant and Prohibited Therapies .......................................................................... 41 
5.6. 
Accountability of Study Drug ........................................................................................ 41 
6. 
Schedule of Assessment ........................................................................................................ 43 
6.1. 
Schedule of Assessments: Heregulin Positive Patients .................................................. 43 
6.2. 
Schedule of Assessments: HRG Negative Patients ........................................................ 45 
6.3. 
Screening and Baseline Visit.......................................................................................... 45 
6.3.1. 
RNA-ISH Heregulin Testing .................................................................................. 45 
6.3.2. 
Heregulin Negative Patients ................................................................................... 46 
6.4. 
On-Study Visits .............................................................................................................. 46 
6.5. 
End of Treatment Visit ................................................................................................... 46 
6.6. 
Survival Follow-up ......................................................................................................... 46 
7. 
Clinical Procedures and Assessments .................................................................................... 46 
7.1. 
Medical History and Demographics ............................................................................... 46 
7.2. 
Adverse Event and Hospitalization Assessment Reporting ........................................... 46 
7.3. 
Vital Signs ...................................................................................................................... 47 
7.4. 
Performance Status Assessment ..................................................................................... 47 
7.5. 
Electrocardiogram (ECG) .............................................................................................. 47 
7.6. 
Echocardiogram or Multiple Gated Acquisition Scan ................................................... 47 
7.7. 
Disease Evaluation ......................................................................................................... 47 
8. 
Laboratory Procedures and Assessments .............................................................................. 48 
8.1. 
Complete Blood Count (CBC) ....................................................................................... 48 
8.2. 
Coagulation Profile ........................................................................................................ 48 
8.3. 
Serum Chemistry ............................................................................................................ 48 
8.4. 
Urine or Serum Pregnancy Test ..................................................................................... 48 
8.5. 
Pharmacokinetic Testing ................................................................................................ 48 
8.5.1. 
Seribantumab PK Samples ...................................................................................... 48 
8.5.2. 
Fulvestrant PK samples........................................................................................... 48 
8.6. 
Anti-Seribantumab Immunogenicity .............................................................................. 49 
8.7. 
Biomarker Samples ........................................................................................................ 49 
8.7.1. 
Tissue for HRG eligibility assessment .................................................................... 49 
8.7.2. 
Tumor Biopsy ......................................................................................................... 49 
8.7.3. 
Serum Samples........................................................................................................ 49 
8.7.4. 
ESR1 Testing .......................................................................................................... 49 
8.7.5. 
Archived Tumor Samples ....................................................................................... 49 
9. 
Adverse Event and Hospitalization Reporting ...................................................................... 50 
9.1. 
Definitions ...................................................................................................................... 50 
9.1.1. 
Adverse Events ....................................................................................................... 50 
9.1.2. 
Serious Adverse Event ............................................................................................ 50 
9.2. 
Assessing and Documenting Adverse Events and Hospitalizations .............................. 51 
9.2.1. 
Hospitalizations....................................................................................................... 51 
9.3. 
Reporting Serious Adverse Events ................................................................................. 51 
9.4. 
Determining the Severity and Relatedness of an Event ................................................. 52 
9.4.1. 
Grading the Severity of an Adverse Event ............................................................. 52 
9.4.2. 
Relatedness to Study Drug ...................................................................................... 53 
9.4.3. 
Reporting and Follow-up of Pregnancy .................................................................. 53 
10. 
Statistical Methods ............................................................................................................. 54 


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10.1. 
General Considerations ............................................................................................... 54 
10.2. 
Statistical Hypothesis and Determination of Sample Size ......................................... 54 
10.3. 
Analysis Populations .................................................................................................. 54 
10.4. 
Disposition, Demographics, and Baseline Characteristics ......................................... 55 
10.5. 
Efficacy Analysis ........................................................................................................ 55 
10.5.1. Primary Efficacy Analysis ...................................................................................... 55 
10.5.2. Secondary Efficacy Analysis .................................................................................. 55 
10.5.3. Subgroup Analyses ................................................................................................. 55 
10.5.4. Safety Analyses ....................................................................................................... 56 
10.5.5. Biomarker Analyses ................................................................................................ 56 
10.5.6. Pharmacokinetic Analyses ...................................................................................... 56 
10.6. 
Data Monitoring Committee ....................................................................................... 56 
11. 
Study Administration ......................................................................................................... 57 
11.1. 
Pre-Study Documentation........................................................................................... 57 
11.2. 
Source Documents ...................................................................................................... 57 
11.3. 
Trial Ethics ................................................................................................................. 57 
11.4. 
Patient Informed Consent ........................................................................................... 57 
11.5. 
Investigational Review Board Approval .................................................................... 58 
11.6. 
Monitoring .................................................................................................................. 58 
11.7. 
Confidentiality ............................................................................................................ 59 
11.7.1. Confidentiality of Biomarker Samples ................................................................... 59 
11.8. 
Protocol Amendments ................................................................................................ 60 
11.9. 
Records Retention....................................................................................................... 60 
11.10. 
Study Termination ...................................................................................................... 60 
12. 
Investigator Signature Page ............................................................................................... 61 
13. 
References .......................................................................................................................... 62 
 
 
 


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List of Figures 
Figure 1: Pro-survival AKT Signaling is Activated by ERBB3 Ligands ................................... 20 
Figure 2: Seribantumab Inhibits HRG-mediated Signaling Through the ErbB2-ErbB3-AKT 
Signaling Pathway ...................................................................................................... 21 
Figure 3: HRG Promotes Proliferation of HR-positive, Her2-negative Breast Cell Lines ........ 21 
Figure 4: Heregulin Activates ER Phosphorylation in MCF-7Ca Cells..................................... 22 
Figure 5: HRG Blocks the Activity of Fulvestrant in HR-positive, HER2-negative Cell Lines 22 
Figure 6: HRG Blocks the Activity of Fulvestrant in HR-positive, Her2-negative Cell Lines and 
Seribantumab Restores Fulvestrant Sensitivity .......................................................... 23 
Figure 7: Seribantumab and Letrozole Co-treatment Delays the Onset of Resistance and 
Restores Sensitivity to Letrozole in MCF-7Ca Xenografts ........................................ 24 
Figure 8: Number of Biomarker Samples Collected and the Analysis Performed for the Three 
Randomized ................................................................................................................ 27 
Figure 9: Positive HRG mRNA Levels Identify a Subgroup of Patients with an Increased Risk 
of Progression on Standard-of-care Therapies ............................................................ 28 
Figure 10: Treatment Effect of Seribantumab in Patients with HRG Positive Tumors ............... 28 
Figure 11: Simulated Seribantumab Pharmacokinetics (Average concentration) by Weight-based 
and Fixed Dosing Regimens and by Dose and Intervals. ........................................... 31 
List of Tables 
Table 1: 
Summary Statistics for Experimental Treatment vs. Control PFS in HRG Positive 
Subgroup ..................................................................................................................... 29 
Table 2: 
Summary Statistics for Experimental Treatment vs. Control PFS in HRG Negative 
Subgroup ..................................................................................................................... 29 
Table 3: 
Final Parameter Estimates from Population PK Analysis of Seribantumab ............... 31 
Table 4: 
Seribantumab PK Collection Timepoints ................................................................... 48 
 


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Abbreviations 
Abbreviations 
Definitions 
ABC 
Advanced breast cancer 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AI 
Aromatase inhibitor  
AKT 
Protein kinase B 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
ASCO 
American Society for Clinical Oncology 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUCt 
Area under the concentration-time curve 
BTC 
Betacellulin 
Cavg 
Average serum concentration 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum serum concentration 
CMH 
Cochran-Mantel-Haenszel (test) 
Cmin 
Minimum serum concentration 
CNB 
Core needle biopsy 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CRO 
Contract research organization 
CT  
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
CTG 
Cell TiterGlo 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG (PS) 
Eastern Cooperative Oncology Group (performance status) 
eCRF 
Electronic case report form 
EGFR 
Epidermal growth factor receptor 
ER 
Estrogen receptor 
ErbB 
Epidermal growth factor family of receptor tyrosine kinases 
ESR1 
Estrogen receptor alpha 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed, paraffin-embedded 
FGF 
Fibroblast growth factor 
FL-IHC 
Fluorescence-based immunohistochemistry 
FNA 
Fine needle aspiration 
g 
Gram 
GCSF 
Granulocyte-colony stimulating factor 
GCP 
Good Clinical Practice 
GnRH 
Gonadotropin-releasing hormone 


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GR 
Grade 
HAHA 
Human anti-human antibodies 
HER2 
Human epidermal growth factor receptor 2 
HGF 
Hepatocyte growth factor 
HIPAA 
Health Insurance Portability and Accountability Act 
HR  
Hazard ratio 
HRG 
Heregulin 
HR-positive 
Hormone receptor positive 
IB 
Investigator’s Brochure 
ICH 
International conference on harmonization 
Ig 
Immunogenicity 
IGF 
Insulin-like growth factor  
IGF-1R 
Insulin-like growth factor 1 receptor 
IHC 
Immunohistochemistry 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRR 
Infusion-Related Reaction 
ISH 
In-situ hybridization 
ITT 
Intent to treat 
MITT 
Modified Intent to treat 
IV 
Intravenous 
IWRS 
Interactive web response system 
kg 
Kilogram 
LDH 
Lactate dehydrogenase 
LH 
Luteinizing hormone 
LVEF 
Left ventricle ejection fraction 
mBC 
Metastatic breast cancer 
mcg 
Micrograms 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mOC 
Metastatic ovarian cancer 
mL 
Milliliter 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
mTOR 
Mammalian target of rapamycin 
MUGA 
Multiple gated acquisition scan 
NCI 
National Cancer Institute 
NRG 
Neuregulin 
NSAID 
Non-steroidal anti-inflammatory drug 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
Objective Response Rate 
OS 
Overall survival 
p.o. 
Per os (oral administration) 
PD 
Progressive disease 
PE 
Pulmonary embolism 
PET-CT 
Positron emission tomography - computed tomography 
PFS 
Progression free survival 
PgR 
Progesterone receptor 
PI3K 
Phosphatidylinositol-3-kinase 


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PK 
Pharmacokinetic(s) 
PR 
Partial response 
PTT 
Prothrombin time 
QD 
Every day 
Q1W 
Every week 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
QW 
Weekly 
RANKL 
Receptor activator of nuclear factor kappa-B ligand 
RBC 
Red blood cell 
RECIST  
Response evaluation criteria in solid tumors 
RNA 
Ribonucleic acid 
RNAi 
Ribonucleic acid interface 
RT-PCR 
Reverse transcription polymerase chain reaction 
SAE 
Serious adverse event 
SAF 
Safety Population 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SERD 
Selective estrogen receptor disruptor 
SERM 
Selective estrogen receptor modifier 
SmPC 
Summary of Product Characteristics 
TCGA 
The Cancer Genome Atlas 
TKI 
Tyrosine kinase inhibitor 
Tmax 
Time to maximum serum concentration 
TTP 
Time to Progression 
ULN 
Upper limit of normal 
US 
United States 
USP 
United States Pharmacopeial Convention 
VDss 
Volume of distribution at steady state 
WBC 
White blood cell 


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Study Synopsis 
SPONSOR: 
Merrimack Pharmaceuticals, Inc. 
One Kendall Square 
Building 700, Suite B7201 
Cambridge, MA, USA 02139-1670  
PROTOCOL TITLE: 
A Double-blind, Placebo-controlled, Phase 2 trial of Seribantumab Plus 
Fulvestrant in Postmenopausal Women with Hormone Receptor-positive, 
Heregulin Positive (HRG+), HER2 Negative Metastatic Breast Cancer 
Whose Disease Progressed After Prior Systemic Therapy 
TRIAL LOCATION: 
North America and Europe 
PROTOCOL 
NUMBER: 
MM-121-02-02-10 
STUDY 
OBJECTIVE(S): 
Primary Objective: 
• 
To determine whether the combination of seribantumab + fulvestrant is 
more effective than placebo + fulvestrant based on investigator assessed 
Progression Free Survival (PFS) in HRG positive patients (defined as 
HRG ISH score of  > 1+) 
 
Secondary Objectives: 
• 
To determine whether the combination of seribantumab + fulvestrant is 
more effective than placebo + fulvestrant in HRG positive patients for 
the following clinical outcome parameters: 
o Time to Progression (TTP) 
o Overall Survival (OS) 
o Objective Response Rate (ORR) based on RECISTv1.1 
• 
To describe the safety profile of seribantumab in combination with 
fulvestrant  
• 
To characterize the pharmacokinetic (PK) profile of seribantumab when 
given in combination with fulvestrant and of fulvestrant when given in 
combination with seribantumab 
 
Exploratory Objectives: 
• 
To assess the correlation for HRG expression between fresh tissue 
biopsies and archival samples where available 
STUDY DESIGN: 
This is a multi-center, randomized, double-blind, placebo-controlled Phase 2 
study of seribantumab or placebo with fulvestrant in patients with ER/PR 
positive, HER2 negative, metastatic, unresectable breast cancer whose tumor 
expresses HRG as measured by RNA in-situ hybridization (RNA-ISH).  
 
Following signing informed consent for biomarker testing and evaluation of 
initial eligibility criteria, all patients will provide a tissue sample (which 
meets the requirements for collection and processing as outlined in the study 
lab manual) to the designated central lab facility for HRG testing. If 
adequate tissue is not available, patients should undergo a tumor biopsy to 
acquire the necessary tissue for HRG testing. For these procedures, 
investigators are asked to choose an easily accessible tumor lesion to 
minimize any possible risk associated with the collection of the tissue. As a 
general guideline, if the selected procedural location of the biopsy has an 
established serious complication rate of >2% at the institution completing 


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the procedure, this is considered a high risk procedure and should be 
avoided. Upon receipt of a tissue sample at the central lab, the 
investigational site will be informed of the results within 7 days. Patients 
with a positive HRG status, defined as HRG ISH score of >1+, will be 
eligible for randomization.  
 
Prior to receiving the first dose, all HRG positive patients that receive HRG 
results for eligibility based on testing of archived samples will also be asked 
to undergo a fresh research biopsy, prior to first dose. An additional sample 
will not be requested from patients who underwent a fresh biopsy for 
eligibility testing. The sample should be collected and processed according 
to the laboratory manual.  
Once all screening procedures have been completed and eligibility for 
treatment randomization (including HRG positive ISH result) has been 
determined, the investigator may randomize the patient.  Patients will be 
randomized in a 1:1 ratio (experimental arm versus comparator arm) using 
an Interactive Web Response System (IWRS). Randomization will be 
stratified based on bone-only disease (yes, no) and geographic region (US, 
non-US). Patients will be assigned to Arm A or Arm B: 
 
Arm A (Experimental Arm):   
Seribantumab: fixed dose of 3000 mg intravenously (IV) on day 1 and 15 of 
each 28-day cycle 
 
Fulvestrant: 500 mg intramuscularly (IM) on Days 1 and 15 of Cycle 1, and 
then on Day 1 of each subsequent 28 day cycle 
 
Arm B (Control Arm):  
Placebo: intravenously (IV) on day 1 and 15 of each 28-day cycle  
Fulvestrant: 500 mg intramuscularly (IM) on Days 1 and 15 of Cycle 1, and 
then on Day 1 of each subsequent 28 day cycle 
 
Treatment will start within 7 days following randomization. It is intended 
that patients will be treated until investigator-assessed disease progression or 
unacceptable toxicity, whichever comes first. Tumor assessments will be 
measured and recorded by the local radiologist every 8 weeks (±5 days) 
from randomization using RECIST guidelines (version 1.1). Tumor 
assessments will be performed every 8 weeks, regardless of dose delays or 
dose interruptions, until investigator-assessed PD. Patients who come off 
study treatment prior to disease progression for reasons including patient or 
physician decision or unacceptable toxicity will continue to undergo tumor 
assessments every 8 weeks (±5 days) until investigator assessed PD. Patients 
will be treated according to local assessment of tumor scans.  
 
All patients will have a follow-up visit scheduled 30 days (±7 days) after the 
last dose of study treatment, regardless of reason for treatment termination.  
Patients will not be allowed to cross over from placebo to seribantumab. 
Survival follow up will be required for all patients every 2 months from the 
30-day follow-up visit until death, loss to follow-up, withdrawal of consent, 
or study termination.  After patients discontinue study treatment, subsequent 


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anti-cancer therapies will be collected according to the same schedule at the 
same time as survival follow-up.  
 
An independent Data Monitoring Committee (DMC) will be established to 
monitor emerging safety data and evaluate for trial efficacy. The DMC will 
regularly monitor safety data over the course of the study in accordance with 
the DMC Charter.  
ESTIMATED # OF 
PATIENTS: 
Approximately 200 patients will be screened to enroll 80 HRG+ patients 
from an estimated 60-80 clinical trial sites from North America and Europe.  
STUDY POPULATION 
Women with metastatic ER/PR positive, HER2 negative, HRG positive 
breast cancer that has progressed following systemic therapy with a CDK 
inhibitor (e.g. palbociclib) in the locally advanced or metastatic disease 
setting. Patients cannot have received more than a total of two prior lines of 
therapy in the locally advanced or metastatic disease setting, and patients 
cannot have received chemotherapy in the locally advanced and metastatic 
disease setting. There is no restriction on chemotherapy use in the 
neoadjuvant or adjuvant setting.  
INCLUSION 
CRITERIA: 
In order for inclusion, patients must have/be:  
• 
Histologically or cytologically confirmed ER+ and/or PR+ (with 
staining of > 1% cells) breast cancer 
• 
Confirmed postmenopausal status due to either surgical/natural 
menopause or ovarian suppression (initiated at least 28 days prior to Day 
1 of Cycle 1) with a gonadotropin-releasing hormone (GnRH) agonist, 
such as goserelin 
• 
HER2 negative per ASCO/CAP guidelines 
• 
A positive in-situ hybridization (ISH) test for heregulin with a score of 
≥1+, as determined by centralized testing of unstained tumor tissue  
• 
Must have at least one lesion amenable to either fresh tissue biopsy  
• 
Progressed following at least one but no more than two prior systemic 
therapies in the locally advanced or metastatic disease setting  
o Received prior CDK inhibitor based therapy for locally advanced or 
metastatic disease  
• 
Documented progression of locally advanced or metastatic disease as 
defined by RECIST v1.1.  Exception: patients with bone-only metastatic 
disease are eligible if they have at least 2 lytic lesions visible on a CT or 
MRI and have documented disease progression on prior therapy, based 
on RECIST v1.1 criteria.  
o Patients with bone-only lesions who have received radiation to those 
lesions must have documented progression following radiation 
therapy. 
• 
Able to understand and sign an informed consent (or have a legal 
representative who is able to do so) 
• 
ECOG Performance Score (PS) of 0 or 1 
• 
Adequate bone marrow reserves as evidenced by: 
o ANC > 1500/µl 
o Platelet count > 100,000/µl; and 
o Hemoglobin > 9 g/dL 
• 
Adequate hepatic function as evidenced by: 


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o Serum total bilirubin ≤ 1.5 x ULN except for patients with Morbus 
Gilbert 
o Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) 
and Alkaline Phosphatase ≤ 2.5 x ULN (≤ 5 x ULN is acceptable if 
liver metastases are present, and ≤ 5 x ULN of Alkaline Phosphatase 
is acceptable if bone metastases are present) 
• 
Adequate renal function as evidenced by a serum creatinine ≤ 1.5 x 
ULN 
• 
Recovered from clinically significant effects of any prior surgery, 
radiotherapy, or other antineoplastic therapy. 
• 
Patients may be treated with bone modifying agents such as 
bisphosphonates or receptor activator of nuclear factor kappa-B 
(RANK)-ligand agents (e.g. denosumab) per American Society of 
Clinical Oncology (ASCO) guidelines; whenever possible, patients 
requiring bone modifying agents should start treatment > 7 days prior to 
study therapy and should continue the same agent throughout study 
unless clinically compelled to change 
• 
≥ 18 years of age 
• 
Patients who have experienced a venous thromboembolic event within 
60 days of signing the main consent form should have been treated with 
anti-coagulants for at least 7 days prior to beginning treatment and for 
the duration of treatment on this study. 
EXCLUSION 
CRITERIA: 
Patients must meet all the inclusion criteria listed above and none of the 
following exclusion criteria: 
• 
Prior treatment with an anti-ErbB3 antibody  
• 
Prior treatment with a chemotherapy in the locally advanced or 
metastatic disease setting 
• 
Patients cannot have received prior fulvestrant or other SERDs in the 
locally advanced or metastatic setting 
• 
Uncontrolled CNS disease or presence of leptomeningeal disease 
• 
Inflammatory breast cancer 
• 
History of another active malignancy that required systemic therapy in 
the last 2 years. Patients with prior history of in-situ cancer or basal or 
squamous cell skin cancer are eligible. 
• 
Active infection, or 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 may be enrolled 
• 
Known hypersensitivity to any of the components of seribantumab, 
fulvestrant, or who have had hypersensitivity reactions to fully human 
monoclonal antibodies 
• 
Received other recent antitumor therapy including: 
o Investigational therapy administered within the 28 days or 5 
half-lives, whichever is shorter, prior to the first scheduled day 
of dosing in this study 
o Radiation or other standard systemic therapy within 14 days 
prior to the first scheduled dose in this study, including, in 


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addition (if necessary), the timeframe for resolution of any 
actual or anticipated toxicities from such radiation 
• 
NYHA Class III or IV congestive heart failure  
• 
Patients with a significant history of cardiac disease (i.e. uncontrolled 
blood pressure, unstable angina, myocardial infarction within 1 year or 
ventricular arrhythmias requiring medication) are also excluded 
• 
Uncontrolled infection requiring IV antibiotics, antivirals, or 
antifungals; or active human immunodeficiency virus (HIV) infection, 
active hepatitis B infection or active hepatitis C infection 
• 
Any other medical condition deemed by the Investigator to be likely to 
interfere with a patient’s ability to sign informed consent, interfere with 
a patient’s ability to cooperate and participate in the study, or interfere 
with the interpretation of the results 
LENGTH OF STUDY: 
A total study duration of approximately 20 months is expected. 
The primary analysis will be initiated when 58 PFS events have occurred.  
STUDY 
TREATMENT(S): 
Seribantumab/fulvestrant or placebo/fulvestrant (1:1) 
INVESTIGATIONAL 
PRODUCT(S) 
FORMULATION: 
Seribantumab is a clear liquid, supplied in sterile, single-use vials at a 
concentration of 25 mg/mL in 20 mM histidine, 150 mM sodium chloride, 
and pH 6.5. Seribantumab  should be stored at 2-8°C. 
ROUTE(S) OF 
ADMINISTRATION: 
Seribantumab for intravenous (IV) infusion over 1 hour 
NON 
INVESTIGATIONAL 
PRODUCT 
FORMULATION: 
Fulvestrant solution for intramuscular injection (50 mg/mL) is commercially 
available. Fulvestrant is stored refrigerated at 2°-8°C (36°-46°F). 
 
Placebo: A clear liquid, supplied in sterile, single-use vials at a containing 
20 mM histidine, 150 mM sodium chloride, at a pH of 6.5. Placebo should 
be stored at 2-8°C. 
ROUTE(S) OF 
ADMINISTRATION: 
Seribantumab and placebo: intravenous (IV) infusion over one hour 
Fulvestrant: intramuscular (IM) injection  
DOSE REGIMEN: 
Seribantumab 3 gm or matched placebo (120 mL) will be administered by 
intravenous infusion over 60 minutes on Days 1 and 15 of a 28 day cycle. 
Fulvestrant 500 mg will be administered intramuscularly on Days 1 and 15, 
and then Day 1 of each subsequent 28 day cycle. 
SAMPLE 
SIZE/STATISTICAL 
CONSIDERATIONS: 
The median PFS for the control arm (fulvestrant + placebo) is assumed to be 
4.0 months in this patient population.  A total of 58 PFS events will be 
required across two treatment arms randomized in a 1:1 ratio, giving 
approximately 80% power to detect a true hazard ratio of HR ≤ 0.57 (mPFS: 
4 v 7), assuming a 1-sided significance level of 0.10.  Approximately 200 
patients will need to be screened in order to accrue 80 randomized in 
approximately 16 months with a total duration of 20 months. 
 
Primary Efficacy and Key Secondary Analysis: 
The primary efficacy analysis will be performed using the Per Protocol (PP) 
population.  PFS is defined as the number of months from the date of 
randomization to the date of the first documented objective disease 
progression (PD) using RECIST v1.1 or death due to any cause, whichever 
occurs first.  If neither death nor progression is observed, data will be 
censored on the date of the last observed tumor assessment date.  Patients 
without a valid tumor response evaluation at randomization will be censored 


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on the date of randomization.  Patients starting a new anti-cancer treatment 
prior to documented PD will be censored at the date of the last observed 
tumor assessment prior to start of the new treatment.  Patients with 
documented PD or death after an unacceptable long interval (i.e., 2 or more 
missed or indeterminate scheduled assessments) will be censored at the time 
of the last observed tumor assessment date.  PFS will be calculated as the 
date of the event/censor minus date of randomization plus one. 
 
The primary analysis will be performed using a stratified log-rank test 
comparing the PFS difference between two treatment arms.  The final PFS 
analysis will preserve the 1-sided alpha at 0.10.  Stratification factors will 
include bone-only disease (yes, no) and geographic status (US, and non-US).  
Kaplan-Meier estimates will be used to display PFS time graphically.  Cox 
proportional hazards model will be used to estimate hazard ratio and the 
corresponding 80% confidence interval.  Median PFS event times and 80% 
confidence interval will be computed as well. 


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Study Schema 
 
 
 
 
HRG screening 
Randomize 
1:1  
(N=80) 
Seribantumab 
+ Fulvestrant 
(N=40)  
Placebo + 
Fulvestrant 
(N=40) 
HRG+ 


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1. Introduction 
1.1. Breast Cancer 
Breast cancer remains one of the most common and deadly cancers in the United States, with 
an expected 231,840 newly diagnosed cases and 40,290 related deaths in 2015 alone 
(American Cancer Society, 2015). Among these, the largest molecular diagnostic subgroup 
(~70%) comprises of patients with hormone receptor positive (ER+/PR+; ER+/PR-; ER-
/PR+) and HER2 negative (IHC <3+ and/or FISH negative) disease (Onitilo, Engel, 
Greenlee, & Mukesh, 2009). For patients with metastatic disease the reported median 
survival ranges from 18-36 months (Eniu, Palmieri, & Perez, 2005). Although metastatic 
breast cancer is not curable, meaningful improvements in survival have been seen, coincident 
with the introduction of newer systemic therapies (Gennari, Conte, Rosso, Orlandini, & 
Bruzzi, 2005). 
1.2. Treatment for ER/PR positive HER2 Negative Advanced Breast Cancer  
The general therapeutic principle for all patients with ER/PR positive metastatic breast cancer is 
aimed at prolonging survival and improving quality of life. This includes surgical intervention 
and the use of endocrine therapies for as long as possible to avoid the inherent toxicities of 
chemotherapy-based regimens. This is reflected in the current NCCN treatment guidelines that 
state: “systemic treatment of breast cancer recurrence or stage IV disease prolongs survival and 
enhances quality of life but is not curative. Therefore, treatments associated with minimal 
toxicity are preferred”.  
Patients with metastatic disease have several first-line options where aromatase inhibitors (AIs) 
or fulvestrant are generally the preferred agents for first-line therapies as single agents.  For 
postmenopausal patients with metastatic breast cancer who are endocrine therapy-naïve, 
progressing >12 months from the end of adjuvant therapy, or who present with de novo 
metastatic breast cancer, the options include an AI plus palbociclib or single-agent therapy using 
fulvestrant or an AI. Fulvestrant is a selective estrogen receptor down-regulator (SERD) and is 
indicated for the treatment of hormone receptor positive metastatic breast cancer in 
postmenopausal patients with disease progression following anti-estrogen therapy.  
Palbociclib (formerly PD 0332991) is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK 
4/6). Palbociclib plus letrozole received US Food and Drug Administration (FDA) 
accelerated approval as first-line therapy for metastatic ER-positive human epidermal growth 
factor receptor 2(HER2)-negative breast cancer in 2015 (Finn et al., 2015). Treatment with 
letrozole plus palbociclib resulted in a statistically significant increase in progression free 
survival (PFS) in the combination arm. Overall survival appeared favorable of the 
combination arm as well, but did not reach statistical significance. We would expect the 
majority of patients to receive this combination as their first line therapy where available 
before enrolling onto this study. Another combination option is available with the 
mechanistic target of rapamycin (mTOR) inhibitor everolimus for postmenopausal patients 
for the treatment of AI-resistant advanced ER+ breast cancer. In combination with 
exemestane, the benefit of everolimus was shown in the Breast Cancer Trials of Oral 
Everolimus (BOLERO-2) trial, which enrolled 724 patients who had progressed on 
anastrozole (Baselga et al., 2012)(Piccart et al., 2014). An improvement in PFS along with a 
higher ORR was observed for this combination but no statistically significant OS benefit was 


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observed at the time of the study publication or more recently in a follow up study on more 
mature OS data. The use of everolimus in an early line setting for advanced disease must be 
tempered by the significant adverse event profile observed in comparison to an AI alone. 
Patients are allowed to receive this combination prior to enrollment onto this study as well. 
There remains limited second-line and beyond endocrine therapy options in the metastatic 
setting with the AI, exemestane, being one of the more commonly used agents, and 
fulvestrant being another established option. 
Innate and acquired resistance to endocrine therapy are significant therapeutic challenges in 
this context, as only those patients who have continuous sensitivity to endocrine therapy 
experience long-term survival with a reasonably good quality of life. Unfortunately, many 
patients develop resistance to endocrine therapy, resulting in very short treatment durations 
and the earlier need to move to cytotoxic chemotherapy, especially in the second-line setting 
and beyond.  For patients who progress after two lines of endocrine therapy, treatment must 
be individualized based on their prior treatment response, tumor burden, and preferences for 
treatment. Finally, due to the obvious clinical benefits and positive tolerability profile of 
endocrine therapies in comparison to both, mTOR inhibitors and chemotherapies, 
identification and targeting of pathways which are mediating resistance to endocrine 
therapies is a thus far unmet clinical need.  
1.3. Predictive Biomarkers for Response to Treatment  
Endocrine therapies directed against the pro-proliferative effects of hormones in breast 
cancer are frontline treatments offering substantial survival benefits to breast cancer patients. 
Unfortunately, evolution of drug resistance in many patients lessens the clinical utility of this 
class of drugs (Harb, 2015). As discussed above, the identification of factors that can predict 
resistance or treatment failure is essential to guide patients to the correct drug treatments and 
courses of treatments.  Personalized medicine aims to improve response rates and reduce 
mortality by getting the right patients the correct drug.  
Endocrine therapy resistance can be classed as broad endocrine resistance or agent specific, 
where a tumor does not entirely rely on hormonal signaling or in the latter case changing to 
alternative anti-hormonals can still elicit significant responses (Dalmau, Armengol-Alonso, 
Muñoz, & Seguí-Palmer, 2014). Multiple molecular mechanisms of resistance have been 
described and investigated in the preclinical setting and followed up by analysis of archived 
tissues (Simon, Paik, & Hayes, 2009). Such mechanisms include ERα protein levels, 
phosphorylation status, PR protein expression, cell cycle regulator expression changes and 
hormone level changes due to metabolism.  In addition, activation of growth factor pathways 
has also been implicated in endocrine treatment resistance, where MAPK and PI3K 
activation leads ERα independent growth or can via cross-talk with ERα promote treatment 
resistance (Hayes & Lewis-Wambi, 2015).  For example, examination of HER1, HER2 and 
HER3 levels in the tamoxifen and exemestane adjuvant multinational (TEAM) trial revealed 
that only patients with HER1-3 negative tumors had a decreased risk of relapse when 
receiving exemestane versus tamoxifen (Bartlett et al., 2013). However, the validation of a 
biomarker in a randomized clinical trial that faithfully predicts the activation of such 
pathways and thus the emergence of resistance is currently not available to fully guide the 
selection of endocrine therapy for real time benefits to patients (Beelen, Zwart, & Linn, 
2012). Neither the BOLERO-2 study nor the PALOMA trials have identified a mechanistic 


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biomarker able to predict which patients will respond to the respective combinations, and 
which are at risk of early disease progression and therapeutic failure. 
Identification and implementation of clinically relevant biomarkers that help physicians 
guide patients treatment programs in ER/PR positive advanced breast cancer are urgently 
needed and represent a highly relevant unmet need in this indication. 
Available pre-clinical and clinical data suggests that the ErbB3-AKT signaling pathway may be 
a key player in mediating such resistance to endocrine therapies. In addition, Merrimack has 
demonstrated that the addition of seribantumab, an ErbB3 directed monoclonal antibody, to 
endocrine based therapies could potentially bring an improved endocrine based treatment option 
to patients who have been selected based on the presence of heregulin (HRG) in their tumors.  
1.4. ErbB3 
ErbB3 was first isolated and characterized in 1989 (Kraus et al., 1989)  The ErbB3 receptor is a 
.
148 kilodalton (kDa) transmembrane receptor tyrosine kinase belonging to the ErbB/EGFR 
family and was shown to be kinase dead (Citri et al., 2003). The ErbB family of transmembrane 
receptor tyrosine kinases impacts the physiology of cells and organs by eliciting ligand-
dependent activation of multiple signal transduction pathways. Upon binding of HRG, the 
physiological ligand for the ErbB3 receptor, ErbB3 dimerizes with other ErbB family members, 
preferentially ErbB2.  
Heregulin, the cognate ligand to ErbB3, has been shown to be involved in several different types 
of cancer: breast, ovarian, endometrial, colon, gastric, lung, thyroid, glioma, medulloblastoma, 
melanoma, as well as squamous cell carcinomas of the head and neck (Breuleux, 2007; Stove & 
Bracke, 2005). In most of these tumor types, HRG regulates growth, invasion, and angiogenesis 
through the presence of either autocrine or paracrine HRG signaling.  It is thought that autocrine 
HRG may give rise to constitutively activated ErbB2 and ErbB3, protecting these tumors against 
apoptosis and generating growth factor independence (Li et al., 2004; Mills & Yarden, 2010; 
Sheng et al., 2010). Disruption of the heregulin autocrine loop by blocking HRG binding to 
ErbB3 or disruption of the ErbB2/ErbB3 dimer is considered to provide an important therapeutic 
measure to control cancer cell growth (Yarden & Pines, 2012; Yarden & Sliwkowski, 2001). 
An important defining feature of the ErbB network is that two members of the family, ErbB2 
(also known as HER2/neu) and ErbB3, are non-autonomous. ErbB2 lacks the capacity to interact 
with the growth-factor ligand, whereas the kinase activity of ErbB3 is defective. Despite this lack 
of autonomy, both ErbB2 and ErbB3 form heterodimeric complexes with other ErbB receptors 
that are capable of generating potent cellular signals. Mechanistic details of this pathway are 
summarized below. 
• HRG is a ligand for ErbB3, where ErbB2 is the main binding and activation partner upon 
ligand binding. 
• The role of ErbB3 and HRG in the development and progression of multiple cancers is 
becoming better established in patients. Indeed, it has recently been shown that ErbB3 
levels are associated with shorter disease-free survival in patients with invasive breast 
carcinoma. ErbB3 expression has also recently been shown to be predictive of poor 
prognosis in multiple cancers. 
• Dimerization of ErbB3 with other ErbB family members results in transphosphorylation 
of ErbB3 on tyrosine residues, six consensus YXXM tyrosine phosphorylation motifs, 


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contained with the cytoplasmic tail of the protein. Such signaling activated downstream 
pathways including MAPK and PI3K/AKT that are known to play a role in cancer. (Dey, 
Williams, Leyland-Jones, & De, 2015) 
• In addition to the effects of ErbB3 and its ligands on the pathophysiology of multiple 
malignancies, they are also believed to be integrally involved in the resistance of several 
tumor types to targeted therapies or chemotherapy. (Ma, Lyu, Huang, & Liu, 2014) 
• Pioneering studies have demonstrated that high expression of ErbB3 can predict early 
escape from the anti-ErbB2 monoclonal antibody trastuzumab. Moreover, ErbB3 
expression has also been associated with resistance to anti-estrogen therapy(Arteaga & 
Engelman, 2014) 
Therefore, monoclonal antibodies like seribantumab that can target the ligand binding domain of 
ErbB3 may represent a novel anti-neoplastic strategy. Based on the data presented in this 
document, Merrimack believes that targeting the ligand binding domain of ErbB3 is a promising 
strategy in HR-positive, HER2-negative mBC. 
1.5. Seribantumab 
Seribantumab is a fully human, monoclonal IgG2 antibody that binds to the HRG domain of the 
ErbB3 receptor with single digit nanomolar affinity and is being developed as an anti-cancer 
therapeutic. By preventing HRG from binding to the ErbB3 receptor, seribantumab effectively 
blocks heterodimer formation of the ErbB3 receptor with e.g. ErbB2 and EGFR and potently 
blocks downstream signaling activation and cancer cell survival. Merrimack Pharmaceuticals 
originally identified the ErbB3 receptor as a novel therapeutic target using a systems biology 
approach which allows for a holistic understanding of the dynamics of a specific signaling 
pathway by applying mechanistic computational models and quantitative biology (Rajkumar, 
Stamp, Hughes, & Gullick, 1996; Schoeberl, Eichler-Jonsson, Gilles, & Müller, 2002; Sheng et 
al., 2010). In addition, the insights gained by computer simulations were also used to generate a 
preclinical biomarker hypothesis that was tested clinically in previous randomized Phase 2 
studies and led to the identification of HRG as the principal biomarker for seribantumab efficacy.  
1.5.1. Pre-Clinical Experience of Seribantumab in Breast Cancer 
In order to identify the most potent pathways that are critical for cancer progression, AKT 
phosphorylation was analyzed as a surrogate marker in the National Cancer Institute (NCI)-60 
panel of 60 cell lines (59 presently available) derived from several different cancer types. These 
include leukemias, melanomas, ovarian, renal, prostate, colon, lung, and central nervous system 
(CNS) cancers. Each of the cell lines in the NCI-60 panel was stimulated with 60 different 
ligands (cytokines, chemokines, hormones, and growth factors), and AKT phosphorylation was 
assessed by enzyme-linked immunosorbent assay. The results showed that HRG1-β1 and the 
epidermal growth factor-like ligands are very potent activators of AKT signaling as compared to 
other growth factors or chemokines. This data indicates that the HRG family of ligands are some 
of the strongest inducers of AKT phosphorylation, which is a prosurvival signal. (Schoeberl et 
al., 2002) 
 
 


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Figure 1: Pro-survival AKT Signaling is Activated by ERBB3 Ligands 
 
The NCI-60 cell panel was screened for AKT activation in response to stimulation with multiple 
growth factor ligands. 
1.5.1.1. 
Seribantumab is a Potent ErbB3 Antagonist 
Based on the results from the sensitivity analysis, the ErbB3 inhibitor simulations, and 
experimental data, we identified ErbB3 as a potential therapeutic target and developed 
seribantumab, a fully human IgG2 mAb that binds specifically to ErbB3. The dissociation 
constant (Kd) for seribantumab was determined to be 769 pM, with an association rate of 1.43 × 
105 M−1 s−1 and a dissociation rate of 1.10 × 10−4 s−1 measured by kinetic exclusion assay 
(KinExA).  The signal inhibitory activity of seribantumab is shown in Figure 2  where cells were 
,
stimulated with HRG in the presence of varying concentrations of seribantumab and 
phosphorylated ErbB2 and ErbB3 and the downstream effector AKT was measured. This data 
illustrates that seribantumab is an effective ErbB3 pathway agonist. 
 
 


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Figure 2: Seribantumab Inhibits HRG-mediated Signaling Through the ErbB2-ErbB3-
AKT Signaling Pathway 
 
Cells were treated with seribantumab for1.5 hours and then stimulated with HRG for 10 min after 
which tyrosine phosphorylated ErbB2 & ErbB3 and serine phosphorylated AKT was measured. 
1.5.1.2. 
Heregulin stimulation promotes Estrogen Receptor Positive Breast Cancer 
Cell Line Proliferation  
To explore the effect of the ErbB3 ligand, HRG on proliferation, we tested the HR-positive, 
HER2-negative cells lines MCF7, T47D and HCC1428 using an established CTG assay that 
measures cellular ATP as an indicator of viability. We found that HRG stimulated proliferation 
of all of the HR-positive, HER2-negative cells lines in vitro, indicating that HRG may be a 
ligand promoting proliferation of this type of breast cancer. This finding is relevant to this 
particular indication as HRG mRNA has been found in approximately 40 to 50% of advanced 
breast cancer patients’ tumor samples. In addition, other cancer indications such as HNSCC, 
HRG mRNA is found in more than 90% of patient tumor samples  
Figure 3: HRG Promotes Proliferation of HR-positive, Her2-negative Breast Cell Lines 
 
Cells were stimulated with HRG for 6 days and proliferation was measured by CTG assay. 
1.5.1.3. 
Heregulin stimulation of ErbB3 promotes Estrogen Receptor Phosphorylation 
To explore the effect of inhibiting HRG-mediated ERBB3 signaling on ER phosphorylation, we 
stimulated MCF-7Ca cells, which exogenously express the CYP19 aromatase gene, in vitro with 
HRG, in the presence and absence of seribantumab, and measured phosphorylated protein levels 


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by immunoblotting. Treatment with HRG potently stimulated ERBB3 and AKT phosphorylation, 
as well as ER phosphorylation at serine 167 and serine 305 (Figure 4 , indicating d
)
irect cross-
talk between the ErbB3 and ER signaling pathways in this cell line. Treatment with 
seribantumab reduced HRG-stimulated phosphorylation of ErbB3, AKT and ER in MCF-7Ca 
cells. 
Figure 4: Heregulin Activates ER Phosphorylation in MCF-7Ca Cells 
 
Serum-starved MCF-7Ca cells were pre-treated with seribantumab (Seri; 1 µM) for 1 h, followed 
by treatment with 10 nM HRG for 10 min 
1.5.1.4. 
Heregulin Blocks the Anti-hormonal Activity of Fulvestrant  
Based on our findings that HRG stimulates the proliferation of HR-positive cell lines and that 
HRG-ErbB3 signaling promotes phosphorylation and activation of the estrogen receptor, we next 
wanted to evaluate the effect such activation had on the activity of anti-hormonal drugs. We 
chose the clinically relevant anti-hormonal, fulvestrant as it has a dual mechanism of action, 
whereby it blocks binding of estrogen to the estrogen receptor and also promotes its degradation 
and is approved for the treatment of HR-positive, HER2-negative advanced breast cancers. 
Figure 5: HRG Blocks the Activity of Fulvestrant in HR-positive, HER2-negative Cell 
Lines 
 
Cells were stimulated with HRG for 6 days and proliferation was measured by CTG assay 
As shown in Figure 5  we found that HRG could block the anti
,
-proliferative effects of the anti-
hormonal, fulvestrant in MCF7, T47D and HCC1428 cell lines when proliferation was measured 
in vitro. These findings suggested that HRG-ErbB3 signaling may be an anti-hormonal resistance 
mechanism in cancer cells that show activation of this pathway and prompted us to evaluate 
inhibition of this signaling axis with seribantumab. 


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1.5.1.5. 
Heregulin Blocks the Anti-hormonal Activity of Fulvestrant and Blocking 
ErbB3 with Seribantumab Restores Sensitivity 
Based on our previous findings that HRG could block the anti-hormonal activity of fulvestrant, 
even in the absence of exogenously added estrogen, we next examined the effect of blocking 
HRG binding to ERBB3 with seribantumab. In this experiment, we added to both HRG and 
estrogen to challenge the system fully. Figure 6 shows that the addition of estrogen to cells 
increases the proliferation rate considerably in both of the cellular models.  As would be 
expected, fulvestrant significantly inhibits the estrogen induced increase in proliferation. 
However, the addition of HRG to cells treated with both estrogen and fulvestrant, shows 
considerable inhibition of fulvestrant activity, which is in agreement with our previous data 
demonstrating that HRG mediates insensitivity to fulvestrant in these cellular models (Figure 5 . 
)
Finally, when we treated cells with seribantumab in the presence of estrogen and HRG we found 
that fulvestrant activity was almost restored completely. Taken as a whole, this data set indicates 
that the HRG-ErbB3 signaling axis may be promoting insensitivity to anti-hormonal agents such 
as fulvestrant and these findings are in agreement with data published from other groups that 
suggest that inhibiting this signaling pathway may offer benefit to patients who have HRG 
present in their tumors (Morrison et al., 2013)(Hutcheson et al., 2011). 
Figure 6: HRG Blocks the Activity of Fulvestrant in HR-positive, Her2-negative Cell Lines 
and Seribantumab Restores Fulvestrant Sensitivity 
 
Cells were stimulated with HRG for 6 days and proliferation was measured by CTG assay 
1.5.1.6. 
Combination of Aromatase Inhibitor and Seribantumab in a HR+ Breast 
Cancer Xenograft Model 
HER2 and HER3 signaling have previously been implicated in the development of resistance to 
anti-estrogens such as tamoxifen, and inhibition of ErbB3 signaling was shown to overcome 
HER2-mediated tamoxifen resistance in ER+ breast cancer cells. More recently, studies using an 
in vivo model of post- menopausal ER+ breast cancer indicated that the development of 
resistance to the non-steroidal AI letrozole was associated with up-regulation of HER2 
expression in xenografts(Curley et al., 2015). 


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In this study, we used this same model of post-menopausal ER+ breast cancer to determine the 
effect of blocking HRG-mediated ERB3 signaling and /or estrogen-mediated ER activation on 
tumor growth (Figure 7 . MCF
)
-7Ca xenograft tumors were generated in female, ovariectomized 
nude mice, which were randomized to receive vehicle (“Control”; 0.3% hydroxypropylcellulose 
(HPC) in 0.9% NaCl, twice weekly (Q2W), intraperitoneal injection (IP); 15 mice/group), 
seribantumab (750 μg/mouse, Q2W, IP; 15 mice/group), letrozole (10 µg/mouse/day x 5 
days/week (QD x 5), subcutaneous injection (SQ); 60 mice/group), or letrozole in combination 
with seribantumab, dosed as indicated for the monotherapies (15 mice/group). Changes in mean 
tumor volume (± SEM) were determined weekly by caliper measurement. Following the 
development of resistance to letrozole (week 14), mice in the letrozole-only group were re-
randomized into 15 mice/group to receive: letrozole alone; seribantumab alone; or a combination 
of letrozole and seribantumab.  
Figure 7: Seribantumab and Letrozole Co-treatment Delays the Onset of Resistance and 
Restores Sensitivity to Letrozole in MCF-7Ca Xenografts 
0
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
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1 6
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1 8
1 9
2 0
0
2 5 0
5 0 0
7 5 0
1 0 0 0
1 2 5 0
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1 7 5 0
W e e k s
M e a n  T u m o r V o lu m e (m m
3 )
C o n tro l
L e tro z o le
L e tro z o le  +  S e rib a n tu m a b
A d d
S e rib a n tu m a b
L e tro z o le
+
S e rib a n tu m a b
 
The MCF-7Ca–derived xenograft tumors initially responded to letrozole, but started to develop 
resistance after approximately 7-8 weeks of treatment (Figure 7). When mice were co-treated 
with letrozole and seribantumab, however, tumor growth was inhibited and resistance to 
letrozole substantially delayed (Figure 7 . This suggests that HRG/ERBB3 signaling was either 
)
active at the outset of the study or developed relatively quickly in response to letrozole treatment. 
Once resistance to letrozole was clearly established (week 14), mice in the letrozole-treated 
group were re-randomized to one of two cohorts: (i) continued letrozole monotherapy or (ii) 
seribantumab in combination with letrozole (Figure 3 . Notably
)
, the letrozole-resistant tumors 
displayed significantly decreased tumor growth when co-treated with letrozole and seribantumab 
compared to treatment with letrozole alone (Figure 3). This is consistent with the hypothesis that 


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blocking both estrogen/ER- and HRG/ErbB33-driven signaling provides greater antitumor 
activity than blocking either pathway alone 
The implications of combining seribantumab and letrozole are that targeting ErbB3 signaling in 
ER+ breast cancer tumors that express HRG may extend the activity of AIs in post-menopausal 
ER+ breast cancer patients after they have progressed on monotherapy AI. Furthermore, it is also 
tempting to speculate that the addition of seribantumab immediately upfront with an AI may 
delay the onset of resistance in these patients, a hypothesis that requires testing in a clinical trial 
setting. 
1.5.2.  Clinical Experience of Seribantumab in Humans 
Seribantumab has been studied in eight previous clinical trials under IND #100605 with a total of 
700 patients being exposed to seribantumab alone or in combination with other anti-cancer 
therapies. The first trial was a phase 1 open label, dose escalation study using a modified “3 + 3” 
design. Six cohorts of patients were enrolled (n=25), at doses of 3.2, 6, 10, 15 and 20 mg/kg and 
a 40 mg/kg loading dose followed by 20 mg/kg weekly maintenance dosing, and an expansion 
cohort of patients was enrolled at 20 mg/kg with a 40 mg/kg loading dose. At the close of the 
study, 43 patients were exposed to seribantumab. A Maximum Tolerated Dose (MTD) was not 
identified, and the highest dose tested was 40 mg/kg loading dose followed by 20 mg/kg on a 
weekly dosing schedule. 
Several other seribantumab trials were initiated in varying indications and chemotherapy 
combinations. Investigators should refer to the seribantumab Investigator’s Brochure for more 
information regarding ongoing and previous trials of seribantumab. Previous experiences in 
breast cancer and safety of seribantumab in combination with endocrine therapies are described 
in more detail below. 
1.5.2.1. 
Previous Experience of Seribantumab in Metastatic Breast Cancer  
Seribantumab was tested in combination with exemestane in a previous placebo-controlled Phase 
2 study in post-menopausal patients with ER/PR+, Her2 negative breast cancer. Using a dose of 
seribantumab as determined from a Phase 1 dose escalation study, patients were randomized to 
receive 25 mg exemestane daily in combination with either 20 mg/kg weekly seribantumab (with 
a 40 mg/kg loading dose) (N=59) or placebo (N=59) as presented at the American Society of 
Clinical Oncology (ASCO) (Higgins et al., 2014). The primary efficacy objective of achieving a 
50% reduction in hazard ratio in the Seribantumab group vs. the placebo group was not reached. 
The estimated median PFS was 15.9 weeks for the seribantumab group vs. 10.7 weeks in the 
placebo group, resulting in a hazard ratio of 0.772 (p=0.2486). 
A pre-planned biomarker analysis using archived tissue samples obtained from patients enrolled 
in the study showed that patients who had HRG positive tumors (as determined by RT-PCR 
testing) had an increased risk of progression when receiving exemestane alone in comparison to 
those patients who had HRG negative tumors. Patients with HRG positive tumors seemed to 
benefit from the addition of seribantumab to exemestane. These data are described in detail in 
Section 1.4. 
Additionally, seribantumab was tested in combination with paclitaxel in a previous Phase 2 study 
in patients with either locally advanced, pre-operative hormone receptor positive and Her2 
negative breast cancer (N=101).  Patients were randomized to receive either a 2- week run-in of 


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seribantumab followed by 4 weeks of weekly seribantumab in combination with paclitaxel or 4 
weeks of weekly paclitaxel alone. Both groups of patients were then treated biweekly with 4 
cycles (8 weeks) of doxorubicin in combination with cyclophosphamide and subsequently 
underwent surgery. The primary efficacy readout was pathologic complete response rate (pCR). 
Patients on the Seribantumab arm had a pCR rate of 10.1% (7/66) and patients on the control arm 
had a pCR rate of 3.3% (1/33). No formal hypothesis testing was done in this study. 
1.5.3. Potential Toxicities with Seribantumab 
The safety profile of Seribantumab has been robustly studied across nine previously conducted 
clinical trials, conducted as a monotherapy and in combination with various targeted and 
cytotoxic therapies. 
Findings from trials of seribantumab in human subjects are comprised of safety data from 962 
patients that have been enrolled into seribantumab studies under the IND #100605, including 700 
patients that have been exposed to seribantumab alone (n=43) or in combination with other anti-
cancer therapies (n=657).  Treatment-emergent adverse events (TEAEs) were reported in 98.9% 
of patients, regardless of relationship to study treatment. More than half the patient population 
reported TEAEs in the following systems organ class: gastrointestinal disorders (88.9% 
treatment, 74.8% control), general disorders and administration site conditions (78.7% treatment, 
72.1% control), skin and subcutaneous tissue disorders (75.9% treatment, 64.1% control), 
metabolism and nutrition disorders (59.3% treatment, 45.0% control), respiratory, thoracic and 
mediastinal disorders (57.4% treatment, 45.4% control), nervous system disorders (57.1% 
treatment, 54.2%) control), and infections and infestations (53.4% treatment, 46.9% control). 
As of July 2014, the most frequently occurring (>20% of patients) treatment emergent adverse 
events across all patients exposed to seribantumab as single agent or in combination therapies 
included: diarrhea (70.3%), fatigue (51.9%), nausea (45.4%), rash (32.9%), decreased appetite 
(29.7%), alopecia (26.4%), anemia (24.9%), vomiting (24.9%), hypokalemia (22.6%), stomatitis 
(22.3%), and peripheral neuropathy (20.1%). 
A breakdown of safety data by study is presented in the Investigator Brochure, including a 
separate study of 27 patients of seribantumab in combination with a PI3K-inihibitor, XL147, 
which was conducted by a different Sponsor.  Toxicities observed with combinations relevant to 
this study are further summarized below. 
1.5.3.1. 
 Previous Safety Experience of Seribantumab in Combination with 
Endocrine Therapies 
Seribantumab has been combined with exemestane in one previous placebo-controlled study, and 
56 patients were dosed with the combination. In this study, the most frequently reported adverse 
events (reported in ≥15% of patients) regardless of relationship included (treatment arm % vs. 
control arm %): diarrhea (50.0% vs 23.7%), nausea (28.6% vs 23.7%), fatigue (25.0% vs 
23.7%), arthralgia (21.4% vs 20.3%), cough (16.1% vs 16.9%), and decreased appetite (16.1% vs 
10.2%).  The most frequently reported adverse events (reported in ≥15% of patients) that were 
assessed by the Investigator to be related to seribantumab include: diarrhea (37.5% vs 11.9%), 
fatigue (19.6% vs 13.6%), and nausea (16.1% vs 18.6%). 


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Serious adverse events were reported in 7 patients (12.5%) on the seribantumab plus exemestane 
arm compared to 11 patients (18.6%) on the control arm. The most frequently reported serious 
event on the seribantumab containing arm was nausea, occurring in 2 patients (3.6%). 
Seribantumab has not been combined with fulvestrant in other clinical studies. It is expected that 
seribantumab will continue to combine well with endocrine agents and with no expected 
increases in frequencies of severe or serious adverse events. Increased reports of mild to 
moderate AEs may be observed for diarrhea, nausea, vomiting, and fatigue. 
1.6. Study Rationale 
Across the three randomized studies conducted with seribantumab in metastatic hormone 
receptor positive, HER2 negative breast cancer (mBC), platinum resistant ovarian cancer (mOC) 
and EGFR wild-type NSCLC that has progressed following a platinum based front-line therapy 
for metastatic or locally advanced disease, a consistent finding emerged: high mRNA levels of 
HRG appeared to be predictive of poor outcome when patients received only the standard of care 
treatment (exemestane (mBC), paclitaxel (mOC) or erlotinib (NSCLC)) (Figure 8). However, the 
data also suggested that the addition of seribantumab to exemestane, paclitaxel and erlotinib 
significantly improved progression free survival in patients who had HRG positive tumors 
(Figure 8). These data have been presented at ASCO and ESMO (Higgins et al., 2014; Liu et al., 
2014; Sequist et al., 2014), and Table 1 provides a summary for the findings in the overall study 
population and the HRG positive subgroups. A summary of the number of the samples and the 
types of assays performed on the biomarker samples received are presented in Figure 8. 
Figure 8: Number of Biomarker Samples Collected and the Analysis Performed for the 
Three Randomized 
 
Phase 2 Studies of Seribantumab 
The results from these pre-planned retrospective analyses were consistent with the hypothesis 
that blockade of HRG-induced ErbB3 signaling by seribantumab can restore sensitivity to 


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standard of care agents impacted by HRG. However, prospective selection of the relevant patient 
population is needed to validate these findings. A comprehensive review of the results from the 
completed seribantumab Phase 2 studies further suggested that the effect of the seribantumab-
mediated blockade of HRG signaling is particularly effective in the context of endocrine 
therapies, as these therapeutic backbones have the potential for substantial baseline efficacy in 
patients with endocrine sensitive disease. 
Figure 9: Positive HRG mRNA Levels Identify a Subgroup of Patients with an Increased 
Risk of Progression on Standard-of-care Therapies 
 
HRG mRNA was measured from fresh tumor biopsies using RNA in-situ hybridization (ISH) in 
the mOC and NSCLC studies and HRG positive was defined as staining positive (noted as 
“high” in the figure) and HRG negative (noted as “low” in the figure) as staining negative. In the 
mBC study HRG was measured using quantitative RT-PCR from archived tissue and HRG 
positive was defined as negative delta CT > -5. HER2 expression was measured using 
quantitative immunohistochemistry in mOC and HER2 low was defined as < 125892 receptors 
per cell which corresponds to an estimate of HER2 2+ using conventional HercepTest™. The 
three Kaplan-Maier plots show Risk of Progression estimates for patients with either high or low 
HRG mRNA levels in NSCLC (erlotinib), mOC (paclitaxel), and mBC (exemestane). 
Figure 10: Treatment Effect of Seribantumab in Patients with HRG Positive Tumors 
 
The addition of seribantumab consistently extended progression-free survival in patients with 
positive HRG mRNA levels (solid lines all graphs). Patients with mOC were also selected for low 
HER2 expression. Patients in the mBC and NSCLC study were HER2 low in accordance with 
inclusion criteria (mBC) or disease biology (NSCLC). 
 
 


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Table 1: Summary Statistics for Experimental Treatment vs. Control PFS in HRG 
Positive Subgroup  
Study group 
N 
Preva 
Seribantumab 
treatment arm vs. 
control arm in HRG 
positive subgroup 
Seribantumab 
Arm 
Comparator Arm 
Events 
PFS time 
(months) 
Events 
PFS time 
(months) 
HR 
95%CI 
P 
n (%) 
Median 
n (%) 
Median 
mBC (exemestane 
+/- Seribantumab) 
21 
37% 
0.32 
0.11-
0.97 
0.044 7 (63.6) 
7.7 
10 
(100) 
1.9 
mOC (paclitaxel 
+/- Seribantumab)b 
57 
38% 
0.37 
0.18-
0.79 
0.009 
26 
(66.7) 
5.8 
13 
(72.2) 
3.5 
NSCLC (erlotinib 
+/- Seribantumab) 
36 
54% 
0.37 
0.17-
0.82 
0.014 
20 
(87.0) 
1.9 
12 
(92.3) 
1.7 
a Prev = Prevalence of HRG positive subpopulation calculated from overall study population  
b In mOC the biomarker predicting benefit was a combination of HER2low and HRG positive 
1.6.1. Previous Experience in Heregulin Negative Patients 
In contrast to the data from the previous three randomized Phase 2 studies indicating that 
heregulin positive patients perform poorly on control treatments, patients whose tumors are 
negative for heregulin were consistently shown across the three trials to perform relatively well 
on control treatments. The data further suggested that, in mOC and NSCLC, patients with HRG 
negative tumors performed better on control than on the experimenta l arm. The statistics of the 
three Phase 2 studies summarized in Table 2 suggest that further development of seribantumab 
should focus on patients with HRG positive tumors. 
Table 2: Summary Statistics for Experimental Treatment vs. Control PFS in HRG 
Negative Subgroup 
Study Group 
Seribantumab treatment 
arm vs. control arm in 
HRGlow 
HRGlow 
Seribantumab arm 
HRGlow control arm 
Events 
PFS time 
(months) 
Events 
PFS time 
(months) 
HR 
95%CI 
P 
n (%) 
median 
n (%) 
median 
mBC (exemestane 
+/- Seribantumab) 
1.06 
0.51-2.19 
0.87 
17 (81.0) 
2.4 
13 (86.7) 
3.5 
mOC (paclitaxel +/- 
Seribantumab)a 
1.54 
0.98-2.44 
0.062 
65 (90.3) 
3.5 
27 (67.5) 
5.4 
NSCLC (erlotinib +/- 
Seribantumab) 
2.43 
1.07-5.55 
0.034 
19 (95.0) 
1.6 
10 (90.0) 
2.9 
a In mOC the biomarker predicting benefit was a combination of HER2low and HRGhigh 
1.6.2. Summary of Study Rationale 
Identification and treatment of resistance to endocrine therapies remains an unmet therapeutic 
need for patients with ER/PR positive, HER2 negative breast cancer in the advanced/ metastatic 
setting. This resistance to endocrine therapies often conflicts with the current treatment paradigm 
that is reflected in the NCCN treatment guidelines which asks for the use of well tolerated 
endocrine therapies as long as possible in the metastatic disease setting. Merrimack has identified 
HRG mRNA expression as a potential resistance marker to endocrine therapies and is evaluating 
a combination of seribantumab + endocrine therapies to overcome the resistance exhibited by 


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HRG positive patients. Seribantumab blocks HRG binding to the ErbB3 receptor and has the 
potential to substantially increase PFS for patients with ER/PR positive, HER2 negative and 
HRG positive metastatic breast cancer, while maintaining an acceptable safety profile. 
1.6.3. Rationale for Seribantumab Dose Selection  
Pharmacokinetic (PK) analyses support using a fixed dosing regimen for seribantumab. 
Seribantumab will be administered at a fixed dose of 3 g on day 1 and 15 of each 28-day cycle. 
Pharmacokinetics of seribantumab were evaluated using population pharmacokinetic analysis 
from 499 patients, comprising 4925 data points from the combined Phase 1 and Phase 2 studies.  
The pharmacokinetic data of seribantumab was described using a two-compartment model, with 
estimated parameters provided in Table 3  . Covariate selection evaluated potential relationships 
between baseline covariates (sex, race, age, weight, intended-dose, and study/indication) with 
volume of distribution and clearance.  The results indicated significant relationships between 
weight, sex, and clearance, with the final parameter estimates provided in Table 3   In particular, 
.
the model assumed a proportional relationship between the log of clearance (CL) and weight, 
and obtained an estimated proportionality constant of 0.203.  In the presence of the relationship 
between weight and clearance, no significant relationship between volume and weight were 
observed. 
To evaluate the benefit of weight-based dosing, a simulation study was conducted by comparing 
pharmacokinetics with weight-based and fixed dose regimens.  The simulation results showed 
comparable variability between both fixed-dosing and weight-based dosing regimens, suggesting 
no benefits of the reduced PK variability with weight-based dosing (Figure 9 . For example, a 
)
weight-based dosing of 20 mg/kg Q2W and a corresponding fixed dose of 1.5 g Q2W have 
comparable maximum, minimum, and average steady-state concentration levels and variability. 
The result can be explained because estimated proportionality between log of CL and weight is 
0.203, and therefore, a weight-based regimen (which assumed a proportionally constant of one 
between log of CL and weight) would tend to overdose higher-weight patients. 
To evaluate the optimization of seribantumab dosing regimens for improved compliance and 
simplicity, a simulation study was conducted to evaluate different dose intervals. The results 
showed the potential to optimize the dosing frequency to once every 2weeks.  A dose regimen of 
3 g Q2W is predicted to have: 
• A comparable maximum concentration (Cmax) to 40 mg/kg Q2W (40 mg/kg was 
previously used as a loading dose for weight-based and weekly seribantumab dosing 
regimens);  
• A comparable steady-state average concentration (Cavg) to previous dose used in the 
previous Phase 2 study (40mg/kg + 20 mg/kg Q1W);  
• A comparable minimum steady-state concentration to a dose regimen of 40mg/kg Q2W 
(the comparable weight-based dose with 3 Q2W).  
Therefore, seribantumab dose regimen of 3 g Q2W has a potential to improve compliance, while 
maintaining the pharmacokinetic levels within the bounds of the exposures observed from 
previously studied seribantumab doses (40mg/kg + 20 mg/kg Q1W). 
 
 


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Table 3: Final Parameter Estimates from Population PK Analysis of Seribantumab 
Parameters 
(Estimated) Values 
Number of patients 
499 
Fixed effects 
CL (L/wk) 
3.15 
V (L) 
3.23 
Q (L/wk) 
2.92 
V2 (L) 
2.68 
Random effects 
Omega CL (%) 
36% 
Cov CL and V (%) 
27% 
Omega V (%) 
37% 
Sigma 
 
Additive 
25.18 
Proportional 
0.23 
Covariate selection 
WT-CL 
0.203 
SEX-CL 
0.255 
WT-V 
0.002 
Figure 11: Simulated Seribantumab Pharmacokinetics (Average concentration) by Weight-
based and Fixed Dosing Regimens and by Dose and Intervals. 
 


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2. Objectives 
2.1. Primary Objective 
The primary objective of this study is to determine whether the combination of seribantumab 
plus fulvestrant is more effective than placebo plus fulvestrant, based on investigator assessed 
Progression Free Survival (PFS) in HRG positive patients (defined as HRG ISH score of  > 1+). 
2.2. Secondary Objectives 
The secondary objectives of this study are as follows: 
• To determine whether the combination of seribantumab plus fulvestrant is more effective 
than placebo plus fulvestrant in HRG positive patients (defined as HRG ISH score of > 1+) 
for the following clinical outcome parameters: 
o Time to Progression (TTP) 
o Overall Survival (OS) 
o Objective Response Rate (ORR) based on RECISTv1.1 
• To describe the safety profile of seribantumab in combination with fulvestrant 
• To characterize the pharmacokinetic (PK) profile of seribantumab, when given in 
combination with fulvestrant, and of fulvestrant, when given in combination with 
seribantumab 
2.3. Exploratory Objectives 
The exploratory objectives of this study are as follows: 
• To assess the correlation of HRG expression between fresh tissue biopsies and archival 
samples where both are available 
3. Study Design 
3.1. Overview of Study Design 
This study is a multi-center, randomized, double-blind, placebo-controlled Phase 2 study of 
seribantumab in women with ER/PR positive, HER2 negative, locally advanced or metastatic 
breast cancer whose tumor expresses HRG as measured by RNA in-situ hybridization (RNA-
ISH).  The purpose of the study is to assess if the addition of seribantumab to fulvestrant is more 
effective than placebo plus fulvestrant in prolonging progression-free survival in this patient 
population.  
Following signing informed consent and evaluation of initial eligibility criteria, all patients will 
provide a tissue sample (which meets the requirements for collection and processing as outlined 
in the study lab manual) for HRG testing. Descriptions of tissue types that are acceptable for 
testing are provided in Section 6.3.1. If adequate tissue is not available, patients should undergo 
a fresh tumor biopsy to obtain the adequate tissue required to perform HRG testing. For these 
procedures, investigators are asked to choose an easily accessible tumor lesion to minimize any 
possible risk associated with the collection of the tissue. As a general guideline, if the selected 
procedural location of the biopsy 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. Upon receipt of a tissue sample at the central lab, the investigational site will be 
informed of the results within 7 days. Patients with a positive HRG status, defined as HRG ISH 


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score of >1+, will be eligible for randomization. Patients with tumors that show no staining for 
HRG (ISH score = 0) will not continue any further procedures for this study and will be 
considered screen failures. Minimal medical history for HRG negative patients will be collected. 
Prior to receiving the first dose, all HRG positive patients that receive HRG results for eligibility 
based on testing of archived samples will also be asked to undergo a fresh research biopsy (either 
FNA or core needle) prior to first dose. An additional sample will not be requested from patients 
who underwent a fresh biopsy for eligibility testing. Once all screening procedures have been 
completed and eligibility for treatment randomization (including HRG positive ISH result) has 
been determined, the may randomize the patient.  Patients will be randomized in a 1:1 ratio 
(experimental arm versus comparator arm) using an Interactive Web Response System (IWRS). 
Randomization will be stratified based on bone-only disease (yes, no), and geographic status 
(US, non-US). 
Patients will be randomized to Arm A or Arm B: 
Arm A (Experimental Arm): 
• Seribantumab: fixed dose of 3000 mg IV on days 1 and 15 of each 28-day cycle 
• Fulvestrant: 500 mg intramuscularly (IM) on days 1 and 15 of Cycle 1, and on Day 1 of 
each subsequent 28 day cycle 
Arm B (Comparator Arm): 
• Placebo: intravenously (IV) on days 1 and 15 of each 28-day cycle 
• Fulvestrant: 500 mg IM on days 1 and 15 of Cycle 1, and on day 1 of each subsequent 28 
day cycle 
Treatment must start within 7 days following randomization. It is intended that patients will be 
treated until investigator-assessed disease progression or unacceptable toxicity, whichever comes 
first. Tumor assessments will be measured and recorded by the local radiologist every 8 weeks 
(+/- 5 days) from randomization using the RECIST guidelines (version 1.1). Tumor assessments 
will be performed every 8 weeks regardless of dose delays or dose interruptions, until 
investigator-assessed progressive disease. Patients who come off study treatment prior to disease 
progression, for reasons including patient or physician decision or unacceptable toxicity, will 
continue to undergo tumor assessments every 8 weeks (±5 days) until investigator assessed PD. 
Patients will be treated according to local assessment of tumor scans, and the primary analysis 
will be conducted based on investigator assessments.  
All patients will have a follow-up visit scheduled 30 days (±7 days) after the last dose of study 
treatment, regardless of reason for treatment termination. Patients will not be allowed to cross 
over from placebo to seribantumab. 
Survival follow up will be required for all patients every 2 months from the 30-day follow-up 
visit until death, loss to follow-up, withdrawal of consent, or study termination. After patients 
discontinue study treatment, subsequent anti-cancer therapies will be collected at the same time 
as survival follow-up. 
An independent data monitoring committee (DMC) will be established to monitor emerging 
safety data and evaluate for trial efficacy. The DMC will regularly monitor safety data over the 
course of the study in accordance with the DMC Charter.  


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4. Study Population 
The target population for this study is women who are candidates to receive single agent 
fulvestrant endocrine therapy for metastatic, ER/PR+ and HER2 negative breast cancer.  Such 
patients shall not have received prior treatment with chemotherapy in the locally advanced or 
metastatic disease setting and must have failed prior systemic therapy with a CDK inhibitor, and 
have tumors that are positive for heregulin (HRG) mRNA as assessed by RNA-ISH testing.  
Patients cannot have received more than a total of two prior lines of therapy in the locally 
advanced or metastatic setting. There is no restriction on chemotherapy use in the neoadjuvant or 
adjuvant settings. The investigator or his/her designee must ensure that all patients meet the 
following inclusion and exclusion criteria before being enrolled in the study:  
4.1. Inclusion Criteria 
To be eligible for participation in the study, patients must meet the following criteria. Patients 
who are HRG negative do not need to complete screening procedures beyond HRG assessment:  
a) Histologically or cytologically confirmed ER+ and/or PR+ (with staining of > 1% cells) 
breast cancer 
b) Confirmed postmenopausal status due to either surgical/natural menopause or ovarian 
suppression (initiated at least 28 days prior to Day 1 of Cycle 1) with a gonadotropin-
releasing hormone (GnRH) agonist such as goserelin 
c) HER2 negative per ASCO/CAP guidelines  
d) A positive in-situ hybridization (ISH) test for heregulin with a score of ≥1+, as 
determined by centralized testing of unstained tumor tissue  
e) Must have at least one lesion amenable to either core needle biopsy or fine needle 
aspiration 
f)  Progressed following at least one but no more than two prior systemic therapies in the 
locally advanced or metastatic disease setting  
• Received prior CDK inhibitor based therapy for locally advanced or metastatic 
disease 
g) Documented progression of locally advanced or metastatic disease as defined by RECIST 
v1.1.  Exception: patients with bone-only metastatic disease are eligible if they have at 
least 2 lytic lesions visible on a CT or MRI and have documented disease progression on 
prior therapy based on the appearance of new lesions.  
• Patients with bone-only lesions who have received radiation to those lesions must 
have documented progression following radiation therapy. 
h) Able to understand and sign an informed consent (or have a legal representative who is 
able to do so) 
i) ECOG Performance Score (PS) of 0 or 1 
j) Adequate bone marrow reserves as evidenced by: 
• ANC > 1500/µl 
• Platelet count > 100,000/µl; and 
• Hemoglobin > 9 g/dL 
k) Adequate hepatic function as evidenced by: 
• Serum total bilirubin ≤ 1.5 x ULN except for patients with Morbus Gilbert 
• Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and Alkaline 
Phosphatase ≤ 2.5 x ULN (≤ 5 x ULN is acceptable if liver metastases are present, 


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and ≤ 5 x ULN of Alkaline Phosphatase is acceptable if bone metastases are 
present) 
l) Adequate renal function as evidenced by a serum creatinine ≤ 1.5 x ULN 
m) Recovered from clinically significant effects of any prior surgery, radiotherapy, or other 
antineoplastic therapy. 
n) Patients may be treated with bone modifying agents such as bisphosphonates or receptor 
activator of nuclear factor kappa-B (RANK)-ligand agents (e.g. denosumab) per 
American Society of Clinical Oncology (ASCO) guidelines; whenever possible, patients 
requiring bone modifying agents should start treatment > 7 days prior to study therapy 
and should continue the same agent throughout study unless clinically compelled to 
change 
o) ≥ 18 years of age 
p) Patients who have experienced a venous thromboembolic event within 60 days of signing 
the main consent form should have been treated with anti-coagulants for at least 7 days 
prior to beginning treatment and for the duration of treatment on this study. 
4.2. Exclusion Criteria 
Patients must meet all the inclusion criteria listed above and none of the following exclusion 
criteria: 
a) Prior treatment with an anti-ErbB3 antibody  
b) Prior treatment with a chemotherapy in the locally advanced or metastatic disease setting 
c) Patients cannot have received prior treatment with fulvestrant or other SERDs in the 
locally advanced or metastatic setting 
d) Uncontrolled CNS disease or presence of leptomeningeal disease 
e) Inflammatory breast cancer 
f) History of another active malignancy that required systemic therapy in the last 2 years. 
Patients with prior history of in-situ cancer or basal or squamous cell skin cancer are 
eligible  
g) Active infection, or 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 may be enrolled 
h) Known hypersensitivity to any of the components of seribantumab, fulvestrant, or who 
have had hypersensitivity reactions to fully human monoclonal antibodies 
i) Received other recent antitumor therapy including: 
• Investigational therapy administered within the 28 days or 5 half-lives, whichever 
is shorter, prior to the first scheduled day of dosing in this study 
• Radiation or other standard systemic therapy within 14 days prior to the first 
scheduled dose in this study, including, in addition (if necessary), the timeframe 
for resolution of any actual or anticipated toxicities from such radiation 
j) NYHA Class III or IV congestive heart failure  
k) Patients with a significant history of cardiac disease (i.e. uncontrolled blood pressure, 
unstable angina, myocardial infarction within 1 year or ventricular arrhythmias requiring 
medication) are also excluded 


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l) Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; or active human 
immunodeficiency virus (HIV) infection, active hepatitis B infection or active hepatitis C 
infection 
m) Any other medical condition deemed by the Investigator to be likely to interfere with a 
patient’s ability to sign informed consent, interfere with a patient’s ability to cooperate 
and participate in the study, or interfere with the interpretation of the results 
4.3. Assessing Heregulin Status in Breast Cancer Specimens 
This study will only enroll patients with HRG positive tumors (defined as tumors with a HRG 
RNA-ISH score of >1+). Patients presenting with HRG negative tumors (HRG ISH score of 0) 
will not undergo any additional study procedures and will be considered screen failures; 
however, some minimal medical history information will be collected. A patient’s tumor HRG 
status will be assessed at a central CLIA certified lab using a qualified RNA in situ hybridization 
(ISH) assay. 
4.3.1. Description of HRG 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 
(IHC) assay. 
4.3.2. Implementation of HRG RNA-ISH Testing 
The HRG RNA-ISH assay can be used to measure mRNA expression on tissue slides obtained 
from formalin-fixed paraffin embedded archived blocks, core biopsies or fine needle aspirates; 
therefore, any of these methods of collection is acceptable for testing. Formalin-fixed clinical 
trial specimens will be submitted directly by clinical sites to the designated CLIA certified 
central lab. Full details regarding collection, processing and shipment of samples are outlined 
within the study lab manual. 
The central lab will process the samples and provide the stained slides to a trained pathologist to 
assess tumor content and percentage of tumor cells expressing HRG mRNA. The pathologist will 
assign scores of 0, 1+, 2+, or 3+ based on HRG mRNA staining. Samples scored at ≥ 1+ will be 
considered HRG positive, and samples scored at 0 will be considered HRG negative. This result 
will be communicated back to the investigative site within 7 days of sample receipt at the central 
lab. 
4.4. Patient Discontinuation 
A patient may withdraw from the study at any time and for any reason. It is intended that patients 
will be treated until investigator-determined progressive disease (radiologic or clinical 
deterioration) or unacceptable toxicity. Some possible reasons for withdrawal from treatment 
include, but are not limited to the following: 
• Progressive neoplastic disease per RECIST v1.1 
• Clinical deterioration 
• Adverse event, including treatment being withheld for 21 consecutive days without 
resolution of toxicities to grade 1 or baseline value 


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• Protocol violation / non-compliance 
• Withdrawal of consent 
• Investigator or sponsor decision 
• Patient is lost to follow-up 
When a patient is discontinued from treatment for any reason, they are to undergo the 
assessments in the End of Treatment visit within 30 days of the last dose. All patients who 
discontinue treatment as a result of an adverse event must be followed until resolution or 
stabilization of the adverse event. At the time a patient withdraws from study treatment, an 
attempt should be made to determine the reason(s) for discontinuation. The patient will continue 
to be followed for survival information every 2 months after completion of the End of Treatment 
visit. All patients, including patients who discontinue treatment for reasons other than 
progressive disease per RECIST 1.1, should undergo a scan to assess disease status at the time of 
treatment discontinuation, and again 8 weeks following treatment termination. 
If a patient does not return to the clinic for the end of treatment visit or is not reached for overall 
survival follow-up, at least 3 documented attempts, including one via certified mail, should be 
made to contact the patient.  If there is no response to these requests, the date of death should be 
captured from public records. 
5. Study Treatment 
5.1. Method of Assigning Patients to Treatment Groups 
If a patient is determined to be HRG positive, investigators will determine whether all other 
study enrollment criteria have been fulfilled. Upon completion of screening assessments, 
eligible, patients will be randomized 1:1 to the treatment or control arm using an Interactive Web 
Response System (IWRS). Randomization will be stratified based on bone-only disease (yes, no) 
and geographic status (US, non-US). 
5.2. Seribantumab 
5.2.1. Seribantumab Formulation, Packaging, and Labeling 
Seribantumab is supplied for IV administration as a sterile, colorless liquid at 25 mg/mL. It is 
packaged in sterile, single-use, clear borosilicate Type 1 glass vials that are closed with a coated 
rubber stopper and flip-off cap with flange.  
Multiple vials of seribantumab will be packaged in a cardboard container.  The individual vials, 
as well as the outside of the cardboard container, will be labeled in accordance with regulatory 
requirements and in compliance with country-specific guidelines.  Additional details are 
provided in the study pharmacy binder. 
5.2.2. Seribantumab Product Storage and Stability 
Seribantumab Drug Product must be stored refrigerated (2-8°C) with protection from light.  
Light protection is not required during preparation or infusion.  Seribantumab must not be 
frozen. 
Based on available stability data, the concentrate for solution for infusion is stable for at least 36 
months when stored according to conditions specified in the clinical supply label. Continued 
stability data are being generated, and longer stability may be available during the course of the 


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study. The date of expiration will be noted on the drug label, or via other pharmacy notifications 
as required by local regulation.  Seribantumab should not be used beyond the date of expiration. 
5.2.3. Seribantumab Dosage, Preparation, and Administration  
Seribantumab should be administered as an IV infusion at a fixed dose of 3000 mg on day 1 and 
day 15 of each 28-day cycle.  
Administration of seribantumab will require multiple vials, all of which should come from the 
same lot number. Seribantumab should be brought to room temperature prior to mixing with 
saline.  Vials of seribantumab should not be shaken.  The appropriate quantity of study drug will 
be removed from the vial, diluted with 0.9% normal saline to a final volume of 250 ml 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 equivalent amount of saline 
should be removed from the infusion bag to fill with seribantumab to 250 ml. The line should be 
flushed before and after the study drug infusion. Study drug should not be administered as a 
bolus or a push. 
5.2.4. Management of Infusion Reactions to Seribantumab 
Like other IV infusions, seribantumab administration may be associated with infusion related 
reactions (IRRs). Infusion related reactions will be defined according to the National Cancer 
Institute CTCAE (Version 4.03) definition of an allergic reaction/infusion reaction and 
anaphylaxis. In past clinical studies, IRRs with seribantumab have been rare with < 1% of 
patients reporting an IRR, of which all were Grade 1 or 2. Study site policies or the following 
treatment guidelines shall be used for the management of infusion reactions. 
Grade 1 
• Slow infusion rate by 50% 
• Monitor patient every 15 minutes for worsening of condition 
Grade 2 
• Stop infusion 
• Administer diphenhydramine hydrochloride 50 mg IV, acetaminophen 500-650 mg orally 
or IV, and oxygen 
• Resume infusion at 50% of the prior rate once infusion reaction has resolved 
• Monitor patient every 15 minutes for worsening of condition 
• For all subsequent infusions, pre-medicate with dexamethasone 10 mg orally or IV  
Grade 3 
• Stop infusion and disconnect infusion tubing from patient 
• Administer diphenhydramine hydrochloride 50 mg IV, dexamethasone 10 mg IV, 
bronchodilators for bronchospasm, and other medications or oxygen as medically 
necessary 
• No further treatment with seribantumab will be permitted 
Grade 4 
• Stop the infusion and disconnect infusion tubing from patient 
• Administer epinephrine, bronchodilators or oxygen as indicated for bronchospasm 


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• Administer diphenhydramine hydrochloride 50 mg IV, dexamethasone 10 mg IV 
• Consider hospital admission for observation 
• No further treatment with seribantumab will be permitted 
For patients who experience a Grade 1 or Grade 2 infusion reaction, at the discretion of the 
investigator, future infusions may be administered at a reduced rate (over 90 minutes). 
For patients who experience a second Grade 1 or 2 infusion reaction, administer dexamethasone 
10 mg IV.  All subsequent infusions should be pre-medicated with diphenhydramine 
hydrochloride 50 mg IV, dexamethasone 10 mg IV, and acetaminophen 500-650 mg orally.  
For patients who experience a Grade 3 or 4 infusion reaction, an anti-seribantumab antibody titer 
will be taken as close to the onset of the infusion reaction as possible for any patient 
experiencing an infusion reaction to seribantumab.  Anti-seribantumab antibody titer should also 
be obtained at the resolution of the event and 28 days (+/- 2 days) following the event. 
5.2.5. Management of Toxicity Related to Seribantumab 
In the event that a patient experiences a toxicity ≥ Grade 3 that is not an IRR and is possibly, 
probably or definitively related to seribantumab treatment, and not related to fulvestrant, it is at 
the investigator’s discretion to hold dosing or discontinue treatment with seribantumab. Prior to 
holding the dose or discontinuing treatment, the investigator must notify the sponsor and Medical 
Monitor.  
In the event that seribantumab treatment has been held for 28 consecutive days, the patient 
should be discontinued. No dose reductions for seribantumab are permitted. 
5.2.5.1. 
Potential Toxicities with the Combination of Seribantumab and Fulvestrant 
In addition to the established toxicities of fulvestrant, it is expected that the addition of 
seribantumab to fulvestrant may lead to an increased frequency of low grade diarrhea, rash, 
alopecia, stomatitis, hypokalemia and hypomagnesaemia. A slight increase in grade 3 diarrhea 
and/or hypokalemia may be observed, as well, in the combination setting. In previous studies, 
these events were generally well controlled with symptomatic treatments per institutional 
standards. 
Pulmonary embolisms, which exist as an identified risk for chemotherapies (Karavasilis et al., 
2014; Kellokumpu-Lehtinen et al., 2012; Matulonis et al., 2008; Reck et al., 2014) have also 
been described as an adverse event of special interest (AESI) for ErbB-pathway related 
inhibitors, including seribantumab when administered in combination with paclitaxel. Increased 
frequencies were observed in combination of seribantumab with paclitaxel in two completed 
randomized studies in neo-adjuvant breast cancer (4 (3.1%) on the treatment arm vs. 0 (0%) on 
the control arm) and platinum-resistant ovarian cancer (6 (4.3%) on the treatment arm vs. 1 
(1.3%) on the control arm). There was no general increase in venous thromboembolic events 
reported for these two studies. Pulmonary embolisms may be observed at a higher frequency 
with the combination of seribantumab and endocrine therapies. No increases in the frequency of 
pulmonary embolisms or other venous thromboembolic complications were observed in 
randomized studies with seribantumab in combination with exemestane in metastatic breast 
cancer. 


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Patients who have experienced a venous thromboembolic event within 60 days of signing the 
main consent form for this study should have been treated with anti-coagulants for at least 7 days 
prior to beginning treatment and for the duration of treatment on this study. 
5.3. Fulvestrant 
Fulvestrant (trade name: Faslodex®) is an estrogen receptor (ER) antagonist that binds to the 
estrogen receptor in order to downregulate the ER protein in human breast cancer cells. 
For managing patients receiving fulvestrant, investigators can use institutional guidelines, the 
fulvestrant package insert, or the following, which has been obtained from the Falslodex® US 
package insert (AstraZeneca, 2012). 
5.3.1. Fulvestrant Formulation, Packaging, Labeling, and Storage 
Please refer to the fulvestrant package insert located in the pharmacy binder for specific 
information on the fulvestrant formulation. 
Fulvestrant will be supplied by the Sponsor and labeled for investigational use only according to 
local regulations. Fulvestrant will be supplied as two 5-mL clear neutral glass barrels, each 
containing 250 mg/5 mL of fulvestrant solution for intramuscular injection and fitted with a 
tamper evident closure. The solution for injection is a clear, colorless to yellow, viscous liquid.  
Fulvestrant should be stored at refrigerated (2-8 °C). It should be stored protected from light and 
in the original packaging until the time of use. 
5.3.2. Fulvestrant Dosage and Administration 
The approved dose of fulvestrant is 500 mg administered intramuscularly into the buttocks. The 
injection should be as two 5 mL injections and should be administered slowly (1-2 minutes per 
injection). Injections should be given on days 1 and 15 of Cycle 1, and on day 1 of each 
subsequent 28 day cycle. 
Technique for administration of the injection is outlined in the package insert. Because 
fulvestrant is administered intramuscularly, it should be used with caution in patients with 
bleeding diatheses, thrombocytopenia, or anticoagulant use. 
5.3.3. Fulvestrant Dose Modifications 
In the event that an Investigator believes a dose modification is required for fulvestrant, the 
Sponsor and Medical Monitor should be contacted. The Investigator should use the local package 
insert for current dose modification guidelines for fulvestrant. 
5.3.4. Potential Toxicities with Fulvestrant 
Because fulvestrant is given intramuscularly, it is should be used with caution in patients with 
bleeding diatheses, thrombocytopenia, or anticoagulant use.  
Investigators should refer to the current fulvestrant package insert for information regarding 
potential interactions and toxicities. 
In a clinical trial of fulvestrant given at 500 mg in advanced breast cancer as described in the 
current US fulvestrant package insert (AstraZeneca, 2012 , the most
)
 frequently reported adverse 
events include: injection site pain (11.6%), nausea (9.7%), and bone pain (9.4%).  Additional 
adverse events reported in ≥5% of patients include: arthralgia (8.0%), headache (7.8%), back 


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pain (7.5%), fatigue (7.5%), extremity pain (6.9%), hot flashes (6.6%), vomiting (6.1%), 
anorexia (6.1%), asthenia (5.8%), musculoskeletal pain (5.5%), cough (5.3%), and constipation 
(5.0%). 
Safety information for fulvestrant can be updated at any time by the original manufacturer. 
Merrimack Pharmaceuticals does not own rights to or make updates to the overall safety 
information distributed for fulvestrant. For this reason, Investigators should refer to the most 
current package insert for fulvestrant for any changes in safety information. 
5.4. Rules for Dose Omissions and Modified Treatment Schedules 
It is intended that seribantumab and fulvestrant dosing occur on schedule per the protocol. In the 
event that dosing of any study drug has been held for 28 consecutive days and the investigator 
does not wish to continue dosing, the patient should be discontinued from treatment.  
Dose modifications of seribantumab are not allowed. Any dose modifications to fulvestrant 
should be performed in line with the local package insert, and should be discussed and approved 
by the Sponsor prior to implementation. 
5.5. Concomitant and Prohibited Therapies 
All intercurrent medical conditions and complications of the underlying malignancy will be 
treated at the discretion of the investigator according to acceptable local standards of medical 
care.  Patients should receive analgesics, antiemetics, antibiotics, anti-pyretics, GCSF, peg-
GCSF, and blood products as necessary.  All concomitant medications, including transfusions of 
blood products, will be recorded on the appropriate page of the case report form. Concomitant 
therapy (non-investigational products) includes any prescription medication, over-the-counter 
preparation, herbal therapy, or radiotherapy used by a patient between the 28 days preceding 
randomization and the study treatment discontinuation visit.  After the End of Treatment Visit, 
only anti-cancer therapies will be collected. 
The following therapies are not permitted while on study treatment: 
• Other anti-neoplastic therapy, including cytotoxics, targeted agents, endocrine therapy or 
other antibodies (patients who have been on GnRH analogues for more than 90 days prior 
to study entry may continue on these while on study) 
• Radiotherapy (patients who require a short course of palliative radiotherapy may continue 
on the study treatment after discussion between the investigator and sponsor) 
• Any other investigational therapy 
5.6. Accountability of Study Drug 
The investigator and investigational site staff are responsible for maintaining an accurate 
inventory and accounting of study drug.  A record of all vials and tablets of study drug received 
and administered will be maintained on an investigational drug inventory form provided by the 
Sponsor or an equivalent drug inventory form.  The following information will be recorded: 
• Date and quantity of study drug received 
• Date and quantity of study drug dispensed from the pharmacy per patient 
• Date and quantity of study drug administered to each patient 
• Date and quantity of study drug destroyed (if prepared and dispensed, but not 
administered for any reason, the study drug may not be returned to inventory) 


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• Date and quantity of study drug returned to sponsor, if applicable 
Each shipment of study drug will contain an invoice describing the amount of drug shipped to 
the investigational site.  The information on the invoice will be verified against the actual amount 
of drug received, after which the investigator or the investigator’s designee will place the invoice 
in the investigator’s file. 
The sponsor’s monitor will reconcile the information on the investigational drug inventory form 
with the actual amount of study drug remaining at each site on a routine basis. At the conclusion 
of the study, the monitor will either package and ship all unused vials of study drug back to 
Sponsor for destruction or document the destruction, in accordance with local regulations and 
institutional policy.  Following use, empty vials of study drug may be destroyed according to 
local regulatory and environmental requirements.  A record of any such destruction will be 
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6. Schedule of Assessment 
6.1. Schedule of Assessments: Heregulin Positive Patients 
Procedure 
Screening 
Visit 
Cycle 16 
Cycle 26 
Additional Cycles6 
Every 8 
weeks 
from first 
dose4 
30 
Day 
Follow
-Up14 
Every 2 
months 
from FU 
Visit 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HRG Testing 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Biopsy11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X2 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
ECOG PS 
X2 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
CBC 
X2 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Serum chemistry 
X2 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Coagulation profile 
X2 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Pregnancy test 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
ECG 
X1,3 
X16 
 
 
 
X16 
 
 
 
X16 
 
 
 
 
 
 
ECHO/MUGA19 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X20 
 
Archived tumor, if 
available 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fresh tumor biopsy 
X11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum for seribantumab 
PK7 
 
X7a 
 
X7b 
 
X7b 
 
X7b 
 
 
 
 
 
 
 
 
Serum for Ig8,9 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Serum for biomarkers14 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Plasma for ESR1 testing 
 
X21 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Plasma for fulvestrant PK 
 
X12 
 
X12 
 
X12 
 
X12 
 
 
 
 
 
 
 
 
Concomitant meds 
X1 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Seribantumab dosing 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Fulvestrant dosing 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
SAE/AE assessment and 
reporting17 
Continuous monitoring 
Hospitalization reporting18 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
Disease evaluation10 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
X5 
X 
 
Overall Survival Reporting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X15 


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1 Procedures to be completed within 28 days of signing the main informed consent form 
2 Procedures to be completed within 7 days of first dose of Seribantumab 
3 Two independent readings at least 5 minutes apart   
4 Evaluations may be performed + 1 week from the scheduled date of visit 
5 Any patient that comes off treatment for reasons other than progressive disease, will have a scan to assess disease status at the time of treatment discontinuation and additional scans 
every 8 weeks (+/- 1 week) until investigator-assessed PD 
6 All procedures should occur ±2 calendar days from scheduled date of visit 
7 Seribantumab PK:  all patients; in relation to seribantumab infusion 
a C1W1: immediately after the end of the Seribantumab infusion (+15 mins)  
b C1W3, C2W1, C2W3: pre-dose  
8 Immunogenicity samples should be collected for all patients prior to dosing. 
9 In the event a patient experiences an infusion reaction at any point in the study, an anti-Seribantumab antibody assay will be taken within 24 hours of the event, in addition to the 
scheduled time-points.  For patients who experience a Grade 3 or 4 infusion reaction to Seribantumab, an anti-Seribantumab antibody titer will be taken as close to the onset of the 
infusion reaction as possible, at the resolution of the event and 28 days (+/- 2 days) following the event. 
10 Disease evaluation per RECIST version 1.1.  
11 Tumor sample is to be collected for all HRG positive patients that receive HRG results for eligibility based on testing of archived samples. An additional sample is not required for 
patients who underwent a fresh biopsy for eligibility testing.  
12 Fulvestrant PK: all patients: prior to seribantumab injection 
13 Serum for biomarkers should be collected pre-infusion on week 1 of each cycle for all patients 
14 End of treatment (30-day Follow-up) visit should be completed within 30 days of the last dose of study drug 
15 Should patients refuse or drop out of survival follow-up, attempts should be made to obtain any death information available via public records. 
16 One reading prior to infusion with seribantumab.   
17 AE/SAE collection to be included. S/AE assessment and reporting will proceed as outlined in Sections 9.2 and 9.3 
18 All patient hospitalizations and/or hospital visits should be collected, whether or not associated with an adverse event. 
19 In addition to the timepoints noted, MUGA or Echocardiogram should be performed post-screening for any study patient who develops symptoms consistent with new onset of 
congestive heart failure. 
20 Unless performed within the last 4 weeks as part of assessments in the previous cycle 
21 Sample to be collected prior to any study treatment. 


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6.2. Schedule of Assessments: HRG Negative Patients 
Procedure 
Screening Visit 
Informed consent1 
X 
SAE assessment and reporting2 
X 
Cancer Diagnosis History3 
X 
Prior Anti-Cancer Therapies3 
X 
Prior Radiotherapies3 
X 
1 To be completed prior to any study-related procedures. 
2 Any serious adverse events considered by the Investigator to be directly related to screening procedures (i.e. 
related to screening biopsy) should be collected and reported from the time of informed consent up to receipt of 
HRG results. 
3 Minimal medical history will be collected from all HRG negative patients. 
6.3. Screening and Baseline Visit 
All procedures for screening and baseline are outlined in Section 6.1  . The window for screening 
procedures begins after signing the main consent form.  For further descriptions of the clinical 
and laboratory assessments required, please refer to Section 7 and 8 respectively. 
6.3.1. RNA-ISH Heregulin Testing 
All patients must submit a tissue sample for RNA-ISH testing of heregulin levels as soon as 
possible following signing the informed consent form, as this will determine patient eligibility 
for treatment randomization and subsequent screening procedures. The HRG RNA-ISH assay 
can be used to measure mRNA expression on tissue slides obtained from formalin-fixed paraffin 
embedded archived blocks, core biopsies or fine needle aspirates; therefore, any of these 
methods of collection is acceptable for testing. 
 If archive tissue is being used for eligibility testing, the most recent sample available should be 
submitted. Heregulin testing can be performed on tissue obtained at the following times: 
• At the time of initial diagnosis 
• At the time of metastatic diagnosis 
• or on tissue obtained from a fresh tumor biopsy. 
If collection of fresh tissue is required in order to provide adequate tissue for testing, attempts 
should be made to acquire tissue from a tumor in a non-significant risk location, as determined 
by the investigator. As a general guideline, if the selected procedural location of the core needle 
biopsy or FNA 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. Primary tumor 
samples and samples obtained from metastatic sites are both acceptable. 
Preparation of samples for HRG testing should be conducted in accordance with the laboratory 
manual. Specific procedures for the collection and processing of bone biopsies are provided in 
the manual. 
Samples will be processed and analyzed at a central facility where they are scored by a 
pathologist as specified in the lab manual with a turnaround time of no longer than 7 days from 
date of receipt by the central lab. Any patient who scores positive (a score of >1+) for HRG 
mRNA will be eligible for the study and should continue with screening procedures. 


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6.3.2. Heregulin Negative Patients 
Any patient whose tissue is negative (score of 0) for heregulin as determined by the RNA-ISH 
test will be considered a screen failure. Minimal medical history for HRG negative patients will 
be collected as outlined in Section 6.2. 
6.4. On-Study Visits 
Patients who are confirmed to meet all inclusion and exclusion criteria will be randomized via an 
IWRS.  Randomization must occur within 7 days of first dose (cycle 1 day 1).   
All on-study procedures and assessments are outlined in Section 6.1   During the treatment 
.
period, a window of ±2 days will apply to all visits, unless otherwise stated. 
6.5. End of Treatment Visit 
When it is decided that a patient will stop receiving treatment on this study, an End of Treatment 
visit must be completed within 30 days of last dose of study drug. All End of Treatment 
procedures and assessments are outlined in Section 6.1. 
6.6. Survival Follow-up 
Survival data will be collected via telephone or clinic visits every 2 months (±10 days) from the 
date of the 30-day follow-up visit until death, loss to follow-up, withdrawal of consent, or study 
termination by the Sponsor.  In addition, any new anti-cancer therapies and procedures should be 
collected and documented. All survival information will be captured using the electronic data 
capture (EDC) system. Should patients refuse or drop out of survival follow-up, attempts should 
be made to obtain any death information via public records whenever possible. 
7. Clinical Procedures and Assessments 
All following clinical procedures should be performed in accordance with the schedule of 
assessments outline in Section 6.1. 
7.1. Medical History and Demographics 
Demographic information including age, date of birth, race, ethnicity and gender will be 
collected.  
A medical history will be collected including all pertinent prior medical conditions, surgeries or 
other medical procedures, allergies, and concomitant medications.  
7.2. Adverse Event and Hospitalization Assessment Reporting 
Investigators should complete all routine and standard of care assessments to evaluate for 
toxicity and symptoms of drug-induced adverse events. This may include, but is not limited to, 
verbal reports from the patient and/or caregiver, physical examination and laboratory findings. 
Adverse events should be reported throughout the course of the study beginning at the time of 
signing the main study informed consent form, until the study termination visit, and followed 
through to resolution as detailed in Section 9.  
Adverse events and serious adverse events should not be reported for patients that only sign the 
biomarker informed consent form unless the event is considered by the investigator to be directly 
related to a study procedure (i.e. tumor biopsy for heregulin testing).  


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In addition, information on patient hospitalizations and/or unscheduled hospital visits should also 
be collected in the eCRF, whether or not associated with an adverse event. 
7.3. Vital Signs 
Vital signs should include height (screening only), weight, resting blood pressure, pulse, 
respiratory rate, and temperature. 
7.4. Performance Status Assessment 
The Eastern Cooperative Oncology Group (ECOG) performance status (PS) will be obtained by 
the PI or his/her designee by questioning the patient about their functional capabilities. 
7.5.  Electrocardiogram (ECG) 
A 12-lead electrocardiogram (ECG) will include a description of the cardiac rate, rhythm, 
interval durations, and an overall impression. QTc should be calculated using the Fridericia 
method (QTcF). ECGs will be performed for all patients at screening to rule out clinically 
significant abnormalities. For randomized patients, ECGs will be performed on week 1 of each 
cycle prior to dosing with seribantumab. 
7.6. Echocardiogram or Multiple Gated Acquisition Scan 
An echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) will be performed to 
determine ejection fraction.  The same procedure (ECHO or MUGA) performed during 
screening to determine the ejection fraction should be employed at subsequent visits. In addition 
to the required timepoints, ECHO or MUGA should be performed post-screening at any time for 
any study patient who develops symptoms consistent with new onset of congestive heart failure. 
7.7. Disease Evaluation 
Tumor response will be evaluated by the local radiologist according to the Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1 (Eisenhauer et al., 2009) to establish disease 
progression by CT or MRI. In addition, other radiographic or scintigraphic procedures (such as 
radionuclide bone scans), as deemed appropriate by the investigator, will be performed to assess 
sites of neoplastic involvement. The same method of assessment must be used throughout the 
study. Please refer to image acquisition guidelines for the requirements for image collection and 
scanner qualification. Investigators should choose target and non-target lesions in accordance 
with RECIST v1.1 guidelines. Follow-up measurements and overall response should also be in 
accordance with these guidelines. To be assigned a status of confirmed partial response (PR) or 
complete response (CR), changes in tumor measurements must be confirmed by repeated 
assessments that should be performed ≥30 days after the criteria for response are first met. 
Disease should be assessed every 8 weeks (±5 days) from randomization regardless of treatment 
schedule until investigator-assessed progression. In cases where there is a suspicion of disease 
progression prior to the next scheduled scan, an unscheduled assessment should take place. All 
patients who come off study treatment prior to disease progression for reasons including patient 
or physician decision or unacceptable toxicity will continue to undergo tumor assessments every 
8 weeks (±5 days) until investigator-assessed progression of disease. 


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8. Laboratory Procedures and Assessments 
8.1. Complete Blood Count (CBC) 
The CBC will include the following: hemoglobin, hematocrit, platelet count, RBC, WBC with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils and other cells).    
8.2. Coagulation Profile 
A coagulation profile will include activated partial thromboplastin time (aPTT), prothrombin 
time (PT), and an international normalized ratio (INR). 
8.3. Serum Chemistry 
Serum chemistry will include electrolytes (sodium, potassium, chloride and bicarbonate), BUN, 
serum creatinine, glucose, bilirubin, AST, ALT, alkaline phosphatase, LDH, uric acid, total 
protein, albumin, calcium, magnesium and phosphate.   
8.4. Urine or Serum Pregnancy Test 
A urine or serum pregnancy test will be obtained for all females of childbearing potential. 
Exempt female patients will include those who have undergone a bilateral oophorectomy or 
hysterectomy, or those who are menopausal (defined as absence of a menstrual cycle for at least 
12 consecutive months). The reason for exemption should be recorded in the medical history. 
8.5. Pharmacokinetic Testing 
8.5.1. Seribantumab PK Samples 
Blood samples will be collected from all patients to determine the levels of monoclonal 
antibodies that comprise seribantumab. The serum PK analysis will be performed post-dose on 
Cycle 1, Week 1, and pre-dose for all subsequent seribantumab infusions until the completion of 
Cycle 2, as outlined in Table 4. Approximately 5 mL of blood will be collected. The real time of 
blood collection must be documented in the respective eCRF. A laboratory manual will be 
provided with instructions for collecting, processing, and shipping the samples.  
PK samples should be collected at the following time-points relative to the seribantumab 
infusion: 
Table 4: Seribantumab PK Collection Timepoints 
Seribantumab PK Sample 
Pre-infusion 
Post-infusion 
Cycle 1, Week 1 
 
X 
Cycle 1, Week 3 
X 
 
Cycle 2, Week 1 
X 
 
Cycle 2, Week 3 
X 
 
8.5.2. Fulvestrant PK samples 
To determine the levels of fulvestrant, blood samples will be collected for all patients prior to the 
seribantumab dose on Cycle 1, Week 1, Cycle 1, Week 3, Cycle 2, Week 1, and Cycle 2, Week 
3. 
Approximately 5 mL of blood will be collected.  The real time of blood collection must be 
documented in the respective eCRF.  A laboratory manual will be provided with instructions for 
collecting, processing, and shipping the samples. 


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8.6. Anti-Seribantumab Immunogenicity 
Serum samples will be collected to determine the presence of an immunologic reaction to 
seribantumab (i.e. human anti-human antibodies; HAHA). A laboratory manual will be provided 
with instructions for collecting, processing, and shipping these samples. 
8.7. Biomarker Samples 
Biomarker data will be explored from collected tissue and serum samples to assess potential 
associations with tumor response. To help further understand the biological phenotype of 
heregulin-positive ER/PR+ and HER2 negative breast cancer, these samples will be used to 
assess the mRNA and/or protein for clinically relevant biomarkers for breast cancer, including 
ErbB receptors, cMET, IGF-1R, and FGF receptor tyrosine kinases and their respective ligands 
(ErbB ligands, HGF, IGFs and FGFs). Efficacy outcomes considered for pre-specified 
mechanistic biomarker analysis will include OS, PFS, and ORR. 
8.7.1. Tissue for HRG eligibility assessment  
The most recent available tumor tissue available from anytime between diagnosis and signing 
consent for this trial can be used for HRG testing. If no tissue is available, patients can undergo a 
fresh tissue biopsy, (either a CNB or FNA) to determine eligibility and are also asked to submit a 
second pass/ core or second aspirate for research purposes if possible. Directions for processing 
and shipping the tissue sample for heregulin testing can be found in the laboratory manual. 
8.7.2. Tumor Biopsy 
Prior to receiving the first dose of study drug, all HRG positive patients should provide one fresh 
tumor biopsy for research purposes. This biopsy will be used to confirm HRG status, and 
samples will be used to conduct exploratory studies to further characterize and correlate possible 
biomarkers that may help to predict or evaluate response to seribantumab. Patients who undergo 
a fresh tumor sample for eligibility testing do not need to provide an additional sample. 
8.7.3. Serum Samples 
Serum samples will be collected at time points described in Section 6.1  . Serum will be collected 
from all patients. The samples will be used to conduct exploratory studies to further characterize 
and correlate possible biomarkers that may help to predict or evaluate response to seribantumab. 
In the event that there is remaining sample available after conducting these analyses, it will be 
stored and used by the Sponsor for future biomarker analysis. At the time of informed consent, 
patients will be able to refuse storage of these remaining samples. Directions for processing and 
shipping the samples can be found in the laboratory manual. 
8.7.4. ESR1 Testing  
Plasma samples will be collected at time points described in Section 6.1 from all patients. These 
samples will be used to test for the ESR1 mutation in order to further characterize and correlate 
whether these mutations may help to predict or evaluate response to seribantumab. Directions for 
processing and shipping these samples can be found in the laboratory manual. 
8.7.5. Archived Tumor Samples 
If available, formalin-fixed paraffin embedded tumor samples (either a tumor block or freshly cut 
slides) obtained at the time of diagnosis will be collected to compare a patients HRG status with 


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the screening tissue sample if different, for example, a fresh biopsy of a metastatic lesion. 
Directions and requirements for processing and shipping the archived tumor samples can be 
found in the laboratory manual. 
9. Adverse Event and Hospitalization Reporting 
9.1. Definitions 
9.1.1. Adverse Events 
An adverse event is any untoward medical occurrence in a patient or clinical investigation patient 
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.   
9.1.2. Serious Adverse Event 
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 (Exception:  
hospitalization for elective treatment of a pre-existing condition that did not worsen 
during the study is not considered an adverse event. NOTE: Complications that occur 
during hospitalization are adverse events and if a complication prolongs hospitalization, 
then the event is serious); 
• 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 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. 
While the term “severe” is often used to describe the intensity (severity) of an event, the event 
itself may be of relatively minor significance (such as a severe headache). This is not the same as 
“serious”, which is based on a patient/event outcome or action criteria usually associated with 
events that pose a risk to a patient’s life or functioning. 
9.1.2.1. 
Progressive Disease 
Because of the natural history of metastatic breast cancer, the vast majority of patients will 
progress on treatment due to their underlying condition, resulting in hospitalization, appropriate 
medical care or death. Therefore, progression of underlying malignancy will not be recorded and 
reported as an adverse event or serious adverse event. In the event that the investigator is unsure 


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whether or not an AE is a result of the underlying malignancy, the AE should be submitted as a 
serious adverse event if it meets the appropriate seriousness criteria. 
9.2. Assessing and Documenting Adverse Events and Hospitalizations 
Adverse event assessment will begin in conjunction with informed consent. Investigators should 
complete all routine and standard of care assessments to evaluate for toxicity and symptoms of 
drug-induced adverse events. This may include, but is not limited to, verbal reports from the 
patient and/or caregiver, physical examination and laboratory findings. 
For all patients between informed consent and eligibility determination and for heregulin positive 
patients during their time on study, all adverse events, whether serious or not, will be described 
in the source documents and the adverse event page of the case report form.  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 the first Overall Survival follow-up visit or phone call, 
must be reported.  However, new adverse events felt by the investigator to be related to study 
treatment, must be reported any time the investigator becomes aware of such an event, even if 
this occurrence is after the first Overall Survival follow-up. All adverse events should be 
followed until resolution, or until the patient discontinues from the overall survival follow-up 
portion of the study. 
Laboratory, vital signs or ECG abnormalities are to be recorded as Adverse Events only if they 
are medically relevant: symptomatic, requiring corrective treatment, leading to discontinuation 
and/or fulfilling a seriousness criterion. 
Information to be 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 
• A determination of relatedness to the study drug 
• Action taken with study drug: none; change in the study drug administration (e.g., 
temporary interruption in dosing); drug treatment required; non-drug treatment required; 
diagnostic or concomitant procedure performed; patient discontinued from the study 
(complete Treatment Termination case report form) 
• Outcome: resolved without sequelae; resolved with sequelae; event ongoing; subject died 
(notify the Sponsor immediately, and complete the Serious Adverse Event page and the 
Subject Death page) 
9.2.1. Hospitalizations 
Information on patient hospitalizations and/or unscheduled hospital visits should be collected in 
the eCRF, whether or not associated with an adverse event. 
9.3. Reporting Serious Adverse Events 
Serious adverse events (SAE) will not be reported for patients who only sign the pre-screening 
consent form or for heregulin negative patients unless the serious event is directly related to a 
study procedure (i.e. tumor biopsy). Serious adverse event reporting will begin in conjunction 


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with the date of signing the main study informed consent. Any SAEs occurring prior to study 
drug administration that the investigator believes may have been caused by a protocol procedure 
must be reported immediately to the Sponsor or its designee and recorded on the case report 
form.  Serious adverse event reporting for HRG negative patients is not required unless the event 
is directly related to a procedure performed for this trial.  
All fatal or life-threatening adverse events must be immediately reported to the Sponsor or 
CRO’s medical team by telephone or e-mail.  Within 24 hours of the event, the Serious Adverse 
Event Form must be faxed to the Drug Safety Manager whether full information regarding the 
event is known or not.  Additional follow-up by the investigator will be required if complete 
information is not known. De-identified source documentation of all examinations, diagnostic 
procedures, etc. which were completed with respect to the event should be included with the 
SAE form. Care should be 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, include the laboratory normal 
ranges. 
In case of accidental or intentional overdose of study drug (seribantumab or fulvestrant), even if 
asymptomatic or not fulfilling a seriousness criterion, the overdose is to be reported to the 
Sponsor or Medical Monitor immediately (within 1 working day) using the AE and SAE forms. 
Overdose of study drug will be defined as ≥3300 mg of seribantumab, or ≥133% of planned dose 
of fulvestrant.  
All other serious adverse events must be reported to the Drug Safety Manager within 24 hours by 
phone, e-mail or fax. Details are outlined in the study procedure manuals.  The Serious Adverse 
Event Form must also 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 
will be required if complete information is not known. 
The Medical Monitor shall be contacted as deemed necessary by the site. Current contact 
information shall be maintained at the site within the regulatory binder. 
All serious adverse events (SAEs) will be evaluated by the 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. 
9.4. Determining the Severity and Relatedness of an Event 
9.4.1. Grading the Severity of an Adverse Event 
Each adverse event will be graded according to the NCI CTCAE V 4.03. For events not listed in 
the CTCAE, severity will be 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 
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• 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 
• Fatal: an event that results in the death of the patient 
9.4.2. Relatedness to Study Drug 
The investigator must attempt 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: 
• 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 pathological 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 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 
9.4.3. Reporting and Follow-up of Pregnancy 
Patients who become pregnant while on study must immediately discontinue study treatment, 
and the pregnancy must be immediately reported to the Medical Monitor.  Pregnancies occurring 
up to 6 months after the completion of the study medication must also be reported to the 
Sponsor.   
The investigator should inform the patient of the risks of continuing with the pregnancy and the 
possible effects on the fetus. Monitoring of the patient should continue 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 should be requested to report the pregnancy to the investigator, who in turn 


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should report it to the Sponsor. The partner should also be informed of the risks of continuing 
with the pregnancy, and the possible effects on the fetus. 
10. Statistical Methods 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a Statistical Analysis Plan (SAP), which will be dated and completed prior to 
database lock. The SAP may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint and/or its analysis will also be reflected in a protocol 
amendment. 
10.1. General Considerations 
Categorical variables will be summarized by frequency distributions (number and percentage of 
patients) and continuous variables will be summarized by descriptive statistics (mean, standard 
deviation, median, minimum, maximum).  Testing will be conducted using a one-sided 
0.025/two-sided 0.05 significance level unless stated otherwise.  Only 95% confidence intervals 
(CI) will be calculated when indicated.  Descriptive statistics will be displayed in abbreviated 
treatment identifiers instead of seribantumab + fulvestrant, fulvestrant, and overall.   
10.2. Statistical Hypothesis and Determination of Sample Size 
The primary hypothesis is to test for differences in progression-free survival (PFS) distributions.   
A stratified log-rank test will be used to analyze PFS differences with the stratification factors in 
the model:  Statistical significance will be determined by using a one-sided type I error of 0.10.  
A stratified Cox proportional hazards model will be used to estimate the hazard ratio using 
geographic region (US, non-US) and bone-only disease (yes, no) as stratification factors. 
The median PFS for the control arm (fulvestrant + placebo) is assumed to be 4.0 months in this 
patient population.  A total of 58 PFS events will be required across two treatment arms 
randomized in a 1:1 ratio giving 80% power to detect a hazard ratio (HR) ≤ 0.57 (mPFS: 4 v 7), 
assuming a 1-sided significance level of 0.10.  Approximately 200 patients will need to be 
screened in order to accrue 80 randomized in approximately 16 months with a total study 
duration of 20 months.   
10.3. Analysis Populations 
Patients that have signed informed consent, are identified as HRG positive based on centralized 
tissue analysis, and have successfully completed study entry criteria will be delineated into the 
following analysis populations:  
• Intent-to-Treat (ITT) population:  This population includes randomized patients.  
Patients will be analyzed in the randomized group.   
• Per Protocol (PP):  This population includes randomized patients.  Patients will be 
analyzed in the randomized group.  The PP population is the primary efficacy population 
and will only include patients that meet inclusion/exclusion criteria as defined in Section 
4.1 and 4.2 and are confirmed HRG positive based on the prospective fresh centralized 
tissue analysis (pre-treatment tissue sample).  
• Safety (SAF) population: The safety population includes patients receiving at least one 
dose of study medication. All safety analyses will be performed on this population.  
• PK population: All treated patients with at least one PK assessment. 


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10.4. Disposition, Demographics, and Baseline Characteristics 
Disposition of patients will be summarized, including those screened, treated, and discontinued. 
Reason for discontinuation will be summarized.  Demographic and baseline characteristics will 
be summarized.  Medical history and prior medications will be tabulated. 
10.5. Efficacy Analysis 
10.5.1. Primary Efficacy Analysis 
PFS is defined as the time from randomization to the first documented radiographical 
progression of disease using RECIST v1.1 or death from any cause, whichever comes first.  
Details of censorship will be thoroughly explained in the SAP.  PFS will be analyzed based on 
investigator assessed.  The primary endpoint will be based on the investigator assessment of 
disease progression.   
The Kaplan-Meier estimates will be used to determine median PFS and 80% CI for each 
treatment group. A stratified log-rank will be used to test for PFS distribution differences.  A 
stratified Cox proportional hazards model will be used to estimate the hazard ratio and 
corresponding 80% confidence intervals.  Stratification factors include: Geographic region (US, 
non-US) and bone-only disease (yes, no).   
10.5.2. Secondary Efficacy Analysis 
Overall Survival (OS) is defined as the time from the date of randomization to the date of death 
from any cause. Patients who are alive or lost to follow-up at the time of the analysis will be 
censored at the last known alive date.  The majority of patients are expected to live at least 2 
years, therefore the proportion of deaths at the time of the PFS analysis will not be sufficient for 
formal hypothesis testing of OS at that time.   
Various sensitivity analyses will be performed on PFS and OS which will be further detailed in 
the SAP.  PFS and OS will also be analyzed as an unstratified log-rank test for the primary and 
all sensitivity analysis as well.  Other analyses include a PFS sensitivity analysis performed by 
declaring all censors as events and testing with a stratified log-rank.  
Objective Response Rate (ORR) is defined as the proportion of patients with a RECIST v1.1 
response recorded from randomization until disease progression characterized as either a 
Complete Response (CR) or Partial Response (PR) relative to the total number of evaluable 
patients.  Frequency and percent will be as descriptive statistics while a Cochran-Mantel-
Haenszel (CMH) test stratified by stratification factor will be tested.  A chi-square test without 
stratification will also be presented.  Frequency and percent along with 95% CI will be 
calculated.  
Time to Progression (TTP) is defined as the time from the date of randomization to the date of 
objective tumor progression.  Those patients without objective tumor progression will be 
censored at the date of last tumor assessment documenting no objective progression.  Patients 
who died prior to first scan will be censored on the date of death. 
10.5.3. Subgroup Analyses 
PFS will be reported for each level of stratification factor and baseline covariate to check the 
homogeneity of treatment effect across levels of factors as defined in the statistical analysis plan. 
Median values for each level of factor will be computed using Kaplan-Meier estimates.  Cox 


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proportional hazards model will be used to calculate hazard ratios and CIs.  Forest plots will be 
generated to display hazard ratio treatment differences across subgroups which will be defined in 
the SAP.   
10.5.4. Safety Analyses 
Safety analyses (adverse events and laboratory analyses) will be performed using the safety 
population.  Adverse events will be coded using the latest MedDRA dictionary.  Severity of 
adverse events will be graded according to the NCI CTCAE version 4.03.   
Treatment-emergent adverse events (TEAEs) are defined as any event that occurred after the first 
dose of study drug and was not present prior to study drug administration or worsened in severity 
after study drug administration.  TEAEs will be collected through the end of treatment visit.  
Frequency and percent summaries will be presented for treatment-emergent adverse events 
(TEAE) defined as adverse events that occur or worsen in severity following the first dose of 
seribantumab, or fulvestrant.  Additional tabulations include serious adverse events (SAE), 
TEAE-related to seribantumab, fulvestrant and TEAE grade ≥ 3, and discontinuation due to 
TEAE.  Adverse events will be summarized by System Organ Class and preferred term.  All 
adverse event data will be listed by patient.   
Maximum and minimum decrease in continuous laboratory data will be reported.  Bar graphs 
depicting treatment arms will be reported.  Frequency and percent of abnormal laboratory values 
(L/ULN, 2*L/ULN) will be assessed.  Shift to most severe toxicity grade will be summarized.  
Vital signs, ECG, and ECHO/MUGA will be tabulated for the change from baseline by time 
point.  Additional analyses may be performed as described in detail within the SAP. 
10.5.5. Biomarker Analyses 
Biomarker data will be explored from collected tissue, as well as serum and whole blood 
samples, to assess potential associations with tumor response. These samples will be used to 
assess additional clinically relevant biomarkers.  PFS, ORR, and TTP may be considered for 
exploratory biomarker analysis. Kaplan Meier methods for displaying graphs and Cox 
proportional models will be used when estimating hazard ratios with 95% confidence intervals.  
Biomarker analyses will be further detailed in the SAP. 
10.5.6. Pharmacokinetic Analyses 
Serum concentrations will be used to determine PK parameters for seribantumab and fulvestrant 
as appropriate using population pharmacokinetic analysis.  The resulting PK parameters will be 
associated with efficacy and safety endpoints as appropriate.  Details will be provided in a 
separate population PK analysis plan. 
10.6. Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will be established to regularly monitor 
emerging safety data and evaluate for trial efficacy as outlined in the DMC charter. The DMC 
will consist of oncology and statistical experts, independent of the Sponsor. The DMC will be 
unblinded to randomization information. The charter of the DMC and the statistical analysis plan 
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11. Study Administration 
11.1. Pre-Study Documentation 
Prior to initiating the trial, the investigator will provide the Sponsor or designee with the 
following documents: 
• A signed FDA Form 1572 (or equivalent information for ex-US sites that do not permit 
completion of the U.S. FDA 1572 form). 
• A current (i.e. updated no more than 24 months prior) curriculum vitae for the Principal 
Investigator and each sub-investigator listed on the FDA Form 1572 or equivalent, that is 
signed and dated.  
• A copy of the current medical license for the investigator and each sub-investigator. 
• A letter from the IRB/EC stipulating approval of the protocol, the informed consent 
document, and any other material provided to potential trial participants with information 
about the trial (e.g. advertisements) 
• The current IRB/EC membership list for the reviewing IRB/EC, or the multiple project 
assurance number from the U.S. Federal Wide Assurance program where applicable 
• A signed Investigator Protocol Agreement 
• A completed financial disclosure form for the investigator and all sub-investigators 
• A current laboratory certification for the local reference laboratory and curriculum vitae 
of the laboratory director 
• A list of current laboratory normal values for the reference laboratory 
11.2. Source Documents 
The investigator will maintain records separate from the case report forms in the form of clinic 
charts, medical records, original laboratory, radiology and pathology reports, pharmacy records, 
etc.  The investigator will document in the clinic chart or medical record the date on which the 
patient signed informed consent prior to the patient’s participation in the trial.  Source documents 
must completely reflect the nature and extent of the patient’s medical care, and must be available 
for source document verification against entries in the case report forms when the Sponsor’s 
monitor visits the investigational site.  Source documents regarding procedures such as scans and 
laboratory evaluations performed as part of the standard of care prior to enrollment in the study 
can be used to fulfill certain screening and baseline assessments.  All information obtained from 
source documents will be kept in strict confidentiality.  Source data sent to the Sponsor or the 
Sponsor’s representative as supporting documentation for serious adverse events will be de-
identified to preserve confidentiality. 
11.3. Trial Ethics 
The study will be performed according to the principles of the Declaration of Helsinki, the 
International Conference on Harmonization Guidance on Good Clinical Practice and the 
requirements of the US FDA and/or local regulatory authorities regarding the conduct of human 
clinical trials. 
11.4. Patient Informed Consent 
No study related procedures will be performed until a patient or a patient’s legal representative 
has given written informed consent.  The Sponsor will provide to the investigator a sample 


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informed consent document that includes all the requirements for informed consent according the 
ICH GCP, U.S. FDA guidelines (21 CFR 50) and/or local regulatory guidelines.  However, it is 
up to the investigator to provide a final informed consent that may include additional elements 
required by the investigator’s institution. Changes to the Sponsor’s sample informed consent 
should receive approval from the Sponsor or the Sponsor’s representative prior to use in the 
study. The informed consent document must clearly describe the potential risks and benefits of 
the trial, and each prospective participant must be given adequate time to discuss the trial with 
the investigator or site staff and to decide whether or not to participate.  Each patient who agrees 
to participate in the trial and who signs the informed consent form will be given a copy of the 
signed, dated and witnessed document.  The provision of informed consent must be documented 
in the medical record. 
11.5. Investigational Review Board Approval 
The trial will not be initiated until there is approval of the protocol, informed consent document 
and any other material used to inform the patient about the nature of the trial by the local IRB or 
EC.  The IRB or EC should be duly constituted according to local regulatory requirements.  
Approval must be in the form of a letter signed by the Chairperson of the IRB/EC or the 
Chairperson’s designee, must be on IRB/EC stationary and must include the protocol by name 
and/or by designated number.  If an investigator is a member of the IRB/EC, the approval letter 
must stipulate that the Investigator did not participate in the final vote, although the investigator 
may participate in the discussion of the trial.  The investigator will also inform the IRB/EC of 
any SAE that the Sponsor reports to regulatory authorities, will report on the progress of the trial 
at least yearly (or more frequently if required by local regulation or guidance) and will provide to 
the IRB/EC a final summary of the results of the trial at the conclusion of the trial. 
11.6. Monitoring 
Overall study monitoring will be conducted through a combination of on-site visit and 
centralized monitoring. A risk-based, data-driven monitoring approach will be used to verify data 
for this trial which will also include a centralized review of data for quality, trends, consistency 
and general safety review. A clinical monitor will make regularly scheduled trips to the 
investigational site to review the progress of the trial, study data and site processes.  At each 
visit, the monitor will review various aspects of the trial including, but not limited to:  screening 
and enrollment logs; compliance with the protocol and study manual and with the principles of 
Good Clinical Practice; completion of case report forms; source data verification; study drug 
accountability and storage; facilities and staff. 
The actual frequency of monitoring trips will depend on the enrollment rate and performance at 
each site.  The investigator will allow Merrimack Pharmaceuticals, and/or its representatives or 
designees, access to all pertinent medical records, as required by federal regulations, in order to 
allow for the verification of data gathered in the CRFs and for the review of the data collection 
process. 
During scheduled monitoring visits, the investigator and the investigational site staff must be 
available to meet with the study monitor in order to discuss the progress of the trial, make 
necessary corrections to case report form entries, respond to data clarification requests and 
respond to any other trial-related inquiries of the monitor. In addition to on-site monitoring visits, 
the Sponsor and/or representatives will also be routinely reviewing data. Any queries identified 


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through this review will be managed within the systems established for query resolution and 
tracking. Inquiries related to study conduct which require further information or action will be 
discussed within the study team for appropriate and documented escalation plans. It is expected 
that response to data clarification requests and other trial-related inquiries will occur throughout 
the course of the study through regular communication with the site monitor, the Sponsor or 
representatives, and review/entry of data into the electronic study database. 
At any time during the course of the study, representatives of the FDA and/or local regulatory 
agencies may review the conduct or results of the study at the investigational site.  The 
investigator must promptly inform Merrimack Pharmaceuticals of any audit requests by health 
authorities, and will provide Merrimack Pharmaceuticals with the results of any such audits and 
with copies of any regulatory documents related to such audits. 
In accordance with HIPAA and associated privacy regulations, a patient’s authorization to use 
personal identifiable health information may be required from each patient before 
commencement of research activities.  This authorization document must clearly specify what 
parties will have access to a patient’s personal health information, for what purpose and for what 
duration. 
11.7. Confidentiality 
It is the responsibility of the investigator to ensure that the confidentiality of all patients 
participating in the trial and all of their medical information is maintained.  Case report forms 
and other documents submitted to the Sponsor must never contain the name of a trial patient.  All 
patients in the trial will be identified by a unique identifier which will be used on all CRF’s and 
any other material submitted to the Sponsor.  All case report forms and any identifying 
information must be kept in a secure location with access limited to the study staff directly 
participating in the trial. 
11.7.1. Confidentiality of Biomarker Samples 
Blood and tissue samples collected as part of the biomarker analysis will be identified only by a 
number assigned to the patient at the study site; this number will be used in lieu of the patient’s 
name in order to protect the patient’s identity. The samples will be stored at a facility designated 
by the Sponsor. Other than the patient’s unique identifying number, no additional patient 
information will be stored with these samples. Samples will be kept until they are used 
completely for the specified biomarker analyses, or, in the event there is remaining tissue or 
blood sample available, such specimens may be stored indefinitely. At the time of informed 
consent, patients will be able to refuse indefinite storage of these remaining samples. If indefinite 
storage is refused, any remaining samples will be destroyed following the completion of the 
study. Similarly, patients may withdraw approval at any time by submitting a written request to 
the study site investigator. Upon receipt of this withdraw of consent, no further analyses will be 
completed and the patient’s remaining samples will be destroyed; however, data already 
collected will not be removed from the study dataset.  
Any samples that a patient consents to be stored indefinitely may be used by the Sponsor for 
future oncological translational work, as directed by the findings of the exploratory biomarker 
evaluation and the results of the initial tissue biomarker evaluation. The results from these 
exploratory analyses may not necessarily be shared with the investigators or the participating 
subjects. 


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11.8. Protocol Amendments 
The protocol will only be amended with the consent of the Sponsor and the IRB/EC.  Changes to 
the protocol must be in the form of a written amendment; changes other than those of a simple 
administrative nature (e.g., a new telephone number for a medical monitor) must be submitted by 
the investigator to the local IRB/EC and such amendments will only be implemented after 
approval of the requisite IRB/EC.  All amendments will also be submitted to the FDA and/or 
local regulatory authorities by the Sponsor.   
Protocol changes to eliminate an immediate hazard to a trial patient may be implemented by the 
investigator immediately.  The investigator must then immediately inform their IRB/EC and the 
Sponsor will immediately notify applicable regulatory authorities. 
11.9. Records Retention 
The investigator will retain the records of the clinical trial (including, but not necessarily limited 
to, CRFs, source documents, informed consent forms, drug accountability records, IRB/EC 
correspondence, Sponsor correspondence, etc.) for 2 years following the date that the last 
marketing application for the study drug is approved (or per local regulatory requirements), or if 
no marketing application is filed, or if such an application is not approved, for 2 years after the 
formal discontinuation of clinical development of the study drug.  The Sponsor or designee will 
notify investigators when retention of study records is no longer required.  Study records must be 
stored in a safe and secure location permitting timely retrieval, if necessary. 
Study records must be retained as per the GCP guidelines and local regulatory requirements, 
including, but not limited to, case report forms, signed informed consents, correspondence with 
the IRB/EC, study drug dispensing and inventory records, source documents (clinic charts, 
medical records, laboratory results, radiographic reports) and screening/enrollment logs. 
Should the investigator relocate or retire the responsibility for maintaining the study records may 
be transferred to another investigator.  The Sponsor must be notified of the identity of the 
individual assuming responsibility for maintaining the study records and the location of their 
storage.  If no other individual at the site is willing to assume this responsibility, the Sponsor will 
assume responsibility for maintaining the study records. 
11.10.  Study Termination 
The Sponsor reserves the right to terminate the study at any site and at any time.  Reasons for 
study termination may include, but are not limited to, the following 
• Investigator non-compliance with the protocol, GCP or regulatory requirements 
• Insufficient enrollment 
• Safety concerns 
• Drug supply or manufacturing issues 
• The Sponsor’s decision to modify or discontinue the development of seribantumab 
• A request to discontinue the study by the FDA and/or local regulatory authorities 
The Sponsor will promptly inform all investigators and the FDA and/or local regulatory 
authorities if the study is suspended or terminated for any reason.  The investigator will promptly 
notify the IRB/EC if the study is suspended or terminated. 
 
 




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Hayes, E. L., & Lewis-Wambi, J. S. (2015). Mechanisms of endocrine resistance in breast 
cancer: an overview of the proposed roles of noncoding RNA. Breast Cancer Research : BCR, 
17, 40. http://doi.org/10.1186/s13058-015-0542-y 
Higgins, M., Doycle, C., Paepke, S., Azaro, A., Martin, M., Semiglazov, V., … Miller, K. 
(2014). A Randomized, Double-Blind Phase II Trial of Exemestane + MM-121, a monoclonal 
antibody targeting ErbB3, or placebo in Postmenopausal Women with Locally Advanced or 
Metastatic ER+/PR+, Her2-negative Breast Cancer. American Society of Clinical Oncology 
Conference, 1. 
Hutcheson, I. R., Goddard, L., Barrow, D., McClelland, R. A., Francies, H. E., Knowlden, J. M., 
… Gee, J. M. W. (2011). Fulvestrant-induced expression of ErbB3 and ErbB4 receptors 
sensitizes oestrogen receptor-positive breast cancer cells to heregulin β1. Breast Cancer 
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Karavasilis, V., Kosmidis, P., Syrigos, K. N., Mavropoulou, P., Dimopoulos, M. A., Kotoula, V., 
… Briasoulis, E. (2014). Docetaxel and Intermittent Erlotinib in Patients with Metastatic Non-
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Kellokumpu-Lehtinen, P.-L., Hjalm-Eriksson, M., Thellenberg-Karlsson, C., Astrom, L., 
Franzen, L., Marttila, T., … Ginman, C. (2012). Toxicity in patients receiving adjuvant docetaxel 
+ hormonal treatment after radical radiotherapy for intermediate or high-risk prostate cancer: a 
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Kraus, M. H., Issing, W., Miki, T., Popescu, N. C., & Aaronson, S. a. (1989). Isolation and 
characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor 
family: evidence for overexpression in a subset of human mammary tumors. Proceedings of the 
National Academy of Sciences of the United States of America, 86(23), 9193–7. 
Li, Q., Ahmed, S., & Loeb, J. a. (2004). Development of an autocrine neuregulin signaling loop 
with malignant transformation of human breast epithelial cells. Cancer Research, 64(19), 7078–
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Liu, J., Ray-Coquard, I., Selle, F., Proveda, A., Cibula, D., Hirte, H., … Pujade-Lauraine, E. 
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Antibody Targeting ErbB3, in Combination with Weekly Paclitaxel, Versus Weekly Paclitaxel 
Alone, in Patients with Platinum Resistant/Refractory Ovarian Cancers. American Society of 
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Cook, R. S. (2013). ErbB3 downregulation enhances luminal breast tumor response to 
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SAP_001.pdf: 
 
 
 
A Double-blind, Placebo-controlled, Phase 3 trial of Exemestane or 
Fulvestrant With or Without Seribantumab in Postmenopausal Patients with 
Hormone Receptor-positive, Heregulin Positive (HRG+), HER2 negative 
Metastatic Breast Cancer Whose Disease Progressed After Prior Systemic 
Therapy 
 
 
Sponsor: 
Merrimack Pharmaceuticals, Inc. 
One Kendall Square 
Suite B7201 
Cambridge, MA 
02139 
 
 
 
 
Confidentiality Statement 
This document and the information it contains is confidential and the proprietary property of Merrimack 
Pharmaceuticals.  The information is not to be disclosed or transmitted to any party without the express 
approval of Merrimack Pharmaceuticals, or its agents, and any such unauthorized use or disclosure is 
expressly prohibited. 


 
 
 
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Signature Page 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, which 
authorizes that the content is acceptable based on the current planned protocol. 
 
Name
Signature
Date
Author: 
Ty McClure
Position 
Senior Director Biostatistics
Company 
Merrimack Pharmaceuticals
 
Approved by: 
Akos Czibere
Position 
Senior Medical Director
Company 
Merrimack Pharmaceuticals
 
 
 


 
 
 
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TABLE OF CONTENTS 
I. 
Contents 
SIGNATURE PAGE ............................................................................................................................................................. 2 
ABBREVIATIONS ............................................................................................................................................................... 5 
1. 
INTRODUCTION ......................................................................................................................................................... 7 
1.1 
Protocol Changes and Clarifications ...................................................................................................................................... 7 
1.2 
Study Design ......................................................................................................................................................................... 7 
1.3 
Study Objectives ................................................................................................................................................................... 7 
2. 
ANALYSIS SETS .......................................................................................................................................................... 7 
2.1 
Intent-to-Treat (ITT) .............................................................................................................................................................. 7 
2.2 
Safety Population (SAF) ........................................................................................................................................................ 8 
2.3 
Pharmacokinetic (PK) ............................................................................................................................................................ 8 
3. 
ENDPOINTS ................................................................................................................................................................. 9 
3.1 
Progression-Free Survival – Investigator Assessed ................................................................................................................ 9 
3.2 
Overall Survival ................................................................................................................................................................... 10 
3.3 
Progression-Free Survival – Independent Radiologic Review .............................................................................................. 10 
3.4 
Time to Progression ............................................................................................................................................................ 10 
3.5 
Objective Response Rate .................................................................................................................................................... 11 
3.6 
Safety Endpoints ................................................................................................................................................................. 11 
3.6.1 
Treatment-Emergent Adverse Events (TEAE) ......................................................................................................................... 11 
3.6.2 
Laboratory, ECG, and Vital Signs Data .................................................................................................................................... 12 
3.7 
Stratification Factors ........................................................................................................................................................... 12 
3.8 
Covariates ........................................................................................................................................................................... 12 
3.9 
Biomarkers ......................................................................................................................................................................... 12 
4. 
HANDLING OF MISSING DATA............................................................................................................................ 13 
4.1 
General Conventions .......................................................................................................................................................... 13 
4.2 
Tumor Assessments ............................................................................................................................................................ 13 


 
 
 
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4.3 
Safety Data ......................................................................................................................................................................... 13 
4.4 
Pharmacokinetic Parameters .............................................................................................................................................. 13 
4.5 
Biomarkers ......................................................................................................................................................................... 13 
5. 
STATISTICAL METHODS ...................................................................................................................................... 14 
5.1 
Statistical Hypothesis and Determination of Sample Size ................................................................................................... 14 
5.1.1 
Safety Review and Interim Analysis ........................................................................................................................................ 14 
5.2 
General Considerations ....................................................................................................................................................... 14 
5.3 
Standards ............................................................................................................................................................................ 15 
5.3.1 
Data Cut-off ............................................................................................................................................................................ 15 
5.3.2 
Analysis of Key Time-to-Event Endpoints ............................................................................................................................... 15 
5.3.3 
Analysis of Key Binary Endpoints ............................................................................................................................................ 16 
5.3.4 
Analysis of Continuous Endpoints .......................................................................................................................................... 16 
5.4 
Baseline Analysis ................................................................................................................................................................ 16 
5.4.1 
Disposition, Populations, and Patients Excluded from Population ........................................................................................ 16 
5.4.2 
Demographics, Cancer Diagnosis, Medical History ................................................................................................................ 16 
5.4.3 
Extent of Disease .................................................................................................................................................................... 17 
5.4.4 
Prior Systemic Cancer Treatment ........................................................................................................................................... 17 
5.5 
Efficacy Analysis .................................................................................................................................................................. 17 
5.5.1 
Primary Efficacy PFS Analysis ................................................................................................................................................. 17 
5.5.2 
PFS Sensitivity and Subgroup Analysis ................................................................................................................................... 17 
5.5.3 
OS, TTP and ORR Secondary Efficacy Analysis ........................................................................................................................ 18 
5.5.4 
Exploratory Biomarker Analysis.............................................................................................................................................. 18 
5.6 
Safety Analysis .................................................................................................................................................................... 18 
5.6.1 
Study Drug Exposure .............................................................................................................................................................. 18 
5.6.2 
Adverse Events ....................................................................................................................................................................... 19 
5.6.3 
Laboratory Evaluation ............................................................................................................................................................ 20 
5.6.4 
Vital Signs ............................................................................................................................................................................... 20 
5.6.5 
Electrocardiogram .................................................................................................................................................................. 21 
5.6.8 
Pharmacokinetic (PK) ............................................................................................................................................................. 22 
6. 
REFERENCES ............................................................................................................................................................ 23 
7. 
APPENDICES ............................................................................................................................................................. 24 
 
 
 
 


 
 
 
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ABBREVIATIONS 
 
AE 
Adverse event 
AUC 
Area under the curve 
BSA 
Body Surface Area 
CBR 
Clinical benefit rate 
CI 
Confidence Interval 
Cmax 
Maximum serum concentration 
CR 
Complete Response 
CRF 
Case report form 
CSR 
Clinical study report 
CT 
Computed tomography  
CTCAE 
Common terminology criteria for adverse events 
DMC 
Data Monitoring Committee 
DOR 
Duration of Response 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
Electronic case report forms 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
HRG 
Heregulin 
ICH 
International conference on harmonization 
ITT 
Intent-to-Treat 
IWRS 
Interactive web response system 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mth 
Month 
MUGA 
Multiple gated accession scan 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
ORR 
Objective response rate 
OS 
Overall Survival 
PD 
Progressive disease 
PFS 
Progression free survival 
PK 
Pharmacokinetic 
PR 
Partial response 
PT 
Preferred term 
QTcF 
Fridericia’s QT correction 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious adverse event 


 
 
 
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SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Organ Class 
SRB 
Safety Review Board 
Tmax 
Time to maximum serum concentration 
t 1/2 
Terminal elimination half-life 
TFL 
Tables, Figures, Listings 
TTF 
Time to treatment failure 
ULN 
Upper limit of normal 
Vdss 
Volume of distribution at steady state 
Wk 
Week 
 
 
 


 
 
 
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1. INTRODUCTION  
This is the Statistical Analysis Plan (SAP) for protocol seribantumab-02-03-10.  
1.1 
Protocol Changes and Clarifications 
No previous signed off SAP versions have been written as of the current sign-off.  The following are clarifications for 
protocol analysis. 
1.2 
Study Design 
This study is a double-blind, placebo-controlled, phase 3 trial of exemestane or fulvestrant with or without 
seribantumab in postmenopausal patients with hormone receptor-positive, heregulin positive (HRG+), 
HER2 negative metastatic breast cancer whose disease progressed after prior systemic therapy.   
1.3 
Study Objectives 
The primary objective of this study is to determine whether the combination of seribantumab plus exemestane or 
seribantumab plus fulvestrant is more effective than placebo + exemestane or placebo + fulvestrant based on 
investigator assessed Progression Free Survival (PFS) in HRG positive patients (defined as HRG ISH score of  > 1+). 
The secondary objectives of this study are as follows:  
 
To determine whether the combination of seribantumab plus exemestane or seribantumab plus fulvestrant is 
more effective than placebo + exemestane or placebo + fulvestrant in HRG positive patients for the following 
clinical outcome parameters: 
o Time to Progression (TTP) 
o Objective Response Rate (ORR) based on RECISTv1.1 
o Overall Survival (OS) 
 
To compare the time from randomization to subsequent chemotherapy between the seribantumab containing 
arms and the comparator arms of the study To describe the safety profile of seribantumab in combination with 
exemestane or fulvestrant 
 
To describe the safety profile of seribantumab in combination with exemestane or fulvestrant  
 
To assess health-related quality of life (HRQOL) using EuroQol 5-Dimension (EQ-5D-5L), Functional 
Assessment of Cancer Therapy – Breast (FACT-B) and Brief Pain Index (BPI) questionnaires 
 
To characterize the pharmacokinetic (PK) profile of seribantumab when given in combination with 
exemestane or fulvestrant and of exemestane or fulvestrant when given in combination with seribantumab 
 
To assess the effect of seribantumab on ECG parameters 
The exploratory objectives of this study are as follows: 
 
To assess the correlation for HRG expression between fresh tissue biopsies and archival samples where 
available 
 
To estimate resources required for hospitalization  
2. Analysis Sets 
2.1 
Intent-to-Treat (ITT) 
The ITT population will include all patients who are randomized, with study drug assignment via an Interactive Web 
Response System (IWRS), irrespective of whether patients receive the intended study drug or a different drug than 


 
 
 
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allocated through randomization.  ITT patients with central lab HRG positive (1+, 2+, 3+, 4+) results will be 
considered the primary efficacy population.  Patients with missing or indeterminate HRG or HRG negative will not be 
part of the ITT primary efficacy population. 
2.2 
Safety Population (SAF) 
This will include all patients in the study receiving at least 1 dose of study drug.  These patients will be defined as the 
safety population. 
2.3 
Pharmacokinetic (PK) 
This population includes all SAF patients with at least 1 on-treatment PK assessment. 
 
 


 
 
 
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3. ENDPOINTS 
3.1 
Progression-Free Survival – Investigator Assessed 
Investigator Assessed (IA) tumors assessments are those determined by the investigator.  PFS is defined as the 
number of months from the date of randomization to the date of death or documented (objective) disease progression 
via RECISTv1.1, whichever occurs earliest.  Length of PFS will be calculated in days and reported in months. 
[Progression/Death/Censor Date - Randomization Date + 1] / 30.4375. 
The tumor assessment (i.e., scan dates) will be used for progression/censor date not the date corresponding to the 
determination of overall response.  When multiple dates occur for assessing target, non-target, and new lesions the 
following rule will be applied: 
 
If documented disease progressions, the first available date will define the tumor assessment date   
 
If censored, the last available date will define the tumor assessment date.   
Per protocol tumor assessments are scheduled to be performed every 8 weeks (± 7 days) from day of first dose until 
investigator-assessed progression, in addition to a 30-day follow-up.   
Censorship:  In general, patients are censored at the date of the last tumor assessment that verified lack of disease 
progression if they are last known to be alive, on-treatment or within 30 days following treatment discontinuation, and 
progression-free.  Censoring is explicitly described below and in table 1.  Patients that do not experience progression 
or death by the time of analysis (data cut-off) will be censored at the date of last tumor assessment defined by any 
overall response other than “not evaluable”.   
 
Patients with an inadequate/incomplete baseline tumor assessment will be censored at the date of 
randomization 
 
Patients with no tumor assessment after dosing will be censored at the date of randomization unless death 
occurred prior to the first planned assessment (in which case the death is an event)   
 
Patients with at least one on-study disease assessment who discontinue treatment without documented disease 
progression or death are censored at the date of the last tumor assessment   
There are two exceptions.   
o Documented progression or death ≤ 30 days after treatment discontinuation then progression or death 
is an event   
o A new anti-cancer treatment is started prior to documented progression and ≤ 30 days after treatment 
discontinuation, then censorship is at the date of the last tumor assessment that verified lack of 
disease progression prior to the new treatment   
 
Patients with documentation of progression or death after an unacceptably long interval (i.e., 2 or more 
consecutively missed or indeterminate/not evaluable assessments) since the last tumor assessment will be 
censored at the date of last tumor assessment documenting no progression 
 
 


 
 
 
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Table 3.1 Documented Disease Progression and Censoring  
Situation 
Date of 
Outcome 
Inadequate baseline tumor assessment
Randomization 
 
 
Censored 
 
No on-treatment assessment and no death prior to 
first scheduled assessment
Death or documented disease progression after ≥ 
2 consecutively missed and/or not evaluable 
scheduled tumor assessments
Last tumor assessment documenting no 
disease progression  
Alive, on-treatment, and no documented disease 
progression 
Last tumor assessment documenting no 
disease progression 
Documented disease progression (on, prior to, or 
≤ 30 days after treatment discontinuation) 
First tumor assessment documenting 
disease progression 
Progression 
(Event)
New anticancer treatment ≤ 30 days after 
treatment discontinuation without disease 
progression  
Last tumor assessment documenting no 
disease progression prior to starting the 
new anticancer treatment
Censored 
Treatment discontinuation due to toxicity, 
undocumented disease progression, or any other 
reason 
Last tumor assessment documenting no 
disease progression prior to 
discontinuation 
Censored 
Death prior to first scheduled assessment
Death
Death (Event)
Death without documented disease progression 
and ≤ 30 days after treatment discontinuation
Death 
Death (Event)
Note:  Follow-up scans can be performed up to 4 weeks from last treatment dose date via protocol 
3.2 
Overall Survival  
Overall Survival (OS) is defined as the time from randomization to the date of death for any cause.  In the absence of 
confirmation of death, survival time will be censored at the last date the patient is known to be alive.  Length of OS 
will be calculated in days and reported in months. 
[Death/Censor Date - Randomization Date + 1] / 30.4375. 
3.3 
Progression-Free Survival – Independent Radiologic Review 
Independent radiologic review (IRR) will be performed using images from all available tumor assessments.  PFS is 
defined as the number of months from the date of randomization to the date of death or documented (objective) 
disease progression via RECISTv1.1, whichever occurs earliest.  Length of PFS will be calculated in days and 
reported in months. 
[Progression/Death/Censor Date – Randomization Date + 1] / 30.4375. 
Censorship rules for PFS per IRR will be defined the same as the investigator assessed.   
3.4 
Time to Progression 
Time to Progression (TTP) will be derived using the investigator-assessed tumor assessment data.  Censorship will 
occur for patients without documented disease progression.  The last tumor assessment documenting no PD will be 


 
 
 
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used as the date of event/censor.  If death occurs prior to first tumor assessment the date of death will be used as the 
date of event/censor.  Length of TTP will be calculated in days and reported in months. 
[Progression/Censor Date – Randomization Date + 1] / 30.4375. 
3.5 
Objective Response Rate 
Objective Response Rate (ORR) will be derived using the investigator-assessed tumor assessment data.  Best Overall 
Response (BOR) is recorded from randomization until documented disease progression or death.  ORR is defined as 
the proportion of patients with a BOR characterized as either a Complete Response (CR) or Partial Response (PR) as 
defined according to RECISTv1.1 guidelines relative to the total number of evaluable patients.  Per RECISTv1.1 
guidelines, patients with documented PR or CR will not need confirmatory tumor assessments to document response.  
Patients without baseline or post-baseline tumor assessments will be considered non-evaluable for this analysis.  The 
following table describes the responder/non-responders for this analysis. 
Table 3.5 ORR Determination  
Criteria 
Responder/Non-
responder 
No Baseline tumor assessment
Not Evaluable
No Post-baseline tumor assessment AND were treatment failure prior to BOR 
determination due to disease progression, symptomatic deterioration, toxicity, death, 
or new anticancer treatment
Non-Responder 
BOR:  Partial Response, Complete Response 
AND were not treatment failure prior to BOR determination due to disease 
progression, symptomatic deterioration, toxicity, death, or new anticancer treatment
Responder 
BOR:  Stable Disease, Progressive Disease, Not Evaluable/Indeterminate
Non-responder
3.6 
Safety Endpoints 
Safety profile will be characterized by type, frequency, and severity of adverse events, coded using the MedDRA 
coding system, as graded by NCI Common Toxicity Criteria for Adverse Events version 4.0 (NCI CTCAEv.4), timing 
and relationship to treatment, laboratory abnormalities, vital signs, and left ventricular imaging data.  
3.6.1 Treatment-Emergent Adverse Events (TEAE) 
Adverse events will be considered treatment-emergent if: 
 
The event occurs for the first time after the start of study treatment and on or before 30 days after final 
dose of study treatment and was not observed prior to start of treatment 
 
The event was observed prior to the start of treatment but increased in NCI CTCAE v4 grade during study 
treatment 
The eCRF will capture TEAEs on the adverse event page, while those events occurring pre-treatment will be 
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3.6.2 Laboratory, ECG, and Vital Signs Data 
Assessments will be assigned to cycles based on the collection date of the sample relative to the start dates of the 
cycles from the study drug administration page.   
Baseline assessments will be considered as those data collected: 
 
Within 28 days prior to first day of study drug and 
 
The closest non-missing data value assessment prior to the first dose date 
3.7 
Stratification Factors 
Randomization will be stratified based on the following prognostic factors: 
 
Prior chemotherapy for locally advanced or metastatic disease (yes, no) 
 
Chemotherapy backbone (exemestane or fulvestrant) 
 
Geographic Region (US, Non-US/Non-Asia, Asia) 
3.8 
Covariates 
Baseline evaluations are those collected within 28 days prior to the start of treatment.  If more than one baseline 
evaluation is available, select the closest non-missing value prior to first dose.  The closest non-missing observation 
may be selected on the day of cycle 1 day 1 if study procedures are indicated prior to dosing.   
The following baseline characteristics will be included as covariates which may be included in model testing 
exercises:  Age, gender, race, ethnicity, primary diagnosis and time from primary cancer diagnosis to randomization, 
time since last prior systemic treatment, investigative site, and others may be identified. 
3.9 
Biomarkers 
Baseline serum and tissue samples will be collected.  Continuous and categorical type of biomarkers may be 
available.  For continuous biomarkers, the value at and above the median will be used to determine the high group, 
while the low group is below.  Categorical parameters will be classified into a maximum of three groups.  Additional 
analyses will be considered exploratory in nature.  Samples will be used to assess additional clinically relevant 
biomarkers, including but not limited to expression levels of the ErbB3 receptor, cMET, IGF-1R, and FGF receptor 
tyrosine kinases and will include assessment of their respective ligands (e.g. HGF, FGF-2, IGF-1, and IGF-2 mRNA 
or protein). 
The only biomarker detailed in this SAP will be HRG positive as per the primary efficacy population analysis. 
 
 


 
 
 
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4. HANDLING OF MISSING DATA 
4.1 
General Conventions 
Dates will be presented in listings as DDMONYYYY.  Listings will be presented as the collected or raw data with 
missing information presented as such:  - - MONYYYY for missing day, DD - - - YYYY for missing month, and 
DDMON - - - - for missing year.  Missing day values will have the first day of that month imputed if calculating a 
start date, while stop dates will have the last day of that month.  Missing month and/or year will require a review of 
patients with similar events.  The month and/or year will be selected such that the mean value is approximated using 
that particular value(s).     
4.2 
Tumor Assessments 
Inadequate tumor assessment does not allow for a RECIST response determination and will be designated as Not 
Evaluable target response evaluation.  An inadequate assessment will be defined as those with at least 1 missing 
measurement or non-measurable target lesion or baseline tumor assessments outside the screening evaluation window 
(i.e., after first dose date and prior to -28 days from first dose date).  If a target lesion is too small to measure and does 
not have unequivocal complete disappearance, a default of 5mm will be assigned. 
Different imaging of lesions should not be performed.  Those tumor assessments that do not vary based on different 
imaging will be allowed.  However, imaging variations that result in PR or CR based on the inconsistency of imaging 
will be reviewed carefully and may result in confirmation of that result at the following visit.  
If non-target disease is not assessed and a patient is considered for a CR target response the overall disease response 
will be PR. 
4.3 
Safety Data 
Missing adverse event, vital sign, ECG, or laboratory data will be considered missing in summary analyses.   
4.4 
Pharmacokinetic Parameters 
Missing values will be considered missing for summarizations and analyses.  NC will be set to missing.  In all data 
presentations other than listings, concentrations below the limit of quantification (BLQ) will be set to zero.  The 
listings will report BLQ as < LLQ or lower limit of quantification.  
Summary tables and plots will be calculated by setting missing concentrations if a concentration has been collected as 
ND (i.e., not done) or NS (i.e., no sample) or NC (i.e., not computable) or a deviation in sampling time is of sufficient 
concern or a concentration has been flagged as a data anomaly.  Individual observations with known to bias the 
plasma concentration due to an unexpected event will be described and not included in summarizations or analysis. 
4.5 
Biomarkers 
Missing or indeterminate HRG values considered as HRG positive will be not be included as part of the primary 
efficacy analysis.  Patients with missing baseline biomarker assessments will not be used in analysis that will include 
baseline biomarker information.  No missing data will be imputed.  


 
 
 
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5. STATISTICAL METHODS 
5.1 
Statistical Hypothesis and Determination of Sample Size 
The primary efficacy analysis will be to compare PFS distributions of seribantumab in combination with physician’s 
choice of fulvestrant and/or exemestane versus control (fulvestrant and/or exemestane alone).  The study is designed 
to test superiority with the null hypothesis of no differences in progression-free survival distributions using 
investigator assessed disease progression between the treatment and control arm. 
The primary PFS analysis will be performed using a stratified log-rank test, where stratification factors are prior 
chemotherapy use (yes, no), chemotherapy backbone (exemestane or fulvestrant), and geographic region (US, Non-
US/Non-Asia, Asia).  The stratified log rank test will be performed using a one-sided significance level at 0.025.   
Interim analysis will be conducted when reporting approximately 50% (approximately 16 months from first patient) of 
the final PFS events have been observed in the primary efficacy population.  Type II error will be preserved using a 
Lan-DeMets (non-binding) beta spending function approach with an O’Brien-Fleming boundary.  Non-binding for the 
futility analysis implies that the futility boundary will be constructed in such a way that it can be overruled if desired 
by the DMC without inflating the type I error rate and without decreasing power.  The interim will be a futility 
analysis only.  The planned interim analysis is detailed in section 5.1.1.   
Since the boundary is dependent on the number of PFS events the actual boundary used will be re-calculated based on 
the number of actual PFS events achieved at the time of the interim analysis.  The DMC will be responsible for 
evaluating the interim analysis and making a recommendation about early termination due to observed study results as 
outlined in the DMC charter.   
Approximately 195 PFS events are be required to have at least 95% power to detect a 43% risk reduction (mPFS: 4 v 
7; HR ≤ 0.57) for patients receiving the combination of seribantumab plus exemestane or fulvestrant versus 
exemestane or fulvestrant alone, using a one-sided, stratified log-rank test at a significance level of 0.025, assuming a 
2:1 ratio.  An accrual of 24 months in length to obtain the required number of 195 PFS events is estimated to be 
achieved at approximately 30 months with a total sample size of 286 patients. 
5.1.1 Safety Review and Interim Analysis 
An independent external DMC will monitor the safety of the patients on a periodic basis.  The DMC will provide 
a recommendation to Merrimack based on periodic safety review and/or the interim analysis whether to terminate 
the trial early due to safety or futility.  Additionally the DMC will make a data recommendation about early 
termination due to observed results.  In an attempt to minimize bias the interim analysis will be generated by an 
unblinded external vendor who will communicate results directly to the DMC.  The DMC will discuss the 
efficacy recommendation with the Merrimack Steering Committee, if necessary.  Details of the interim analysis 
and Steering Committee will be described in the DMC Charter. 
5.2 
General Considerations 
All analyses discussed in this SAP will be generated for the final CSR.  All datasets, documentation, and the SAP will 
be archived in the Trial Master File (TMF).  Tables, figures, and listings (TFLs), as described in this document and in 
the mock shells, will be created using SAS version 9.2 or higher.  Mock table, listing, and figure shells will be 
developed for detailed information on the layout.  The mock tables, listings, and figure shells will not be considered as 
part of the SAP signoff. 


 
 
 
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5.3 
Standards 
The information presented in this section describes the standard displays/mocks and analysis to be performed.  
Standard table displays will include columns for treatment groups called: seribantumab+fulvestrant/exemestane 
(seri+BB), seribantumab+fulvestrant (seri+f), seribantumab+exemestane (seri+e), placebo+fulvestrant/exemestane 
(pla+BB), placebo+fulvestrant (pla+f), placebo+exemestane (pla+e), and Overall.  The primary comparisons are 
based on seri+BB versus pla+BB.   
Continuous variables, as deemed appropriate, will be summarized using the number of non-missing observations, 
mean, standard deviation, median, minimum and maximum values.  Missing data values will be treated as missing in 
summarization.  No imputation of missing data will be performed.   
Categorical variables will be summarized using the number of non-missing observations, frequency and percentage 
out of the number of non-missing observations in each category.  Percentages will be presented to one decimal place 
(e.g., xx.x).  Percentages will not be presented when zero counts occur.   
Enrolled will be defined as those patients signing informed consent and completing entry criteria.   
All p-values will be presented as two-sided using a SAS format (pvalue5.3).  Primary efficacy inferential analyses 
will be tested against a one-sided, alpha at 0.025 (i.e., two-sided 0.05) unless stated otherwise.    
5.3.1 Data Cut-off  
A database snapshot will be determined at the time of the confirmed number of PFS events: 195 final.  The 
snapshot will not be performed until the minimum number of PFS events have occurred.  The snapshot will 
include all data entered and cleaned up to that particular point in the study and data will not be changed, edited, or 
updated on or prior to this particular date.  A separate snapshot of this data will be maintained in the biostatistics 
and programming area.  Patients that have completed the study will require investigator signature.  Continuing 
patients will have data reviewed and approved.  Data entered after the data cut-off dates will continue to be 
cleaned but not reported at the time of the interim or final analysis.   
A final database lock will be performed upon determination of the final PFS event.  Any necessary changes to 
previously entered data will be documented.  The final database lock will include all data for all timepoints and 
will be conducted at a later timeframe.  Site investigators will provide signatures for any remaining patient data 
which was outstanding at the time of soft lock. 
5.3.2 Analysis of Key Time-to-Event Endpoints 
Time-to-event endpoints between two treatment arms will be compared with a 1-sided, α = 0.025, stratified log-
rank test, unless specified otherwise.  Stratification factors will include: prior chemotherapy use (yes, no), 
chemotherapy backbone (exemestane or fulvestrant), and geographic region (US, Non-US/Non-Asia, Asia).  
Stratified Cox proportional hazards models will be constructed with stratification factors and treatment in the 
model to estimate hazard ratio and 2-sided 95% confidence interval (CI). 
Additional comparisons between treatment groups will be performed using an unstratified log-rank test.  Cox 
proportional hazards model with treatment group only will be constructed to estimate the hazard ratio and 2-sided 
95% confidence intervals. 
Potential influences of other baseline patient characteristics on various populations may be explored.  Candidate 
covariates for the multivariate model will be selected using a stepwise selection process with treatment always in 
the model.  Only covariates significant at a 15% level will be entered in the model and covariates significant at 


 
 
 
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15% will be considered for the final multivariate model.  Treatment-by-covariate effects will be explored only for 
the set of factors included in the final model.  The estimated hazard ratio and 2-sided 95% CI will be reported.  
Forest plots will be displayed for subgroup analyses. 
The assumption of proportional hazards will be explored using a variety of graphical displays and testing.  Hazard 
ratios and log (-log) of the survival probability estimates over time will be graphed.  A scatterplot of smoothed 
Schoenfeld residuals over log of time will be displayed to check the primary efficacy analysis assumptions.  The 
assumption of proportional hazards will be reviewed for the primary efficacy endpoint using the available 
graphical information.  No formal testing will be performed in place of the stratified log-rank, if the assumption of 
proportional hazards does not hold.   
Kaplan-Meier methods will be used in estimating the probability of event and displayed graphically.  Time-to-
event calculations will be performed in months unless specified otherwise.  Median event times and 2-sided 95% 
CI will be provided based on Brookmeyer-Crowley methods.  Probability of event estimates at 6, 9, 12, 15, and 
18 month intervals will be reported in tables. 
5.3.3 Analysis of Key Binary Endpoints 
Frequencies and percentages will be reported for binary endpoints.  The rate of binary endpoints between 2 
treatment arms will be compared using a Cochran Mantel-Haenszel (CMH) test stratified according to the 
stratification factors and a Pearson χ2 test, both at a 2-sided, α = 0.05 level.  The relative risk ratio estimate will be 
used to contrast treatment effects on response rates.  Point estimates of the rates for each treatment arm will be 
provided along with the corresponding exact 2-sided 95% CI using exact methods based on the binomial 
distribution.       
5.3.4 Analysis of Continuous Endpoints 
Mean, standard deviation, median, minimum, maximum will be reported for continuous endpoints.  Least-squares 
mean and standard error with 95% confidence intervals will be reported for models.  Models will be tested using a 
2-sided, α = 0.05 level.         
5.4 
Baseline Analysis 
5.4.1 Disposition, Populations, and Patients Excluded from Population 
Treatment termination and study termination will be summarized overall and by reason.  Included in the 
summarization will be deaths.  Overall number of deaths, deaths on-treatment (up to 30 days post last dose date), 
deaths after treatment. 
A listing of patients and those excluded from a population along with reason will be provided, if available.  
Protocol deviations will be listed and major protocol deviations will be summarized. 
5.4.2 Demographics, Cancer Diagnosis, Medical History 
Descriptive statistics will be reported for Age (years), sex (male, female), race (white/Caucasian, Black or African 
American, Alaska native or American Indian, Asian/Oriental, Native Hawaiian or Pacific Islander, other), height 
(cm), weight (kg), ethnicity, and ECOG at baseline.  Other cancer diagnosis factors such as frequency of 
adenocarcinoma, squamous cell; TNM Stage; Bone disease, brain metastisis, visceral metastisis, number of prior 
chemotherapies, EGFR mutation status, KRAS status, best response will be reported.  Time from cytological or 
histo-pathologic diagnosis to randomization will be analyzed as a continuous parameter. 


 
 
 
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Stratification factors will be summarized by frequencies and percentages.  Frequency of patients randomized 
within each site by country will be summarized. 
Prior surgical therapy (yes/no), prior radiation therapy (yes/no) will be characterized. 
Medical history will be coded using the latest version of MedDRA coding.  Medical history will be summarized 
by System Organ Class and preferred term. 
5.4.3 Extent of Disease 
Number of patients with target lesions only, non-target lesions only, and both target and non-target 
lesions will be summarized.  Individual disease sites for target or non-target lesions will be summarized. 
5.4.4 Prior Systemic Cancer Treatment 
The following will be summarized categorically unless stated as a continuous parameter. 
 Type of prior anti-cancer treatment 
 Number of prior anti-cancer treatment 
 Time since last anti-cancer treatment prior to study enrollment will be summarized as a 
continuous parameter 
5.5 
Efficacy Analysis 
5.5.1 Primary Efficacy PFS Analysis 
PFS analysis will be performed using a stratified log-rank test.  Stratification factors will include: prior 
chemotherapy use (yes, no), chemotherapy backbone (exemestane or fulvestrant), and geographic region (US, 
Non-US/Non-Asia, Asia).  Patients with missing stratification factor will be included in the primary efficacy 
analysis by merging them into the largest category for that factor.  Misclassification of stratification factor will be 
analyzed as the actual (or ITT) analysis.  A sensitivity analysis using the planned (or appropriate strata) will be 
performed.  Seri+BB will be compared relative to pla+BB using a one-sided significance level at 0.025.     
5.5.2 PFS Sensitivity and Subgroup Analysis 
PFS will be performed using a variety of methodology to assess the sensitivity to deviations and covariate factors.  
The same one-sided significance level at 0.025 will be used for all situations.  
 
Unstratified log-rank test will be performed and a Cox proportional hazards model with treatment only in 
the model to estimate the hazard ratio and 95% confidence intervals 
 
Treatment group comparison using interval-censored methods 
 
Evaluation of influences of baseline covariates and biomarker factors using stepwise selection methods 
 
Treat all censors on the seribantumab arm as events on the date of censorship 
 
Cox proportional hazard models will include treatment and covariate in the model.  Additional models 
will include treatment, covariate, and the interaction effect in the model.  Hazard ratios and 95% 
confidence intervals will be reported for all models.  In addition, median event estimates and 95% 
confidence intervals will be reported.  Forest plots of the hazard ratio estimates and confidence intervals 
will be displayed for the aforementioned models.   
PFS will also be analyzed using IRR.  PFS will be analyzed using a stratified Cox proportional hazard models 
similar to the primary analysis.  Cox proportional hazard models will include treatment and covariate in the 


 
 
 
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model.  Additional models will include treatment, covariate, and the interaction effect in the model.  Hazard ratios 
and 95% confidence intervals will be reported for all models.  In addition, median event estimates and 95% 
confidence intervals will be reported.  Forest plots of the hazard ratio estimates and confidence intervals will be 
displayed with for the aforementioned models.   
5.5.3 OS, TTP and ORR Secondary Efficacy Analysis 
OS and TTP will be analyzed in the all study populations defined earlier as time-to-event analyses.  Stratifed and 
unstratified log-rank tests will be performed for the ITT study population.   
Frequencies and percentages of ORR responders will be summarized.  CMH and Pearson’s chi-square test will be 
performed for responders.  A relative risk estimator will be used to contrast the treatment effects.  Risk difference 
estimate and 95% confidence intervals will be calculated using the normal approximation. 
Waterfall plots for best response and best percentage change will be displayed for study and subpopulations. 
5.5.4 Exploratory Biomarker Analysis  
Descriptive statistics will be used to characterize the biomarkers within treatment groups over time.  Continuous 
markers will be summarized using the change from baseline and observed values.  Change from baseline to last 
observed will be analyzed using an ANCOVA model with baseline and stratification factors, treatment as fixed 
effects.  Interaction effects may be tested and included in the final model(s) if deemed important.  Least squares 
means and 95% confidence intervals will be reported.  Categorical markers will be summarized using shift from 
baseline to last observed.  CMH test using stratification factors will be used to analyze parameters. 
The biomarker relationship to outcomes OS and PFS will be analyzed using a stratified log-rank test.  Screening 
values of biomarker values will be used in the following analysis.  Continuous biomarker values will be 
dichotomized by ≥ median, < median; as well as quartiles.  Biomarker analyses will consist of performing 
analysis on the overall PFS endpoint.  Kaplan-Meier displays will be reported.  Kaplan-Meier curves will include 
the following: 
 
seribantumab, Control – According to categorical grouping  
 
Control Only – According to categorical grouping  
Included in the graphs will be hazard ratio and 95% confidence intervals, median PFS and 95% confidence 
intervals, number and percentage of events and censors.  These will be performed for all markers identified.  
Forest plots will be used to describe the biomarker subgroups relationship via hazard ratios and 95% confidence 
intervals. 
5.6 
Safety Analysis 
All safety analysis will be performed using the safety population.   
5.6.1 Study Drug Exposure 
Extent of treatment exposure will be summarized for seribantumab, fulvestrant, and exemestane as follows: 
 
Number and percentage of patients beginning 1, 2, 3, …., 6 and > 6 cycles 
 
Number of cycles started will be treated as a continuous variable  
 
Actual Dose received defined as total actual dose (mg) divided by BSA (m2) 


 
 
 
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 
Relative Actual Dose = [Total actual dose (mg) divided by Total intended dose (mg)] x 100, where total 
intended dose is defined as the dose as prescribed which is summed from first to last date irrespective of 
missing, interruption, or reduction. 
 
Total Exposure (weeks) derived as (last dose date – first dose date + 1) 
 
Dose intensity (mg/m2/wk) will be summarized as Actual Dose received divided by (duration in days 
multiplied by 7) 
Treatment Delays and Dose Modifications 
Definitions: 
A dose reduction is defined as actual dose taken is ≤33% than the prescribed dose on any given day for any 
reason with the exception of a day with total dose administered of 0mg is not considered a dose reduction. 
A dose interruptions/delay/missed dose is defined as a planned dosing day with 0 mg administered 
Patients will be summarized by frequency and percentage according to: 
 
Patients with at least one dose reduction overall and by cycle 
 
Patients with at least one dose reduction due to an adverse event 
 
Total number of dose reductions per patient 
 
Number of dose interruptions/missed overall and by cycle 
5.6.2 Adverse Events 
Adverse events will be coded using the latest MedDRA dictionary at the time of coding.  NCI CTCAE v4.0 will 
be used to grade severity.  Frequencies and percentages will be reported by System Organ Class (SOC) and 
preferred term (PT).  Patients with multiple events for a category will be counted once in the highest CTCAE 
classification.  Summary tables will include treatment-emergent AEs, unless specified otherwise.  Treatment-
emergent adverse events (TEAEs) will be defined as patients based on the event onset date relative to first dose of 
study drug in the study.  Missing onset date for an event will be considered as TEAE.  Adverse events with a 
starting date 30 or more days after the last dose date are not considered TEAEs.  Relatedness will be considered:  
Possibly, Probably, or Definitely related per case report form classification.  If relatedness is missing the adverse 
event will be considered TEAE.  The order of reporting the events in summary tables will be according to the 
following where applicable: 
 SOC will be alphabetically reported 
 Descending order of frequencies according to the number of patients in the seribantumab 
treatment group experiencing an adverse event 
 PT will be alphabetically reported 
The following tables will be reported:  
 TEAE 
o Any TEAE by SOC 
o Any TEAE by SOC and PT* 
o Any TEAE by PT  
o Any TEAE by PT by NCI CTCAE Grade 
o Any TEAE by PT by cycle 


 
 
 
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o Any TEAE by PT by NCI CTCAE Grade by cycle 
 
 Related TEAE 
o Any TEAE by SOC and PT* 
o Any TEAE by PT  
o Any TEAE by PT by NCI CTCAE Grade 
 
 TEAE - NCI CTCAE Grade 3 or higher 
o Any TEAE by SOC and PT 
o Any TEAE by PT  
 
 Related TEAE - NCI CTCAE Grade 3 or higher 
o Any TEAE by SOC and PT 
o Any TEAE by PT 
 
 SAE – TEAEs only 
o Any SAE by SOC and PT* 
o Any SAE by PT  
 
 TEAE - Various 
o Any TEAE Resulting in Dose Reduction 
o Any TEAE Resulting in Treatment Discontinuation 
o Any TEAE Resulting in Death 
In the AE preferred term summary tables, a patient having multiple events within a System Organ Class is 
counted only once for that SOC. Similarly, a patient having multiple events under a preferred term is counted only 
once for that PT.  Listings will be provided for all adverse event data.  
5.6.3 Laboratory Evaluation 
Laboratory analytes will be summarized according to panel (i.e., hematology, chemistry, urinalysis).   
Shift in laboratory analyte grade will be characterized by worst from baseline and at end of treatment.  Shift 
categories will include normal grade 1 to grade 5 and totals.  Percentages will be based on the number with 
baseline and postbaseline values for that particular analyte. 
5.6.4 Vital Signs 
Vital sign parameters: systolic and diastolic blood pressure (mmHg), respiratory rate (breaths per minute), body 
temperature (C◦), weight (kg) and pulse rate (beats per minute) will be summarized by observed and change from 
baseline according to minimum and maximum values.  Additionally the frequency and percentage of patients for 
each observed parameter outside the normal range during treatment (up to 30 days post last dose date) will be 
reported.     


 
 
 
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Table 5.6.4.1  Vital Signs Normal Range  
Parameter 
Units 
Normal Range 
Systolic Blood Pressure
mmHg
90 - 180
Diastolic Blood Pressure
mmHg
50 - 105
Pulse Rate
Beats per minute
50 - 120
Respiratory Rate
Breaths per minute
12 – 25
 
5.6.5 Electrocardiogram 
The number and percentage of patients with worst ECG result as order: Abnormal, Clinically Significant, 
Abnormal, not Clinically Significant, Normal will be summarized at screening.  Results will be counted once for 
each patient and scheduled visit.  
Exposure-Response Analysis: The relationship between seribantumab plasma concentration and QTcF (change-
from-baseline QTcF) will be quantified using a linear mixed effects model with QTcF as the dependent variable, 
plasma concentration as continuous covariate, and treatment (active or placebo) and time as categorical factors, 
and a random intercept and slope per subject.  The geometric mean of the individual Cmax values for subjects on 
seribantumab will be determined.  The predicted effect and its two-sided 90% CIs for QTcF (placebo-corrected 
change-from-baseline QTcF) at this geometric mean Cmax will be obtained. 
By-Timepoint Analysis: The analysis for QTcF will be based on a linear mixed effects model with QTcF as the 
dependent variable, baseline QTcF as covariate, and time (categorical), treatment (seribantumab and placebo), and 
time by treatment interaction as factors.  An unstructured covariance matrix will be specified for the repeated 
measures at post-dose timepoints within subject.  If the model with unstructured covariance matrix fails to 
converge, other covariance matrix such as compound symmetry can be considered.  For this analysis a 90% 2-
sided confidence interval (CI) will be calculated for the contrasts " seribantumab - placebo" for each time point, 
separately.  For change-from-baseline as well as the placebo-corrected change-from-baseline HR, PR, and QRS, 
descriptive analysis including number of subjects, mean, median, min, max, standard deviation (SD), standard 
error (SE), and 90% confidence interval (CI; from t-distribution) will be calculated for each treatment and 
timepoint. 
Categorical Analysis: The analysis results for categorical outliers and T-wave morphology will be 
summarized in frequency tables with counts and percentages for both number of subjects and number of 
timepoints. For categorical outliers, the number (percentage) of subjects as well as timepoints with 
increases in QTcF from baseline of >30 and >60 msec and absolute QTcF values >450, >480, and >500 
msec; increase in PR interval from baseline >25% and a PR interval >200 msec; increase in QRS 
interval from baseline >25% and a QRS interval >120 msec; decrease in HR from baseline >25% and a 
HR <50 bpm; and increase in HR from baseline >25% and a HR >100 bpm will be determined by each 
treatment group, respectively. For T-wave morphology, the analysis will be focused on the 
treatment-emergent changes. 


 
 
 
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5.6.8 Pharmacokinetic (PK) 
A Non-compartmental Analysis (NCA) will be used to analyze the pharmacokinetic parameters based on plasma 
concentration versus time.  Mean concentration curves will be displayed using linear and semi-log scales.  
Standard errors will be displayed on the graphs for each collection day.  A summary of PK parameters will be 
developed for each study drug and will include the previously indicated parameters.  Additional analyses may be 
performed if deemed necessary. 
 


 
 
 
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6. REFERENCES 
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247 
Cui L, Hung HMJ, and Wang S (1999). Modification of sample size in group sequential clinical trials. Biometrics, 55, 
853-857 
Hochberg, Y. (1988). A sharper Bonferroni procedure for multiple tests of significance. Biometrika, 75(4), 800–2. 
 
 


 
 
 
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7. APPENDICES 
CATEGORIZING LESIONS AT BASELINE 
Measurable Lesions - Defined as lesions accurately measured in at least one dimension. 
 
Lesions with longest diameter twice the slice thickness and at least 10 mm or greater when assessed by CT or 
MRI (slice thickness 5-8 mm) 
 
Lesions with longest diameter at least 20 mm when assessed by Chest X-ray 
 
Superficial lesions with longest diameter 10 mm or greater when assessed by caliper 
 
Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT. 
NOTE: Shortest axis is used as the diameter for malignant lymph nodes, longest axis for all other measurable 
lesions. 
Non-measurable disease - Defined as lesions too small to be considered measurable (including nodes with short axis 
between 10 and 14.9 mm) and truly non-measurable disease such as pleural or pericardial effusions, ascites, 
inflammatory breast disease, leptomeningeal disease, lymphangitic involvement of skin or lung, clinical lesions that 
cannot be accurately measured with calipers, abdominal masses identified by physical exam that are not measurable 
by reproducible imaging techniques. 
 
Bone disease:  Not measurable with the exception of soft tissue components that can be evaluated by CT or 
MRI and meet the definition of measurability at baseline. 
 
Previous local treatment: A previously irradiated lesion (or lesion subjected to other local treatment) is non-
measurable unless it has progressed since completion of treatment. 
Normal sites 
 
Cystic lesions: Simple cysts should not be considered as malignant lesions and should not be recorded either 
as target or non-target disease. Cystic lesions thought to represent cystic metastases can be measurable 
lesions, if they meet the specific definition above. If non-cystic lesions are also present, these are preferred as 
target lesions. 
 
 
Normal nodes: Nodes with short axis <10 mm are considered normal and should not be recorded or followed 
either as measurable or non-measurable disease. 
 
 


 
 
 
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RECORDING TUMOR ASSESSMENTS 
All sites of disease must be assessed at baseline. Baseline assessments should be done as close as possible prior to 
study start. For an adequate baseline assessment, all required scans must be done within 28 days prior to treatment and 
all disease must be documented appropriately. If baseline assessment is inadequate, subsequent statuses generally 
should be not evaluable. 
Target lesions 
 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, representative of all 
involved organs, should be identified as target lesions at baseline. Target lesions should be selected on the 
basis of size (longest lesions) and suitability for accurate repeated measurements.  Record the longest 
diameter for each lesion, except in the case of pathological lymph nodes for which the short axis should be 
recorded. The sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions at baseline will be the basis for comparison to assessments performed on study. 
 
If two target lesions coalesce the measurement of the coalesced mass is used. If a large target lesion splits, the 
sum of the parts is used. 
 
Measurements for target lesions that become small should continue to be recorded. If a target lesion becomes 
too small to measure, 0 mm should be recorded if the lesion is considered to have disappeared; otherwise a 
default value of 5 mm should be recorded. 
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement should still be recorded. 
Non-target disease 
All non-measurable disease is non-target. All measurable lesions not identified as target lesions are also included as 
non-target disease. Measurements are not required but rather assessments will be expressed as ABSENT, 
UNEVALUATED, PRESENT, UNEQUIVOCAL PROGRESSION.  Multiple non-target lesions in one organ may be 
recorded as a single item on the case report form (e.g., ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’). 
 
 


 
 
 
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OBJECTIVE RESPONSE STATUS AT EACH EVALUATION 
Disease sites must be assessed using the same technique as baseline, including consistent administration of contrast 
and timing of scanning. If a change needs to be made the case must be discussed with the radiologist to determine if 
substitution is possible. If not, subsequent objective statuses are not evaluable. 
Target disease 
 
Complete Response (CR): Complete disappearance of all target lesions with the exception of nodal disease. 
All target nodes must decrease to normal size (short axis < 10 mm). All target lesions must be assessed. 
 
Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum of diameters of all 
target measurable lesions. The short diameter is used in the sum for target nodes, while the longest diameter is 
used in the sum for all other target lesions. All target lesions must be assessed. 
 
Stable: Does not qualify for CR, PR or Progression. All target lesions must be assessed. Stable can follow PR 
only in the rare case that the sum increases by less than 20% from the nadir, but enough that a previously 
documented 30% decrease no longer holds.  
 
Documented Progression Disease (PD): 20% increase in the sum of diameters of target measurable lesions 
above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a 
minimum absolute increase of 5 mm. 
 
Not Evaluable:  Progression has not been documented, and  
o one or more measurable target lesions have not been assessed  
o or assessment methods used were inconsistent with those used at baseline  
o or one or more target lesions cannot be measured accurately (e.g., poorly visible unless due to being too 
small to measure)  
o or one or more target lesions were excised or irradiated and have not reappeared or increased 
Non-target disease 
 
CR: Disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must 
be ‘normal’ in size (<10 mm short axis). 
 
Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level above the normal limits. 
 
PD: Unequivocal progression of pre-existing lesions. Generally the overall tumor burden must increase 
sufficiently to merit discontinuation of therapy. In the presence of SD or PR in target disease, progression due 
to unequivocal increase in non-target disease should be rare. 
 
Not Evaluable: Progression has not been determined and one or more non-target sites were not assessed or 
assessment methods were inconsistent with those used at baseline. 
 
 
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD. If a new lesion is equivocal, for example due 
to its small size, continued assessment will clarify the etiology.  If repeat assessments confirm the lesion, then 
progression should be recorded on the date of the initial assessment. A lesion identified in an area not previously 
scanned will be considered a new lesion. 
Supplemental Investigations 


 
 
 
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If CR determination depends on a residual lesion that decreased in size but did not disappear completely, it is 
recommended the residual lesion be investigated with biopsy or fine needle aspirate.  If no disease is identified, 
objective status is CR. 
If progression determination depends on a lesion with an increase possibly due to necrosis, the lesion may be 
investigated with biopsy or fine needle aspirate to clarify status. 
Symptomatic/clinical progression 
Subjects requiring discontinuation of treatment without objective evidence of disease progression should not be 
reported as PD on tumor assessment CRFs. Every effort should be made to document objective progression even after 
discontinuation of treatment. 
Table 1. Objective Response Status at each Evaluation 
Target Lesions 
Non-target Lesions 
New Lesions 
Objective Status 
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
NE, or Missing
No
PR
PR
Non-CR/Non-PD, NE, or Missing
No
PR
SD
Non-CR/Non-PD, NE, or Missing
No
SD
NE or Missing
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD