Clinical trial NCT02387216
Conditions: Non-Small Cell Lung Cancer NSCLC Adenocarcinoma Heregulin
Keywords: NSCLC Non-Small Cell Lung Cancer heregulin ErbB3 docetaxel
Sponsor: Elevation Oncology
Start date: 2015-02-01; Completion date: 2019-01-02
Enrollment: 153 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine whether the combination of MM-121 plus docetaxel is more effective than docetaxel alone in regards to PFS in patients with heregulin-positive NSCLC.

Detailed description:
This study is a randomized, open-label, international, multi-center, phase 2 study in patients with Heregulin-positive NSCLC histologically classified as adenocarcinoma that have progressed following no more than two systemic therapies for locally advanced or metastatic disease, one of which must have been a platinum containing regimen. All patients will initially be screened for heregulin status. Eligible patients will be randomized to receive MM-121 in combination with docetaxel versus docetaxel alone.

Arms: arm 1: MM-121 in combination with Docetaxel arm 2: Docetaxel alone
Interventions: intervention 1: MM-121 intervention 2: Docetaxel
Intervention descriptions: intervention 1: Investigational, fully human antibody targeting and inhibiting ErbB3 intervention 2: approved chemotherapy treatment for NSCLC

Protocol documents:
Prot_000.pdf: 
 
 
 
 
SHERLOC: A Phase 2 Study of MM-121 in Combination 
with Docetaxel versus Docetaxel Alone in Patients with 
Heregulin Positive, Locally Advanced or Metastatic Non-
Small Cell Lung Cancer 
Merrimack Pharmaceuticals, Inc. 
 
 
Version 4.0: 02Mar2017 
IND Number: 129253 
EudraCT# 2014-003673-42 
 
 
 
 
 
 
 
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 Abbreviations ...................................................................................................................... 6 
Study Synopsis ................................................................................................................................ 9 
Study Schema................................................................................................................................ 16 
1 Introduction ............................................................................................................................. 17 
1.1 
Non-Small Cell Lung Cancer ...........................................................................................17 
1.2 
ErbB3 ................................................................................................................................17 
1.3 
MM-121 ............................................................................................................................18 
1.3.1 
Pre-Clinical Experience of MM-121 and NSCLC .................................................. 19 
1.3.2 
Clinical Experience of MM-121 in Humans ........................................................... 22 
1.3.3 
Potential Toxicities with MM-121 .......................................................................... 23 
1.4 
Study Rationale ................................................................................................................25 
1.4.1 
Previous Experience in Heregulin Negative Patients ............................................. 28 
1.4.2 
Rationale for MM-121 Dose Selection in Combination with Docetaxel ................ 28 
2 Objectives ............................................................................................................................... 30 
2.1 
Primary Objective .............................................................................................................30 
2.2 
Secondary Objectives .......................................................................................................31 
2.3 
Exploratory Objectives .....................................................................................................31 
3 Study Design ........................................................................................................................... 31 
3.1 
Overview of Study Design ...............................................................................................31 
4 Study Population ..................................................................................................................... 32 
4.1 
Inclusion Criteria ..............................................................................................................33 
4.2 
Exclusion Criteria .............................................................................................................33 
4.3 
Assessing Heregulin Status in NSCLC Specimens ..........................................................34 
4.3.1 
Description of HRG RNA-ISH Assay .................................................................... 35 
4.3.2 
Implementation of HRG RNA-ISH Testing ........................................................... 35 
4.4 
Patient Discontinuation ....................................................................................................35 
5 Study Treatment ...................................................................................................................... 36 
5.1 
Method of Assigning Patients to Treatment Groups ........................................................36 
5.2 
MM-121 ............................................................................................................................36 
5.2.1 
MM-121 Formulation, Packaging, and Labeling .................................................... 36 
5.2.2 
MM-121 Product Storage and Stability .................................................................. 36 
5.2.3 
MM-121 Dosage, Preparation, and Administration ................................................ 36 
5.2.4 
Management of Infusion Reactions to MM-121 ..................................................... 36 
5.2.5 
Management of Toxicity Related to MM-121 ........................................................ 37 
5.3 
Docetaxel ..........................................................................................................................38 
5.3.1 
Docetaxel Formulation, Packaging, Labeling, and Storage .................................... 38 
5.3.2 
Docetaxel Dosage, Preparation, and Administration .............................................. 38 
5.3.3 
Docetaxel Dose Modifications ................................................................................ 39 
5.3.4 
Pre-treatment Regimen for Docetaxel .................................................................... 39 
5.3.5 
Potential Toxicities with Docetaxel ........................................................................ 39 
5.4 
Guidelines for Safety Review of MM-121 and Docetaxel Combination .........................40 
5.5 
Rules for Dose Omissions and Modified Treatment Schedules .......................................41 
5.6 
Concomitant and Prohibited Therapies ............................................................................41 
5.7 
Accountability of Study Drug ..........................................................................................42 
6 Schedule of Assessments ........................................................................................................ 43 
6.1 
Schedule of Assessments: Treatment Group ....................................................................43 


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6.2 
Screening and Baseline Visit ............................................................................................45 
6.2.1 
RNA-ISH Heregulin Testing .................................................................................. 45 
6.2.2 
Heregulin Negative Patients ................................................................................... 45 
6.3 
On-Study Visits ................................................................................................................45 
6.4 
End of Treatment Visit .....................................................................................................45 
6.5 
Survival Follow-up ...........................................................................................................45 
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 ........................................................................................................................46 
7.4 
Performance Status Assessment .......................................................................................46 
7.5 
Electrocardiogram (ECG) .................................................................................................46 
7.6 
Disease Evaluation ...........................................................................................................46 
8 Laboratory Procedures and Assessments ................................................................................ 47 
8.1 
Complete Blood Count (CBC) .........................................................................................47 
8.2 
Coagulation Profile ...........................................................................................................47 
8.3 
Serum Chemistry ..............................................................................................................47 
8.4 
Urine or Serum Pregnancy Test .......................................................................................47 
8.5 
Pharmacokinetic Testing ..................................................................................................47 
8.5.1 
MM-121 PK samples .............................................................................................. 47 
8.5.2 
Docetaxel PK samples ............................................................................................ 48 
8.6 
Anti-MM-121 Immunogenicity ........................................................................................48 
8.7 
Biomarker Samples ..........................................................................................................48 
8.7.1 
Tumor Biopsy ......................................................................................................... 48 
8.7.2 
Archived Tumor Samples ....................................................................................... 48 
8.7.3 
Serum Samples........................................................................................................ 49 
9 Adverse Event and Hospitalization Reporting ........................................................................ 49 
9.1 
Definitions ........................................................................................................................49 
9.1.1 
Adverse Events ....................................................................................................... 49 
9.1.2 
Serious Adverse Event ............................................................................................ 49 
9.1.3 
Hospitalizations....................................................................................................... 51 
9.2 
Reporting Serious Adverse Events ...................................................................................51 
9.3 
Determining the Severity and Relatedness of an Event ...................................................51 
9.3.1 
Grading the Severity of an Adverse Event ............................................................. 51 
9.3.2 
Relatedness to Study Drug ...................................................................................... 52 
9.3.3 
Reporting and Follow-up of Pregnancy .................................................................. 52 
10 Statistical Methods .................................................................................................................. 53 
10.1 General Considerations ....................................................................................................53 
10.2 Statistical Hypothesis and Determination of Sample Size ...............................................53 
10.3 Analysis Populations ........................................................................................................53 
10.4 Disposition, Demographics, and Baseline Characteristics ...............................................54 
10.5 Efficacy Analysis .............................................................................................................54 
10.5.1 
Primary Efficacy Analysis ...................................................................................... 54 
10.5.2 
Secondary Efficacy Analysis .................................................................................. 55 
10.5.3 
Subgroup Analyses ................................................................................................. 55 
10.5.4 
Safety Analyses ....................................................................................................... 55 
10.5.5 
Biomarker Analyses ................................................................................................ 56 


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10.5.6 
Pharmacokinetic Analyses ...................................................................................... 56 
10.6 Data Monitoring Committee ............................................................................................56 
11 Study Administration .............................................................................................................. 56 
11.1 Pre-Study Documentation ................................................................................................56 
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 ......................................................................................................59 
11.9 Records Retention ............................................................................................................60 
11.10 Study Termination ............................................................................................................60 
12 Investigator Signature Page .................................................................................................... 61 
13 References ............................................................................................................................... 62 
 
 


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List of Tables 
Table 1: 
Summary statistics for experimental treatment vs. control PFS in HRG positive 
subgroup .......................................................................................................................28 
Table 2: 
Summary statistics for experimental treatment vs. control PFS in HRG negative 
subgroup .......................................................................................................................28 
Table 3: 
Final parameter estimates from population PK analysis of MM-121 ..........................30 
Table 4: 
MM-121 PK Collection Time points for Arm A Patients............................................47 
List of Figures 
Figure 1: Capacity of HRG to induce proliferation in a panel of NSCLC cell lines in vitro is 
indicative of single-agent response to MM-121 in vivo. .............................................19 
Figure 2: (A) 5nM HRG induces resistance to docetaxel (111nM) and pemetrexed 
(1111nM) in a 3D spheroid proliferation assay after 96hrs. 
(B)  MM-121 (1µM) restores sensitivity in NSCLC cell lines (A549, EKVX, 
H358, H322M, Calu-3, H661, H441, H1355, H430). .................................................20 
Figure 3: (A) A549 NSCLC xenograft model treated with 300µg q3d MM-121, 20 mg/kg 
paclitaxel and the combination of MM-121 + paclitaxel q3d   
(B) A549 NSCLC xenograft model treated with 20 mg/kg up to day 29 with 
Paclitaxel followed by paclitaxel + MM-121 ..............................................................21 
Figure 4: HRG mRNA expression levels across different indications based on the TCGA 
data set .........................................................................................................................22 
Figure 5: HRG mRNA expression across NSCLC tissue samples..............................................22 
Figure 6: Number of biomarker samples collected and the analysis performed for the three 
randomized Phase 2 studies of MM-121 .....................................................................26 
Figure 7: Positive HRG mRNA levels identify a subgroup of patients with an increased risk 
of progression on standard-of-care therapies ...............................................................27 
Figure 8: Treatment effect of MM-121 in patients with HRG positive tumors ..........................27 
Figure 9: Simulated MM-121 Pharmacokinetics (Average concentration) by weight-based 
and fixed dosing regimens and by dose and intervals..................................................30 
 
 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AKT 
Protein kinase B 
ALK 
Anaplastic lymphoma kinase 
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 
ECOG (PS) 
Eastern Cooperative Oncology Group (performance status) 
eCRF 
Electronic case report form 
EGFR 
Epidermal growth factor receptor 
ErbB 
Epidermal growth factor family of receptor tyrosine kinases 
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 
GCP 
Good Clinical Practice 
GnRH 
Gonadotropin-releasing hormone 
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 


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Abbreviation 
Definition 
HRG 
Heregulin 
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 
IV 
Intravenous 
IWRS 
Interactive web response system 
kg 
Kilogram 
LDH 
Lactate dehydrogenase 
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 
MM-121 
Seribantumab 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
mTOR 
Mammalian target of rapamycin 
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-L1 
Programmed death ligand 1 
PET-CT 
Positron emission tomography - computed tomography 
PFS 
Progression-free survival 
PI3K 
Phosphatidylinositol-3-kinase 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
PR 
Partial response 
PTT 
Prothrombin time 
PWB 
Physical well-being domain of FACT-L 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
QW 
Weekly 
RBC 
Red blood cell 
RECIST  
Response evaluation criteria in solid tumors 
RNA 
Ribonucleic acid 
RNAi 
Ribonucleic acid interface 


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Abbreviation 
Definition 
RT-PCR 
Reverse transcription polymerase chain reaction 
SAE 
Serious adverse event 
SAF 
Safety Population 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
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 
One Kendall Square 
Cambridge, MA  USA 02139-1670 
Protocol Title: 
SHERLOC: A Phase 2 Study of MM-121 in Combination With Docetaxel 
versus Docetaxel Alone in Patients with Heregulin Positive, Locally Advanced 
or Metastatic Non-Small Cell Lung Cancer  
Protocol Number: MM-121-01-02-09 
Phase of 
Development: Phase 2 
Trial Locations: International 
Number of sites: Approximately 80-100 sites worldwide 
Patient 
Population: 
Patients who are candidates to receive single agent docetaxel therapy for non-
small cell lung cancer (NSCLC) that is histologically classified as 
adenocarcinoma. Such patients have received either one or two lines of systemic 
therapy for locally advanced and/or metastatic disease, and shall have tumors 
that are positive for heregulin (HRG) mRNA as assessed by central testing. 
Estimated Number 
of Patients: 
Approximately 300 patients will be screened, and approximately 110-150 
patients will need to be enrolled to support randomization of 80 HRG positive 
patients that meet the Per Protocol Population criteria according to Protocol 
version 4.0. 
Primary 
Objective: 
• 
To determine whether the combination of MM-121 plus docetaxel is more 
effective than docetaxel alone based on investigator assessed Progression-
Free Survival (PFS) according to RECIST 1.1 in HRG positive patients 
(defined as HRG ISH score of ≥1+). 
Secondary 
Objectives: 
• 
To determine whether the combination of MM-121 plus docetaxel is more 
effective than docetaxel alone in HRG positive patients (defined as HRG 
ISH score of > 1+) for the following clinical outcome parameters: 
o Overall Survival (OS) 
o Objective Response Rate (ORR) based on RECISTv1.1 
o Time to Progression (TTP) 
• 
To describe the safety profile of MM-121 in combination with docetaxel  
• 
To characterize the pharmacokinetic (PK) profile of MM-121 when given in 
combination with docetaxel and of docetaxel when given in combination 
with MM-121 
Exploratory 
Objective: 
• 
To evaluate if mechanistically linked exploratory biomarkers from tumor 
tissue or blood samples correlate with clinical outcomes 
Study Design: 
This study is a randomized, open-label, international, multi-center, phase 2 
study in patients with NSCLC histologically classified as adenocarcinoma that 
has progressed following one or two lines of systemic therapy for locally 
advanced and/or metastatic disease, of which one must have been a platinum 
containing regimen. 
 
Following signing the pre-screening informed consent form, 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 archived tissue is not available, patients 
should undergo a procedure (e.g. fine needle aspiration (FNA), core needle 
biopsy (CNB), thoracentesis, or excisional biopsy) to acquire the necessary 
tissue for HRG testing. For these procedures, investigators are asked to choose 


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an easily accessible tumor lesion to minimize any possible risk associated with 
the collection of the tissue. As a general guideline, if the selected procedural 
location has an established serious complication rate of >2% at the institution 
completing the procedure, this is considered a high risk procedure and should be 
avoided. 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 a HRG ISH score of >1+, will sign the full study consent form 
and continue with screening procedures.  Patients with tumors that show no 
staining for HRG, HRG ISH score of 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. 
 
In order to obtain fresh tissue from all patients enrolled, all patients that receive 
a positive HRG result for eligibility based on testing of archived samples will 
also be required to undergo a fresh research biopsy (e.g. FNA, CNB, 
thoracentesis, or excisional biopsy) prior to first dose. It is important that no 
systemic therapy is administered between collection of this tissue and dosing on 
this study. An additional sample will not be requested from patients who 
underwent a fresh biopsy for eligibility testing. 
 
After all screening procedures and determination of eligibility for treatment 
randomization (including HRG positive ISH result) have been completed, 
eligible patients will be randomized in a 2:1 ratio (experimental arm versus 
comparator arm) using an Interactive Web Response System (IWRS). 
Randomization will be stratified based on the number of prior systemic 
therapies for locally advanced and/or metastatic disease (1 or 2) and prior anti-
PD-1 or anti-PD-L1 will be capped at approximately 30% per group. Patients 
will be assigned to Arm A or Arm B: 
 
Arm A (Experimental Arm): 
MM-121: fixed dose of 3000 mg intravenously (IV) on day 1 of each 21-day 
cycle 
Docetaxel: 75 mg/m2  IV on day 1 of each 21-day cycle  
 
Arm B (Comparator Arm): 
Docetaxel: 75 mg/m2  IV on day 1 of each 21-day cycle 
Treatment must start within 7 days following randomization. Patients are 
expected to be treated until investigator-assessed progressive disease or 
unacceptable toxicity. Tumor assessments will be measured and recorded by the 
local radiologist every 6 weeks (+/- 1 week) and evaluated using the RECIST 
guidelines (version 1.1). All patients that come off treatment for reasons other 
than progressive disease will have a scan at the time of the End of Treatment 
visit. After patients come off treatment, survival information and information 
about subsequent therapies will be collected until death or study closure, 
whichever occurs first.  Final analysis will be triggered following the last 
recorded event as recorded in the database. 
 
In prior studies, MM-121 has been administered in combination with taxanes 
(paclitaxel and cabazitaxel) at the standard doses with no maximum tolerated 
dose (MTD) reached. However, no data was available for the combination of 
MM-121 and docetaxel prior to starting the current study.  Therefore, 
enrollment into this backbone was paused after the twelfth patient was 


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randomized to docetaxel or MM-121 + docetaxel and completed one full cycle 
of treatment, and the emerging safety data on both arms was reviewed by 
investigators, medical monitors and representatives from the sponsor. The safety 
review decided that enrollment to docetaxel alone or MM-121 + docetaxel can 
continue at the current dose level without modification as outlined in the study 
protocol. The DMC will monitor safety data over the course of the study in 
accordance with the DMC Charter. 
Inclusion Criteria: 
To be eligible for participation in the study, patients must meet the following 
criteria. Patients who are assessed to be HRG negative do not complete any 
screening procedures beyond HRG assessment. 
• 
Patients with cytologically or histologically documented NSCLC classified 
as adenocarcinoma that is presenting as either: 
o Stage IV (metastatic disease) or 
o Stage IIIB disease not amenable to surgery with curative intent or 
o Recurrent or progressive disease following multimodal therapy 
(chemotherapy, radiation therapy, surgical resection or definitive 
chemoradiation therapy for locally advanced or metastatic disease) 
• 
Disease progression or evidence of recurrent disease during or after the last 
systemic therapy as documented by radiographic assessment 
• 
Received one prior platinum-based regimen for management of primary or 
recurrent disease  
• 
Received nivolumab, pembrolizumab, or other anti-PD-1 or anti-PD-L1 
therapy, where available and clinically indicated  
• 
Clinically eligible for treatment with docetaxel once every three weeks per 
the investigator’s judgment 
• 
Must have at least one lesion amenable to collection of tissue 
• 
A positive in-situ hybridization (ISH) test for heregulin with a score of  
>1+, as determined by centralized testing  
• 
ECOG performance status (PS) of 0 or 1  
• 
Screening ECG without clinically significant abnormalities  
• 
Women of childbearing potential, as well as fertile men and their partners, 
must be willing to abstain from sexual intercourse or to use an effective 
form of contraception (an effective form of contraception is an oral 
contraceptive or a double barrier method or as defined by country-specific 
guidelines) during the study and for 6 months, in males and females, 
following the last dose of study drug(s), or greater, as in accordance with 
the label requirements or institutional guidelines for docetaxel 
• 
≥ 18 years of age 
• 
Able to provide informed consent, or have a legal representative able and 
willing to do so 
• 
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: 
To be eligible for randomization, patients must not meet any of the following 
criteria: 
• 
Known Anaplastic Lymphoma Kinase (ALK) gene rearrangement 
• 
Presence of exon 19 deletion or exon 21 (L858R) substitution of the EGFR 
gene 
• 
Pregnant or lactating 


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• 
Prior radiation therapy to >25% of bone marrow-bearing areas 
• 
Received >2 prior lines of systemic anti-cancer drug regimens for locally 
advanced and/or metastatic disease 
o Any type of maintenance therapy, e.g. pemetrexed maintenance 
following first line treatment with cisplatin and pemetrexed, is not 
considered a separate line of therapy 
• 
Prior treatment with an anti-ErbB3 antibody 
• 
Prior treatment with docetaxel for advanced/ metastatic disease  
• 
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 addition (if necessary), 
the timeframe for resolution of any actual or anticipated toxicities from 
such radiation 
• 
CTCAE grade 3 or higher peripheral neuropathy  
• 
Presence of an unexplained fever > 38.5°C during screening visits that does 
not resolve prior to the first day of dosing. If the fever and active infection 
have resolved prior to randomization, the patient will be eligible. At the 
discretion of the investigator, patients with tumor fever may be enrolled.  
• 
Clinically active CNS metastasis  
• 
Use of strong CYP3A4 inhibitors  
• 
Any other active malignancy requiring systemic therapy  
• 
Known hypersensitivity to any of the components of MM-121 or previous 
CTCAE grade 3 or higher hypersensitivity reactions to fully human 
monoclonal antibodies 
• 
History of severe hypersensitivity reactions to docetaxel  
• 
Known hypersensitivity to polysorbate (Tween) 80 or arginine 
• 
Inadequate bone marrow reserve as evidenced by: 
o ANC < 1,500/µl or 
o Platelet count < 100,000/µl or 
o Hemoglobin < 9 g/dL (5.59 mmol/L) 
• 
Serum/plasma creatinine > 1.5 x ULN  
• 
Inadequate hepatic function as evidenced by:  
o Aspartate aminotransferase (AST) and/or alanine aminotransferase 
(ALT) > 1.5 x ULN concomitant with Alkaline phosphatase (AP) > 2.5 
x ULN 
o Serum/plasma total bilirubin > ULN  
• 
Clinically significant cardiac disease, including: symptomatic congestive 
heart failure, unstable angina, acute myocardial infarction within 12 months 
of planned first dose, or unstable cardiac arrhythmia requiring therapy 
(including torsades de pointes)  
• 
Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; or 
active human immunodeficiency virus (HIV) infection, active hepatitis B 
infection or active hepatitis C infection 
• 
Patients who are not appropriate candidates for participation in this clinical 
study for any other reason as deemed by the investigator 


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Length of Study: 
It is intended that patients will be treated until radiographic disease progression 
per RECIST 1.1, death or intolerable toxicity, as assessed by the investigator. 
The primary analysis will be event driven.  It is estimated that the accrual will 
be approximately 5-6 patients per month over an approximately 15 month 
period.  
Investigational 
Product: 
MM-121 is a clear liquid solution, supplied in sterile, single-use vials for 
injectable use at a concentration of 25 mg/mL. MM-121 Drug Product should be 
stored at 2-8°C. 
Docetaxel: 
Docetaxel is a commercially available pyrogen-free, non-aqueous solution for 
intravenous use supplied in multi-use vials containing either 4 mL or 8 mL of 
docetaxel at a concentration of 10 mg/mL. Docetaxel should be stored at 20-
25°C (68 - 77°F) and should be retained in the original packaging to protect 
from light. 
Sample Size: 
The primary endpoint of the study is Progression-Free Survival (PFS). 
Approximately 61 PFS events in 80 patients are required to have at least 80% 
power to detect a 2 month improvement in median PFS with the combination of 
MM-121 plus docetaxel or MM-121 versus docetaxel alone with a baseline 
median PFS assumption of 3 months (i.e., hazard ratio ≤ 0.60), using a one-
sided, stratified log-rank test at a significance level of 0.15 with a 2:1 ratio.   
Statistical 
Considerations 
and Data 
Reporting: 
General: 
Categorical variables will be summarized by frequency distributions (number 
and percentages of patients) and continuous variables will be summarized by 
descriptive statistics (mean, standard deviation, median, minimum, maximum).   
 
Analysis Populations: 
The primary analysis will occur on the Per Protocol (PP) population, defined as 
patients that meet all inclusion/exclusion criteria as defined in Protocol version 
4.0 and that are confirmed HRG positive based on centralized analysis of tissue 
collected after progression on the most recent line of therapy (pre-treatment 
tissue sample). 
 
Due to the adjusted entry criteria, patients randomized prior to this amendment 
will be maintained as evaluable for the primary efficacy analysis where 
applicable.  A thorough review of all patient level data will be performed on 
those already randomized.  Those patients meeting the new entry criteria will be 
eligible to be part of the primary efficacy analysis and may contribute to the 
total sample size of 80 patients enrolled under Version 4.0 of the protocol, as 
long as no major protocol violations exist which would exclude them from the 
per protocol population. Major protocol violations include those not meeting the 
new entry criteria, those with no baseline measurable lesions, and those patients 
that never received at least 1 dose of study drug.  The total number of patients 
randomized will not exceed the number needed to randomize 80 patients who 
qualify for the per protocol population of Version 4.0. It is estimated to be in the 
range of 110-150 patients. 
 
Patients that meet eligibility criteria but have existing protocol violations which 
would exclude them from the per protocol population will be analyzed as part of 
a sensitivity analysis by pooling them with the per protocol population. 
Any patient randomized and not meeting the new entry criteria will be pooled 
with all other patients and analyzed as part of a sensitivity analysis population. 
 


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All patients previously randomized under previous protocols will be used either 
as part of the primary efficacy analysis in the per protocol population or in some 
form of sensitivity analysis.  All patients dosed will contribute to the safety 
population. 
 
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 and dosed 
patients.  The PP population is the primary efficacy population and will 
only include patients that meet all inclusion/exclusion criteria as defined 
in Protocol Version 4.0 and that are confirmed HRG positive based on 
centralized analysis of tissue collected after progression on the most 
recent line of therapy (pre-treatment tissue sample).  The PP will 
exclude those patients with major protocol violations, which will be 
defined in the SAP in more detail and assessed in an unbiased ongoing 
manner.  Primary considerations for exclusion will be those patients 
with no measurable baseline tumor, non-evaluated baseline non-target 
tumor assessments, and incomplete tumor evaluations.  Not all 
circumstances will result in exclusion, however a continual review of 
patient data will be performed to address data inconsistencies by the 
medical director, statistician, and clinical trial manager.  Data will be 
reviewed without knowledge of progression/non-progression. 
• 
Safety (SAF) population: The safety population includes patients 
receiving at least one dose of study medication. Patients will be 
analyzed by the treatment received and not by the treatment to which 
they were randomized.  All safety analyses will be performed on this 
population.  
• 
PK population: All treated patients with at least one PK assessment 
 
Primary Efficacy Analysis:  
PFS, based on investigator assessment is the primary endpoint of the study.  
PFS is defined as the time from randomization to the first documented 
radiographical progression of disease using RECIST 1.1, or death from any 
cause, whichever comes first.  Details of censorship will be thoroughly 
explained in the SAP.  The primary efficacy will be performed on the per 
protocol (PP) population using a stratified log-rank test.  The Kaplan-Meier 
method will be used to estimate median PFS for each treatment group. A 
stratified Cox proportional hazard model will be used to obtain an estimate 
hazard ratio and corresponding 70% confidence intervals.  Stratification factors 
include: Number of prior systemic treatments for locally advanced and/or 
metastatic disease (1, 2). 
 
Secondary Efficacy Analysis: 
Overall Survival (OS):  
Overall Survival (OS) is defined as the time from the date of randomization to 
the date of death from any cause.  The Kaplan-Meier method will be used to 
estimate median OS for each treatment group. A stratified Cox proportional 


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hazard model will be used to obtain an estimate hazard ratio and corresponding 
95% confidence intervals. 
Objective Response Rate (ORR): 
Objective response rate (ORR) is determined by RECIST v1.1 (CR+PR).  An 
estimate of the ORR and its 95% CI will be calculated.  CMH tests will be 
performed as appropriate. 
 
Time to Progression (TTP): 
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. 
 
Biomarkers and standard covariates will be analyzed with respect to OS, PFS, 
ORR, and TTP. 
 
Additional OS, PFS, ORR and TTP sensitivity analyses will be conducted using 
various study populations.  In addition, OS and PFS will have different 
censoring rules applied to assess parameter sensitivity to changes in 
specifications.  These will be clearly detailed in the statistical analysis plan 
(SAP). 
 
Safety Analysis: 
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 will be graded according to the NCI CTCAE 
version 4.03. Patients will be analyzed according to the treatment received.  
Pemetrexed patients will be summarized accordingly. 
 
Treatment-emergent adverse events (TEAEs), TEAE grade 3 and higher, 
TEAE-related, SAEs, and discontinuation due to AE will be reported by 
frequency and percent summaries.  Adverse events will be summarized by 
System Organ Class and preferred term.  All adverse event data will be listed by 
patient.   
 
Laboratory, vital signs, and ECG data will be summarized according to 
parameter type. 
 
Pharmacokinetic Analysis: 
Serum concentrations will be used to determine the MM-121 PK parameters and 
plasma concentrations will be used to determine docetaxel parameters 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.  
 
Exploratory Translational Analyses: 
Biomarker data will be explored from collected tissue and serum to assess 
potential associations with tumor response. Efficacy outcomes considered for 
exploratory biomarker analysis will include OS, PFS, and ORR.  Kaplan Meier 
methods for displaying graphs and Cox proportional models will be used when 
estimating hazard ratios with 95% confidence intervals. 


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Study Schema 
 
 
 
Progression after platinum-
based regimen 
Screening 
(N~300) 
HRG-ISH  
Negative 
HRG-ISH 
Positive 
(n=80) 
Screen Failure 
R 
2:1 
MM-121 + Docetaxel (53) 
Docetaxel    (27) 


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1 Introduction 
1.1 
Non-Small Cell Lung Cancer 
Lung cancer is projected to be the leading cause of all cancer-related deaths worldwide in 2014. 
It is estimated that there will be 224,410 new cases diagnosed in 2014 alone, making up 
approximately 13% of all cancer diagnoses. For cases diagnosed during the period of 2003-2009, 
the 1- and 5-year survival rates were 43% and 17% respectively (“American Cancer Society 
Facts and Figures 2014,” 2014). Over 80% of lung cancers are comprised of non-small cell lung 
cancers (NSCLC), and nearly two thirds of these are diagnosed at an advanced stage.  A 
platinum-based doublet regimen with a third-generation agent (paclitaxel, docetaxel, 
gemcitabine, vinorelbine, pemetrexed) is considered standard of care worldwide for the 
treatment of advanced NSCLC (Kawaguchi et al., 2014)  However, only one third of patients that 
.
receive this regimen reach an objective response during first-line therapy, and another 20-30% 
achieves stabilization of disease. Unfortunately, almost all patients ultimately see progression of 
their disease (Gridelli et al., 2008). 
There are currently three agents approved for second-line treatment of advanced NSCLC. 
Docetaxel was the first regimen approved for second-line treatment after several phase 2 and 
phase 3 studies established the standard regimen (Shen et al., 2014)  The dose of 75 mg/m
.
2 once 
every three weeks was shown to demonstrate longer survival and better quality of life than the 
best supportive care at that time, and was shown to demonstrate an increase in 1-year survival 
rates in comparison to vinorelbine or ifosfamide (Manegold et al., 2013)  Pemetrexed receiv
.
ed 
approval as second-line therapy due to its similarity in survival and response with lower toxicity 
levels than those of docetaxel, although statistically, it was not proven to be better or inferior to 
docetaxel (Hanna et al., 2004; Paz-Ares et al., 2008)  Erlotinib was also approved on the basis of 
.
increased survival in comparison to best supportive care.  
Although these regimens do show an increase in survival rates and better quality of life from 
supportive care, there is still much room for improvement. Docetaxel given at 75 mg/m2 once 
every three weeks is associated with a 1-year survival of 30-40%. While this is a higher rate of 
survival, it is a clear indication that a more effective treatment for patients with advanced 
NSCLC is needed. 
1.2 
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; 


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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). 
The role of ErbB3 and heregulin in the development and progression of multiple cancers has 
been well-established. ErbB2/ErbB3 heterodimers and heregulin have been identified as being 
instrumental for breast cancer cell growth (Holbro et al., 2003; Hutcheson et al., 2007; Perez-
Nadales & Lloyd, 2004; Yarden & Sliwkowski, 2001). Elevated levels of tyrosine-
phosphorylated ErbB3 are frequently found in breast tumors that overexpress ErbB2 (Lemoine et 
al., 1992; Naidu et al., 1998). In addition, ErbB3 expression has recently been shown to be 
predictive of poor prognosis in ovarian cancer (Tanner et al., 2006) and, nuclear expression of 
ErbB3 has been shown to correlate with the risk of disease progression and hormone-refractory 
status in prostate cancer (Koumakpayi et al., 2006)  .  
There exist potential clinical implications of the HRG-activated ErbB2/3 and EGFR/ErbB3 
heterodimers, as these are believed to be integrally involved in the resistance of several tumor 
types to targeted therapies or chemotherapy. Such heterodimers act as potent activators of cancer 
cell survival signaling through AKT and MAPK and have been associated with cancer cell 
insensitivity to both cytotoxic and targeted agents (Chakrabarty, Sánchez, Kuba, Rinehart, & 
Arteaga, 2012; Engelman et al., 2007; Sheng et al., 2010). Indeed, pioneering studies have 
demonstrated that high expression of kinase-dead ErbB3 can predict early escape from the anti-
ErbB2 monoclonal antibody trastuzumab. In addition, the growth-inhibitory effects of ErbB1/2 
tyrosine kinase inhibitors (TKIs) were previously found to be attenuated in the presence of HRG. 
(Hutcheson et al., 2007). Interestingly, ErbB3 has recently been shown to play an important role 
in TKI resistance in both breast and lung cancer cells (Engelman et al., 2007; Sergina et al., 
2007). The experimental abrogation of ErbB3 resistance by small interfering RNA knockdown 
of ErbB3 restores potent pro-apoptotic activity to otherwise cytostatic ErbB TKIs, suggesting 
that anti-ErbB3 therapeutics may be useful in combination with other antitumor agents. 
Furthermore, ErbB3 was also shown to promote resistance to chemotherapy in various cancer 
models. The chemotherapeutic drug doxorubicin upregulates HRG to activate the 
ErbB3/PI3K/AKT signaling axis in ovarian cancer cells and targeting of ErbB3 may significantly 
sensitize ovarian tumors to the killing effects of platinum-based or other chemotherapy regimens 
(Bezler, Hengstler, & Ullrich, 2012)  . Knuefermann et al. showed that co-expression of ErbB2 
and ErbB3 in human breast cancer cell lines induced activation of PI3K/AKT signaling and was 
associated with an increased resistance to multiple chemotherapeutic agents, such as paclitaxel, 
doxorubicin, 5-fluorouracil, etoposide, and camptothecin (Knuefermann et al., 2003). These 
findings are in agreement with our clinical data obtained with MM-121. Yu et al. showed that the 
pemetrexed resistant A549 lung cell line expresses increased levels of ErbB3 and EGFR. Within 
this particular cell line, the knock-down of EGFR or ErbB3 by RNAi resensitized the cells to 
therapy (Yu et al., 2014). 
Overall these data suggest a broad implication of HRG driven ErbB3 signaling in mediating 
resistance to chemotherapies making it an attractive target for therapeutic intervention when used 
in combination with cytotoxic therapies.  
1.3 
MM-121 
MM-121 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, MM-121 effectively blocks 


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heterodimer formation of the ErbB3 receptor with e.g. ErbB2 and EGFR and as such 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 MM-121 efficacy.  
1.3.1 Pre-Clinical Experience of MM-121 and NSCLC 
Pre-clinical data demonstrated single agent response to MM-121 in lung cancer cell lines (in 
vivo) in those cell lines that are receptive to heregulin (HRG) stimulation in vitro. In vitro studies 
carried out at Merrimack indicate that 9 out of 25 EGFR wild-type NSCLC cell lines are 
responsive to HRG: they exhibit increased cell proliferation in response to exogenously added 
HRG, as measured by CTG using 3D spheroid cultures (Figure 1A). Two HRG-responsive cell 
lines and two non-responsive cell lines were selected to assess single agent activity of MM-121 
in subcutaneous mouse xenografts. The mice were dosed with 300 g MM-121 every three days 
(Q3D). As shown in Figure 1B, the HRG-responsive cell lines also responded to MM-121 as a 
single agent in vivo. In contrast, H460 and Hop92, which were not responsive to HRG in vitro, 
did not respond to MM-121 in vivo (Figure 1C). High tissue HRG mRNA levels were measured 
in the MM-121-responsive xenograft tumors (data not shown). Interestingly, both human HRG 
mRNA, indicative of autocrine HRG signaling, and mouse HRG mRNA, indicative of stroma-
derived paracrine signaling, were observed in the HRG-responsive tumors. These data indicate 
that a subset of EGFR wild-type NSCLC cell lines are responsive to HRG, that these cell lines 
elicit the production of HRG, and that the presence of HRG in tissue appears to be necessary for 
MM-121 response in vivo further supporting exclusion of patients whose tumors do not express 
HRG. 
Figure 1: Capacity of HRG to induce proliferation in a panel of NSCLC cell lines in vitro 
is indicative of single-agent response to MM-121 in vivo. 
 


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As depicted in Figure 2, HRG induces resistance to pemetrexed and docetaxel in a panel of 9 
lung cancer cell lines.  HRG-driven ErbB3 signaling mediates survival signaling through the 
PI3K/AKT pathway and has been implicated as a general mechanism that imparts insensitivity to 
cytotoxic chemotherapy. As shown in Figure 2A, HRG induces resistance to pemetrexed and 
docetaxel in a subset of EGFR wild-type NSCLC cell lines. Proliferation was measured in the 
presence or absence of HRG in a panel of nine cell lines using 3D spheroid cultures. Full dose 
response curves were obtained but results are only shown for a single relevant dose of 
chemotherapy. In three of these cell lines – those most responsive to HRG – inhibition of cell 
viability by both docetaxel and pemetrexed was decreased upon the addition of HRG. In fact, 
HRG induced proliferation even in the presence of chemotherapy, as noted by the negative 
values for % inhibition. Importantly, when MM-121 was added in addition to HRG, sensitivity to 
both docetaxel and pemetrexed was restored in these cell lines (Figure 2B).  
Figure 2: (A) 5nM HRG induces resistance to docetaxel (111nM) and pemetrexed 
(1111nM) in a 3D spheroid proliferation assay after 96hrs.  
(B)  MM-121 (1µM) restores sensitivity in NSCLC cell lines (A549, EKVX, H358, 
H322M, Calu-3, H661, H441, H1355, H430). 
 
Based on Merrimack’s preclinical research and previous clinical experience, HRG-induced 
ErbB3 signaling appears to be a general resistance mechanism for several standard-of-care 
therapies used to treat NSCLC and MM-121 may provide a way to sensitize tumor cells when 
this pathway is active. An in vivo example is shown in Figure 3A and Figure 3B. The 
combination of MM-121 and paclitaxel controls tumor growth significantly better than either 
agent alone (Figure 3A).  Figure 3B describes the effect of drug scheduling. A549 tumors were 
grown in mice and only exposed to paclitaxel for the first 29 days.  Single agent paclitaxel did 


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not inhibit tumor growth, only when paclitaxel was combined with MM-121 tumor shrinkage 
was observed (Figure 3B).  
Figure 3: (A) A549 NSCLC xenograft model treated with 300µg q3d MM-121, 20 mg/kg 
paclitaxel and the combination of MM-121 + paclitaxel q3d  
(B) A549 NSCLC xenograft model treated with 20 mg/kg up to day 29 with 
Paclitaxel followed by paclitaxel + MM-121 
 
Previous randomized phase 2 clinical trials of MM-121 in breast and ovarian cancer provided a 
threshold level of HRG expression measured by quantitative RT-PCR above which increased 
PFS was observed upon the addition of MM-121 to standard-of-care therapy.  This RT-PCR data 
threshold was applied to the Cancer Genome Atlas (TCGA) dataset to determine the prevalence 
of HRG expression above this threshold in a wide variety of solid tumors (Figure 4 . Based on 
)
this analysis, 87% of the squamous cell carcinoma samples were above the defined threshold. 
Squamous cell carcinoma is one of the indications with the highest prevalence of HRG 
expression among all solid tumor types. 45% of the adenocarcinoma samples had HRG mRNA 
levels above this threshold (Figure 4 . Overall, these data suggest that NSCLC is one indication 
)
in which HRG-driven ErbB3 signaling is particularly prevalent.  


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Figure 4: HRG mRNA expression levels across different indications based on the TCGA 
data set 
 
In addition, HRG expression was assessed using an RNA in situ hybridization (RNA-ISH) assay 
in pre-treatment core needle biopsies obtained from patients enrolled in the MM-121-01-101 
study of MM-121 in EGFR wild-type NSCLC. Overall 54% of the samples scored 1+ or higher 
(Figure 5A).  Furthermore, we expanded our analysis and analyzed an additional 53 archival 
lesions and biopsies that were procured from Cureline (Figure 5B). Comparable to the findings 
in the MM-121-01-101 lung study, the prevalence of HRG mRNA by RNA-ISH with a score of 
>1+ was found to be 44%, again supporting development of MM-121 in NSCLC. 
Figure 5: HRG mRNA expression across NSCLC tissue samples 
 
1.3.2 Clinical Experience of MM-121 in Humans 
MM-121 has been studied in eight previous clinical trials under IND #100605 with a total of 700 
patients being exposed to MM-121 alone or in combination with other anti-cancer therapies. The 
ER/PR+, HER2- 
Breast
45%
Bladder
39%
Liver
48%
Pancreatic
33%
ER-/PR-/HER2+ 
Breast
Cervical
Lung, Adeno
Prostate
35%
59%
59%
45%
Triple Negative 
Breast
Colorectal
Lung, Squamous
Melanoma
49%
28%
87%
34%
ER/PR+, HER2+ 
Breast
53%
Head & Neck
97%
Ovarian
Uterine
33%
21%


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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 MM-121. 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 MM-121 trials were initiated in varying indications and chemotherapy 
combinations. Investigators should refer to the MM-121 Investigator’s Brochure for more 
information regarding ongoing and previous trials of MM-121. Previous experiences in NSCLC 
and safety of MM-121 in combination with chemotherapy are described in more detail below. 
1.3.2.1 
Previous Experience of MM-121 in NSCLC 
MM-121 was tested in combination with erlotinib in a phase 1/2 study in NSCLC. Following a 
3+3 dose escalation design in the phase 1 portion of the trial and selection of a phase 2 dose (as 
presented at the American Society of Clinical Oncology (ASCO)) (Sequist et al., 2012) patients 
were assigned to three different treatment groups. Group A enrolled 129 NSCLC patients whose 
tumors are wild-type for EGFR and who have progressed after at least one prior line of standard 
chemotherapy that did not contain an EGFR TKI. Patients were randomized 2:1 to receive MM-
121 every other week at a dose of 20 mg/kg IV in combination with daily 100 mg erlotinib p.o. 
(N=85) or to receive daily 150 mg erlotinib p.o. alone (N=44). The primary efficacy objective of 
achieving a 50% reduction in hazard ratio in the MM-121 group vs. the erlotinib group alone was 
not reached. A total of 95 out of the 129 patients were documented as having a PFS event, 
resulting in a hazard ratio of 0.816 [95%CI: 0.552-1.207]. Overall, the median PFS of the 
experimental arm was 1.9 months versus 1.8 months on the control arm.  
A preplanned biomarker analysis using fresh tissue biopsies obtained from all patients enrolled 
into group A of the study showed that patients who had HRG positive tumors had a poor 
outcome on the erlotinib only arm, and seemed to benefit from the addition of MM-121 to 
erlotinib. These data are described in detail in Section 1.4. 
1.3.3 Potential Toxicities with MM-121 
The safety profile of MM-121 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 MM-121 in human subjects are comprised of safety data from 962 
patients that have been enrolled into MM-121 studies under the IND #100605, including 700 
patients that have been exposed to MM-121 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),  


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As of July 2014, the most frequently occurring (>20% of patients) treatment emergent adverse 
events across all patients exposed to MM-121 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 MM-121 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. 
1.3.3.1 
Previous Safety Experience of MM-121 in Combination with Taxanes 
MM-121 was administered in combination with paclitaxel in a Phase 1 dose escalation study 
with no MTD observed and a randomized phase 2 trial in platinum-refractory or resistant 
advanced/metastatic ovarian cancer. Patients on the treatment arm were given MM-121 weekly 
at a loading dose of 40 mg/kg IV followed a week later by weekly doses of 20 mg/kg IV. 
Paclitaxel was administered at 80 mg/m2 IV weekly for all patients regardless of assignment. Of 
the 220 patients enrolled on the study, 134 patients (95.7%) on the treatment arm reported at 
least one TEAE that was considered related to treatment, mostly due to diarrhea (63.6% 
treatment, 28.8% control), nausea (36.4% treatment, 36.3% control), fatigue (35.7% treatment, 
33.8% control), and alopecia (33.6% treatment, 30.0% control). 
Grade 3 or higher TEAEs that were considered related to treatment were reported in 51/140 
patients (36.4%) on the treatment arm and in 24/80 patients (30.0%) on the control arm. The 
most frequently reported grade 3 or higher TEAEs that were assessed as related to treatment on 
the treatment arm included anemia, occurring in 8 patients (5.7%) versus 4 patients (5.0%) on the 
control arm, and diarrhea, occurring in 8 patients (5.7%) versus 2 patients (2.5%) on the control 
arm. 
MM-121 was also combined with cabazitaxel in an open-label phase 1 cohort of 11 advanced 
solid tumor patients who had received multiple lines of prior chemotherapy. In this dose 
escalation study, MM-121 was administered at either 12 mg/kg weekly with a loading dose of 20 
mg/kg, or at 20 mg/kg weekly with a loading dose of 40 mg/kg. Cabazitaxel was administered at 
a dose of either 20 mg/m2 or 25 mg/m2 Q3W. Of the 11 patients, 100% reported at least one 
TEAE of any grade that was considered related to the study combination treatment, primarily 
diarrhea (11 patients, 100%), fatigue (5 patients, 45.5%), hypophosphatemia (5 patients, 45.5%), 
and nausea (5 patients, 45.5%). Of the grade 3 TEAEs reported, two instances each of fatigue, 
febrile neutropenia, hypophosphatemia, neutropenia, and thrombocytopenia were assessed by the 
investigator(s) to be related to the treatment regimen, as well as one instance of decreased white 
blood cell count. Additionally, two grade 4 events of neutropenia and thrombocytopenia were 
assessed as related to study treatment regimen. 
No MTD was identified for the combination of MM-121 and cabazitaxel with the highest tested 
combination dose being 40/20 mg/kg weekly for MM-121 (loading dose followed by 
maintenance dose) and 25 mg/m2 for cabazitaxel once every three weeks.   
1.3.3.2 
Safety Review of MM-121 and Docetaxel Combination 
While extensive data supports the safety of the combination of MM-121 with taxanes, there was 
no data available for the safety of the combination of MM-121 and docetaxel, specifically, at the 
beginning of the current study, MM-121-01-02-09. As such, a safety data assessment took place 


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in accordance with the guidelines outlined in Section 5.4. Enrollment into the docetaxel 
backbone was paused 21Apr2016 after the twelfth patient was randomized to docetaxel or MM-
121 plus docetaxel and completed one full cycle of treatment, and the emerging safety data on 
both arms was reviewed by investigators, medical monitors and representatives from the sponsor.  
At the time of the safety review, 8 patients had been randomized to receive MM-121 plus 
docetaxel (median number of cycles started = 4.5, range = 1-11) and 4 patients randomized to 
receive docetaxel alone (median number of cycles started = 1.5, range = 1-2). The reviewed data 
included patient demographics, medical history, extent of drug exposure, dose modifications, and 
all adverse and serious adverse events recorded. One patient randomized to docetaxel alone 
withdrew consent after the first dose of docetaxel and so no safety data was available for this 
patient.  
Of the 12 patients reviewed, 7 patients (87.5%) on the treatment arm reported at least one TEAE 
that was considered possibly, probably, or definitely related to treatment by the Investigator(s) 
(or relatedness either not reported or reported as unknown) compared to 3 patients (75.0%) on 
the control arm.  The related TEAEs reported for >20% of patients on the treatment arm 
included:  fatigue (75.0% treatment, 25.0% control), weight decrease (50.0% treatment, 0.0% 
control),  diarrhea (37.5% treatment, 25.0% control), neutropenia (37.5% treatment, 50.0% 
control), nausea (37.5% treatment, 25.0% control), alopecia (37.5% treatment, 25.0% control), 
dehydration (25.0% treatment, 25.0% control), neutrophil count decrease (25.0% treatment, 
0.0% control), stomatitis (25.0% treatment, 0.0% control), anemia (25.0% treatment, 0.0% 
control), and vomiting (25.0% treatment, 0.0% control). 
Grade 3 or higher TEAEs that were considered possibly, probably, or definitely related to 
treatment by the Investigator(s) (or with relatedness either not reported or reported as unknown) 
were reported in 6/8 patients (75.0%) on the treatment arm and in 2/4 patients (50.0%) on the 
control arm. The reported grade 3 or higher TEAEs that were assessed as related to treatment on 
the treatment arm were neutropenia (37.5% treatment, 50% control), decreased neutrophil count 
(25.0% treatment, 0% control), leukopenia (12.5% treatment, 25.0% control), anemia (12.5% 
treatment, 0% control), fatigue (12.5% treatment, 0% control), GI hemorrhage (12.5% treatment, 
0% control), and pneumonia (12.5% treatment, 0% control). 
There were no adverse events that led to study drug discontinuation or death in patients exposed 
to MM-121 plus docetaxel. On 02May2016 the safety review team decided that enrollment to 
docetaxel alone or MM-121 + docetaxel can continue at the current dose level without 
modifications as outlined in the study protocol. 
1.4 
Study Rationale 
Across the three randomized studies conducted with MM-121 in metastatic hormone receptor 
positive, HER2 negative breast cancer (mBC), platinum resistant ovarian cancer (mOC) and 
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 7 . However, 
)
the data also 
showed that the addition of MM-121 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 (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 


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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 6. 
Figure 6: Number of biomarker samples collected and the analysis performed for the 
three randomized Phase 2 studies of MM-121 
 
The results from these pre-planned retrospective analyses were consistent with the hypothesis 
that blockade of HRG-induced ErbB3 signaling by MM-121 can restore sensitivity to 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 
MM-121 phase 2 studies further suggested that the effect of the MM-121-mediated blockade of 
HRG signaling is particularly effective in the context of therapeutic backbones that have 
substantial baseline efficacy.  As such, erlotinib was not found to be an optimal combination 
partner as its activity in 2nd line NSCLC is fairly limited. Given the strong impact HRG signaling 
has on the efficacy of chemotherapies and the high prevalence of patients who have HRG 
positive tumors within NSCLC, we hypothesize that the combination of MM-121 with 
chemotherapy will deliver substantial clinical benefit to patients with NSCLC who have HRG 
positive tumors. 


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Figure 7: 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 8: Treatment effect of MM-121 in patients with HRG positive tumors 
 
The addition of MM-121 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 
MM-121 treatment arm 
vs. control arm in HRG 
positive subgroup 
MM-121 Arm 
Comparator Arm 
Events 
PFS time 
(months) 
Events 
PFS time 
(months) 
HR 
95%CI 
P 
n (%) 
Median 
n (%) 
median 
mBC (exemestane 
+/- MM-121) 
21 
37% 
0.32 
0.11-0.97 
0.044 
7 (63.6) 
7.7 
10 (100) 
1.9 
mOC (paclitaxel +/- 
MM-121)b 
57 
38% 
0.37 
0.18-0.79 
0.009 
26 (66.7) 
5.8 
13 (72.2) 
3.5 
NSCLC (erlotinib +/- 
MM-121) 
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 
1.4.1 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 experimental arm. The statistics of the 
three phase 2 studies summarized in Table 2 suggest that further development of MM-121 should 
focus on patients with HRG positive tumors. 
Table 2: Summary statistics for experimental treatment vs. control PFS in HRG negative 
subgroup 
Study Group 
MM-121 treatment arm vs. 
control arm in HRGlow 
HRGlow MM-121 Arm 
HRGlow Control Arm 
Events 
PFS time 
(months) 
Events 
PFS time 
(months) 
HR 
95%CI 
P 
n (%) 
median 
n (%) 
median 
mBC (exemestane +/- 
MM-121) 
1.06 
0.51-2.19 
0.87 
17 (81.0) 
2.4 
13 (86.7) 
3.5 
mOC (paclitaxel +/- 
MM-121)* 
1.54 
0.98-2.44 
0.062 
65 (90.3) 
3.5 
27 (67.5) 
5.4 
NSCLC (erlotinib +/- 
MM-121) 
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 
1.4.2 Rationale for MM-121 Dose Selection in Combination with Docetaxel 
Pharmacokinetic (PK) analyses from previous studies support using a fixed dosing regimen for 
MM-121. As such, MM-121 will be administered at a fixed dose of 3000 mg on day 1 of each 
21-day cycle in sync with the chemotherapy regimens administered in this study. 
Pharmacokinetics of MM-121 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 MM-121 was described using a two-compartment model, with estimated 
parameters provided in Table 3  Covariate selection ev
.
aluated 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, 


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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.  Post-hoc estimates of PK 
parameters from each of the 499 patients were used in the simulation.  The simulated dose for the 
fixed dosing regimen was chosen by rounding up to the closest 500 mg dose unit. 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 MM-121 dosing regimens for improved compliance and 
simplicity, a simulation study was conducted by comparing the simulation pharmacokinetics 
(averaged and minimum concentration) by different dose intervals. The results showed the 
potential to optimize the dosing frequency to once every 3 weeks. A dose regimen of 3000 mg 
Q3W is predicted to have: 1) a comparable maximum concentration (Cmax) to 40 mg/kg Q3W, a 
dose level previously used as a loading dose for weight-based and weekly MM-121 dosing 
regimens; 2) a comparable minimum concentration (Cmin) to 20 mg/kg Q2W which was the dose 
used in the previous MM-121 study in NSCLC in combination with 100 mg erlotinib; and 3) an 
average steady-state concentration that is in between 20 mg/kg Q2W and 20 mg/kg Q1W which 
is the previously studied regular dose for MM-121 following the 40 mg/kg loading dose in 
combination with chemotherapy. Therefore, this simulation study suggests that a MM-121 dose 
regimen of 3000 mg Q3W has a potential to improve compliance while maintaining the 
pharmacokinetic levels within the bounds of the exposures observed from previously studied 
MM-121 doses (40mg/kg + 20 mg/kg Q1W and 20mg/kg Q2W).  In addition, no MTD was 
identified when MM-121 was combined with standard doses of pemetrexed, paclitaxel or 
cabazitaxel. In these studies, MM-121 was given together with full doses of the chemotherapy 
agents at 40 mg/kg as a loading dose followed by weekly doses of 20 mg/kg. The loading dose of 
40 mg/kg equals 3000 mg in an average patient weighing 75kg. As such, the cumulative MM-
121 dose proposed for this study, 3000 mg MM-121 Q3W as a fixed dose, does not exceed 
previously tested dose regimens. 
 
 


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Table 3: Final parameter estimates from population PK analysis of MM-121 
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 9: Simulated MM-121 Pharmacokinetics (Average concentration) by weight-based 
and fixed dosing regimens and by dose and intervals. 
 
2 Objectives 
2.1 
Primary Objective 
The primary objective of this study is to determine whether the combination of MM-121 plus 
docetaxel is more effective than docetaxel alone based on investigator assessed Progression-Free 


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Survival (PFS) according to RECIST 1.1 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 MM-121 plus docetaxel is more effective than 
docetaxel alone in HRG positive patients (defined as HRG ISH score of  > 1+) for the 
following clinical outcome parameters: 
o Overall Survival (OS) 
o Objective Response Rate (ORR) based on RECISTv1.1 
o Time to Progression (TTP) 
• To describe the safety profile of MM-121 in combination with docetaxel  
• To characterize the pharmacokinetic (PK) profile of MM-121 when given in combination 
with docetaxel and of docetaxel when given in combination with MM-121 
2.3 
Exploratory Objectives 
The exploratory objective of this study is: 
• To evaluate if mechanistically linked exploratory biomarkers from tumor tissue or blood 
samples correlate with clinical outcomes. 
3 Study Design 
3.1 
Overview of Study Design 
This study is a randomized, open-label, international, multi-center, phase 2 study in patients with 
locally advanced or metastatic NSCLC histologically classified as adenocarcinoma that has 
progressed following one or two lines of systemic therapy for locally advanced and/or metastatic 
disease, of which one must have been a platinum containing regimen.  The purpose of the study 
is to assess in patients with HRG positive tumors if the addition of MM-121 to docetaxel is more 
effective than docetaxel alone in prolonging progression-free survival. 
Following signing the pre-screening informed consent form, 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 archived tissue is not 
available, patients may undergo a procedure (e.g. fine needle aspiration (FNA), core needle 
biopsy (CNB), thoracentesis, or excisional biopsy) to obtain 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 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 
score of >1+, will sign the full study consent form and will continue with screening procedures. 
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.  
In order to obtain fresh tissue from all patients enrolled, all patients that receive a positive HRG 
result for eligibility based on testing of archived samples will also be required to undergo a fresh 


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research biopsy (e.g. FNA, CNB, thoracentesis, or excisional biopsy) prior to first dose. It is 
important that no systemic therapy is administered between collection of this tissue and dosing 
on this study. An additional sample will not be requested from patients who underwent a fresh 
biopsy for eligibility testing. 
After all screening procedures and determination of eligibility for treatment randomization 
(including HRG positive ISH result) have been completed, eligible patients will be randomized 
in a 2:1 ratio (experimental arm versus comparator arm) using an Interactive Web Response 
System (IWRS). Randomization will be stratified based on number of prior systemic therapies 
for locally advanced and/or metastatic disease (1 or 2) and prior anti-PD-1 or anti-PD-L1 will be 
capped at approximately 30% per group.  
Patients will be randomized to Arm A or Arm B: 
Arm A (Experimental Arm):   
• MM-121: fixed dose of 3000 mg IV on day 1 of each 21-day cycle 
• Docetaxel: 75 mg/m2 IV on day 1 of each 21-day cycle 
Arm B (Comparator Arm): 
• Docetaxel: 75 mg/m2 IV on day 1 of each 21-day cycle 
Treatment must start within 7 days following randomization. Patients are expected to be treated 
until investigator assessed progressive disease or unacceptable toxicity. Tumor assessments will 
be measured and recorded by the local radiologist every 6 weeks (+/- 1 week) using the RECIST 
guidelines (version 1.1). All patients that come off treatment for reasons other than progressive 
disease will have a scan at the time of the End of Treatment visit. After patients come off 
treatment, survival information and information about subsequent therapies will be collected 
until death or study closure, whichever occurs first.  After a minimum of  61 PFS events in the 
per protocol population have been reported, the final analysis will be performed. 
In prior studies, MM-121 has been administered in combination with taxanes (paclitaxel and 
cabazitaxel) at the standard doses with no MTD reached. However, no data was available for the 
combination of MM-121 and docetaxel prior to starting the current study.  Therefore, enrollment 
into this backbone was paused after the twelfth patient was randomized to docetaxel or MM-121 
+ docetaxel and completed one full cycle of treatment, and the emerging safety data on both 
arms was reviewed by investigators, medical monitors and representatives from the sponsor in 
accordance with Section 5.4. The safety review team decided that enrollment to docetaxel alone 
or MM-121 + docetaxel can continue at the current dose level without modifications as outlined 
in the study protocol. The DMC will continue to monitor safety data over the course of the study 
in accordance with the DMC Charter. 
4 Study Population 
The target population for this study is patients who are candidates to receive single agent 
docetaxel therapy for locally advanced or metastatic non-small cell lung cancer (NSCLC) that is 
histologically classified as adenocarcinoma.  Such patients have received one or two lines of 
systemic therapy for locally advanced and/or metastatic disease, and shall have tumors that are 
positive for heregulin (HRG) mRNA as assessed by central testing. The investigator or his/her 
designee must ensure that all patients meet the following inclusion and exclusion criteria before 
being enrolled in the study:  


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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) Patients with cytologically or histologically documented NSCLC classified as 
adenocarcinoma that is presenting as either: 
• Stage IV (metastatic disease) or 
• Stage IIIB disease not amenable to surgery with curative intent or 
• Recurrent or progressive disease following multimodal therapy (chemotherapy, 
radiation therapy, surgical resection or definitive chemoradiation therapy for 
locally advanced or metastatic disease) 
b) Disease progression or evidence of recurrent disease during or after the last systemic 
therapy as documented by radiographic assessment 
c) Received one prior platinum-based regimen for management of primary or recurrent 
disease 
d) Received nivolumab, pembrolizumab or other anti-PD-1 or anti-PD-L1 therapy, where 
available and clinically indicated  
e) Clinically eligible for treatment with docetaxel once every three weeks per the 
investigator’s judgment  
f) Must have at least one lesion amenable to collection of tissue 
g) A positive in-situ hybridization (ISH) test for heregulin with a score of ≥1+, as 
determined by centralized testing 
h) ECOG performance status (PS) of 0 or 1  
i) Screening ECG without clinically significant abnormalities  
j) Women of childbearing potential, as well as fertile men and their partners, must be 
willing to abstain from sexual intercourse or to use an effective form of contraception (an 
effective form of contraception is an oral contraceptive or a double barrier method or as 
defined by country-specific guidelines) during the study and for 6 months, in females and 
males, following the last dose of study drug(s), or greater, as in accordance with the label 
requirements or institutional guidelines for docetaxel 
k) ≥ 18 years of age 
l) Able to provide informed consent, or have a legal representative able and willing to do so  
m) 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 who meet any of the following criteria will be excluded from randomization: 
a) Known Anaplastic Lymphoma Kinase (ALK) gene rearrangement 
b) Presence of exon 19 deletion or exon 21 (L858R) substitution of the EGFR gene 
c) Pregnant or lactating 
d) Prior radiation therapy to >25% of bone marrow-bearing areas 
e) Received >2 prior lines of systemic anti-cancer drug regimens for locally advanced 
and/or metastatic disease 
• Any type of maintenance therapy, e.g. pemetrexed maintenance following first 
line treatment with cisplatin and pemetrexed, is not considered a separate line of 
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f) Prior treatment with an anti-ErbB3 antibody 
g) Prior treatment with docetaxel for advanced/ metastatic disease  
h) 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 
i) CTCAE grade 3 or higher peripheral neuropathy  
j) Presence of an unexplained fever > 38.5°C during screening visits that does not resolve 
prior to the first day of dosing. If the fever and active infection have resolved prior to 
randomization, the patient will be eligible. At the discretion of the investigator, patients 
with tumor fever may be enrolled. 
k) Clinically active CNS metastasis  
l) Use of strong CYP3A4 inhibitors  
m) Any other active malignancy requiring systemic therapy  
n) Known hypersensitivity to any of the components of MM-121 or previous CTCAE Grade 
3 or higher hypersensitivity reactions to fully human monoclonal antibodies 
o) History of severe hypersensitivity reactions to docetaxel  
p) Known hypersensitivity to polysorbate (Tween) 80 or arginine 
q) Inadequate bone marrow reserve as evidenced by: 
• ANC < 1,500/µl or 
• Platelet count < 100,000/µl or 
• Hemoglobin < 9 g/dL (5.59 mmol/L) 
r) Serum/plasma creatinine > 1.5 x ULN for patients receiving docetaxel  
s) Inadequate hepatic function as evidenced by:  
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 x 
ULN concomitant with Alkaline phosphatase (AP) > 2.5 x ULN 
• Serum/plasma total bilirubin > ULN  
t) Clinically significant cardiac disease, including: symptomatic congestive heart failure, 
unstable angina, acute myocardial infarction within 12 months of planned first dose, or 
unstable cardiac arrhythmia requiring therapy (including torsades de pointes)  
u) Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; or active human 
immunodeficiency virus (HIV) infection, active hepatitis B infection or active hepatitis C 
infection 
v) Patients who are not appropriate candidates for participation in this clinical study for any 
other reason as deemed by the investigator 
4.3 
Assessing Heregulin Status in NSCLC Specimens 
This study will only enroll patients with HRG positive tumors (defined as tumors with a HRG 
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. A patient’s 
tumor HRG status will be assessed at a central CLIA certified lab using a qualified in situ 
hybridization (ISH) assay. 


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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 excision samples, core biopsies, fine needle aspirates or 
thoracenteses; therefore, any of these methods of collection is acceptable for testing.  Specimens 
will be submitted directly by clinical sites to the designated CLIA certified central lab according 
to the collection, processing and shipment instructions 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+, or 2+ 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 
• 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 4 weeks 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 that come off treatment for reasons other than progressive disease per RECIST 
1.1, should undergo a scan to assess disease status at the End of Treatment visit. 
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 the patient does not respond to these requests, the date of death 
should be captured from public records.  


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5 Study Treatment 
5.1 
Method of Assigning Patients to Treatment Groups 
If a patient is determined to be HRG positive, investigators will determine if the patient meets all 
other eligibility criteria. Once all study enrollment criteria have been fulfilled, patients will be 
randomized 2:1 to the treatment or comparator arm using an Interactive Web Response System 
(IWRS). Randomization will be stratified based on the number of prior systemic therapies for 
locally advanced and/or metastatic disease (1 or 2) and prior anti-PD-1 or anti-PD-L1 will be 
capped at approximately 30% per group. 
5.2 
MM-121 
5.2.1 MM-121 Formulation, Packaging, and Labeling 
MM-121 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 MM-121 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 MM-121 Product Storage and Stability 
MM-121 Drug Product must be stored refrigerated (2-8°C) with protection from light.  Light 
protection is not required during preparation or infusion.  MM-121 must not be frozen. 
Based on available stability data, the concentrate for solution for injection 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 
study. The date of expiration will be noted on the drug label, or via other pharmacy notifications 
as required by local regulation.  MM-121 should not be used beyond the date of expiration. 
5.2.3 MM-121 Dosage, Preparation, and Administration  
MM-121 should be administered as an IV infusion once every 3 weeks at a fixed dose of 3000 
mg.  
Administration of MM-121 will require multiple vials, all of which should come from the same 
lot number. MM-121 should be brought to room temperature prior to mixing with saline.  Vials 
of MM-121 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 0.20 or 0.22 micrometer in-line filter. The line should be flushed before and after the 
study drug infusion. Study drug should not be administered as a bolus or a push. 
MM-121 should be administered immediately following the administration of docetaxel.  
5.2.4 Management of Infusion Reactions to MM-121 
Like other IV infusions, MM-121 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 MM-121 have been rare with < 1% of patients 


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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 MM-121 will be permitted 
Grade 4 
• Stop the infusion and disconnect infusion tubing from patient 
• Administer epinephrine, bronchodilators or oxygen as indicated for bronchospasm 
• Administer diphenhydramine hydrochloride 50 mg IV, dexamethasone 10 mg IV 
• Consider hospital admission for observation 
• No further treatment with MM-121 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-MM-121 antibody titer will 
be taken as close to the onset of the infusion reaction as possible for any patient experiencing an 
infusion reaction to MM-121.  Anti-MM-121 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 MM-121 
In the event that a patient experiences a toxicity ≥ Grade 3 that is not an IRR and is possibly, 
probably or definitively related to MM-121 treatment, and not related to docetaxel it is at the 
investigator’s discretion to hold dosing or to discontinue treatment. Prior to reducing the holding 
or discontinuing treatment, the investigator must notify the sponsor and Medical Monitor.  
In the event that MM-121 treatment has been held for 21 consecutive days, the patient should be 
discontinued. No dose reductions for MM-121 are permitted. 


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5.2.5.1 
Potential Toxicities with the Combination of MM-121 and Docetaxel 
In addition to the established toxicities of docetaxel, it is expected that the addition of MM-121 
to docetaxel 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 such as docetaxel 
(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 MM-121 when administered in combination with paclitaxel. 
Increased frequencies were observed in combination of MM-121 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. As such, pulmonary embolisms may be observed at a 
higher frequency with the combination of MM-121 and docetaxel. No increases in the frequency 
of pulmonary embolisms were observed in randomized studies with MM-121 in combination 
with erlotinib in NSCLC and in combination with exemestane in metastatic breast cancer. 
Patients who have experienced a venous thromboembolic event within 60 days of signing the 
main consent form for this study should be treated with anti-coagulants for at least 7 days prior 
to beginning treatment and remain on treatment for their participation on this study. 
5.3 
Docetaxel 
Docetaxel (trade name: Taxotere®) is an antineoplastic agent belonging to the taxoid family that 
acts by disrupting the microtubular network in cells that is essential for mitotic and interphase 
cellular functions. It stabilizes microtubules and as a result, interferes with the normal 
breakdown of microtubules during cell division. It is indicated for patients with breast cancer, 
non-small cell lung cancer (NSCLC) and prostate cancer. 
For managing patients receiving docetaxel, investigators can use institutional guidelines, the 
docetaxel package insert or the following which has been obtained from the Taxotere® US 
package insert (Hospira, 2012): 
5.3.1 Docetaxel Formulation, Packaging, Labeling, and Storage 
Please refer to the docetaxel package insert located in the pharmacy binder for specific 
information on the docetaxel formulation. 
Docetaxel will be supplied by the Sponsor and labeled for investigational use only according to 
local regulations. Docetaxel will be supplied as a USP infusion solution at 80 mg/8 mL or 80 
mg/4 mL in a multi-use vial. 
Docetaxel should be stored at room temperature (20 to 25°C). It should be retained in the 
original package to protect from light. It does not need to be protected from light during infusion. 
5.3.2 Docetaxel Dosage, Preparation, and Administration 
The approved dose of docetaxel in the second-line treatment of NSCLC is 75 mg/m2 
intravenously over 60 minutes once every 3 weeks. Docetaxel should be administered prior to 
MM-121 dosing. 


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Preparation, administration, and storage of docetaxel should be per the docetaxel package insert 
or SmPC.  
5.3.3 Docetaxel Dose Modifications 
Docetaxel should not be administered to patients with bilirubin > ULN, or to patients with AST 
and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN. Values for these 
indicators of liver function should be obtained prior to each treatment with docetaxel.  
Docetaxel should also not be administered to patients with neutrophil counts < 1500 cells/mm3. 
Frequent blood cell counts should be performed on all patients receiving docetaxel to monitor the 
occurrence of neutropenia. 
Patients who experience either febrile neutropenia, ANC <500 cells/mm3 for more than one 
week, severe or cumulative cutaneous reactions, or other Grade 3-4 non-hematological toxicities 
should have treatment withheld until resolution of the toxicity and then resume at 55 mg/m2 or 
following your institutional guidelines. If treatment is held, at the discretion of the Investigator, 
and the time required for recovery from toxicity is more than 21 days, a patient’s continuation on 
study should be discussed between the investigator and sponsor regarding risks and benefits of 
continued treatment.  If the patient continues to experience these toxicities after the dose is 
reduced, no further treatment is allowed.  The MM-121 dose should remain at the same dose 
level. Patients who develop > Grade 3 peripheral neuropathy should have docetaxel treatment 
discontinued entirely.  
All patients randomized on the docetaxel-containing chemotherapy backbone should receive 
docetaxel at a dose of 75 mg/m2 on cycle 1, week 1. However, if it is in the best interest of the 
patient, the dose may be reduced to 55 mg/m2 for subsequent cycles at the investigator’s 
discretion to improve tolerability. 
5.3.4 Pre-treatment Regimen for Docetaxel 
Due to the commonly experienced side effects of docetaxel, pre-treatment is suggested for all 
patients receiving this agent. Per the docetaxel package insert, all patients should be pre-
medicated with oral corticosteroids such as dexamethasone (e.g. 8 mg twice daily) for 3 days, 
starting 1 day prior to docetaxel administration.  For patients requiring dexamethasone pre-
medication as a result of an MM-121 IRR, the patient should receive a total of 10 mg 
dexamethasone at the timepoints for pre-medication outlined in Section 5.2.4. 
If institutional guidelines on docetaxel pre-medication differ, please follow institutional 
guidelines. 
5.3.5 Potential Toxicities with Docetaxel 
In the package insert, the warnings for docetaxel include toxic deaths, hypersensitivity reactions, 
hematologic effects, hepatic impairment and fluid retention. 
The incidence of treatment-related mortality associated with docetaxel administration is 
increased in patients with abnormal liver function, in patients receiving higher doses, and in 
patients with NSCLC with a history of prior treatment with platinum-based chemotherapy who 
receive docetaxel as a single agent at a dose of 100 mg/m2; however it is not planned that doses 
of 100 mg/m2 will be assessed in this study. 


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Patients should be observed closely for hypersensitivity reactions, especially during the first and 
second infusions.  Docetaxel should not be administered to patients who have a history of severe 
hypersensitivity reactions to docetaxel or other drugs formulated with polysorbate 80. 
Neutropenia (<2000 neutrophils/mm3) occurs in virtually all patients given 60 – 100 mg/m2 of 
docetaxel and grade 4 neutropenia (<500 cells/mm3) occurs in 85% of patients given 100 mg/m2 
and 75% of patients given 60 mg/m2. 
Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline 
phosphatase are at increased risk for the development of grade 4 neutropenia, febrile 
neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity and 
toxic death.  Patients with isolated elevations of transaminase >1.5 x ULN also had a higher rate 
of grade 4 febrile neutropenia but did not have an increased incidence of toxic death. 
The most common adverse reactions across all docetaxel indications as outlined in the package 
insert include: infections, neutropenia, anemia, febrile neutropenia, nail disorders, fluid retention, 
asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. 
In a clinical study of 92 patients, severe fluid retention occurred in 6.5% of patients that were 
pre-medicated and was characterized by one or more of the following events: poorly tolerated 
peripheral edema, generalized edema, pleural effusion requiring urgent drainage, dyspnea at rest, 
cardiac tamponade, or pronounced abdominal distention due to ascites. 
In a clinical trial of 176 NSCLC patients receiving docetaxel as a monotherapy in a second-line 
treatment, neutropenia was experienced by 84% patients, and 65% of those were grade 3 or 4 
events. Other commonly experienced adverse events include anemia (91%), leukopenia (84%), 
alopecia (56%), fatigue (53%), pulmonary disorders (41%), infection (34%), nausea (34%), 
stomatitis (26%), diarrhea (23%), and vomiting (22%). 
In studies of docetaxel in combination with an EGFR inhibitor, similar toxicities to docetaxel 
alone were observed. In a phase 1 dose-escalation trial of docetaxel combined with afatinib, 31 
patients were enrolled to receive the combination at varying dose levels. Nine patients (29%) 
experienced a dose-limiting toxicity (DLT) of diarrhea (n=3) or febrile neutropenia (n=6). All 
patients experienced at least one adverse event, and the most frequently reported events were 
diarrhea (74%), neutropenia (65%), and rash (39%). Grade 3 and 4 adverse events were most 
hematological (Marshall et al., 2013).  
Like other IV infusions, docetaxel administration may be associated with infusion reactions 
which should be treated per the US package insert, SmPC or per institutional guidelines. 
5.4 
Guidelines for Safety Review of MM-121 and Docetaxel Combination 
After the twelfth patient was randomized to receive either MM-121 + docetaxel or docetaxel 
alone and completed a full cycle of therapy (i.e. 21 days after the patient’s first dose of study 
drug administration), randomization to the docetaxel containing study arms was paused to permit 
a review of safety information related to the combination of MM-121 + docetaxel. Any patients 
currently in screening for the arm continued with screening and randomization; however, no new 
patients were presented the study for consideration until the data review had occurred. 
The Sponsor compiled available safety data and convened a panel of investigators, study medical 
monitors and sponsor representatives to review the data. Data that were reviewed and considered 
included emerging safety and other relevant data from all patients receiving docetaxel on the 
study (experimental and comparator arm). Investigator and sponsor assessment of the overall 


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safety of the MM-121 + docetaxel combination carefully took into account the commonly 
experienced toxicities associated with docetaxel, as outlined in Section 5.3.5., and the currently 
available information on docetaxel. Attention was paid to the following adverse events before 
making a decision on the tolerability of the combination: 
• Any MM-121 related (denoted as ‘probably’ or ‘definitely’ by the investigator) grade 3-4 
non-hematologic toxicity which is determined to be not related to docetaxel by the 
investigator. 
• Grade 3 or higher fatigue/asthenia lasting > 2 weeks in duration  
• Grade 3 or higher vomiting or diarrhea lasting >72 hours despite confirmed treatment 
with an optimal anti-emetic or anti-diarrheal regimen 
• Grade 3 hyperglycemia, hypomagnesaemia and hypokalemia lasting ≥7 days despite 
confirmed maximal medical management 
After the safety review was completed, the safety review panel concluded that no critical safety 
findings were observed and that enrollment to the study may continue as planned without dose 
modifications. Documentation of this meeting is maintained in the study files and is available 
upon request. A summary of the safety of MM-121 plus docetaxel is in Section 1.3.3.2. 
5.5 
Rules for Dose Omissions and Modified Treatment Schedules 
It is intended that MM-121 and docetaxel dosing occur on the same day. For cycles 1 through 6, 
if the dose of one or both study drugs is being held or delayed for up to 21 days, administration 
of both drugs should be held until the patient can be given both drugs. In this case, the date of 
dosing will be considered the start of the new cycle and the next cycle should begin 21 days after 
the dose was administered.  In the event that dosing has been held for 21 consecutive days and 
the investigator does not wish to continue dosing at the current dose or at a reduced dose, the 
patient should be discontinued.  
For cycles 7 and beyond, docetaxel treatment can be withheld at the discretion of the investigator 
if deemed necessary for the patient to recover from cumulative chemotherapy toxicities, in line 
with institutional guidelines.  During any break from docetaxel dosing, MM-121 dosing should 
continue every three weeks and all procedures outlined in the schedule of assessments should be 
completed.  As soon as the patient condition allows, dosing of docetaxel should be re-started on 
the next planned date of MM-121 treatment.  
5.6 
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: 


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• 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  
• The use of strong CYP3A4 inhibitors is prohibited.  If it becomes necessary to use any of 
these medications, it may permitted on a case by case basis requiring approval by the 
Sponsor prior to initiation of treatment 
5.7 
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 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) 
• 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 
placed in the investigator’s file. 
 


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6 Schedule of Assessments 
6.1 
Schedule of Assessments: Treatment Group 
Procedure 
Screening 
Visit 
Cycle 17 
Cycle 27 
Additional Cycles7 
Every 
6w after 
1st dose10 
End of 
Treatment 
(EoT)16 
Every 2 
mo. after 
EoT 
Wk 1 
Wk 2 
Wk 3 
Wk 1 
Wk 2 
Wk 3 
Wk 1 
Wk 2 
Wk 3 
Informed consent0 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HRG Testing 
X11 
 
 
 
 
 
 
 
Medical history 
X1 
 
 
 
 
 
 
 
Demographics 
X1 
 
 
 
 
 
 
 
Vital signs 
X2 
X 
X 
X 
X 
 
X 
 
ECOG PS 
X2 
X 
X 
X 
X 
 
X 
 
CBC 
X2 
X 
X 
X 
X 
 
X 
 
Serum chemistry 
X2 
X 
X 
X 
X 
 
X 
 
Tumor Biopsy13 
X 
 
 
 
 
 
 
 
Coagulation profile 
X2 
X 
X 
X 
X 
 
X 
 
Pregnancy test 
X2 
 
 
 
 
 
X 
 
ECG 
X1,3 
X20 
 
X20 
X20 
 
X 
 
Archived tumor, if 
available 
X1 
 
 
 
 
 
 
 
Serum for MM-121 PK 
 
X5 
X 
X 6 
X 6 
 
 
 
Serum for Ig8,14 
 
X 
 
X 
X 
 
X 
 
Serum for biomarkers15 
 
X 
 
X 
X 
 
X 
 
Plasma for docetaxel PK 
 
 
 
X17 
 
 
 
 
Concomitant meds 
X1 
X 
X 
X 
X 
 
X 
 
MM-121 dosing 
 
X 
 
X 
X 
 
 
 
Docetaxel dosing 
 
X 
 
X 
X 
 
 
 
SAE/AE assessment and 
reporting18 
X- continuous monitoring 
Hospitalization reporting19 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Disease evaluation9 
X1 
 
 
 
 
X 
X4 
 
Overall Survival 
Reporting12 
 
 
 
 
 
 
 
 
 
 
 
X 
0. There are two informed consent forms on this study. Patients should sign the Pre-Screening Consent Form prior to submitting any type of tissue for HRG testing, including 
fresh tissue. Following receipt of HRG results and prior to any other study procedures, HRG+ patients should sign the full study consent form before continuing with 
screening. 
1. Procedures to be completed within 28 days of first dose of study drug 


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2. Procedures to be completed within 7 days of first dose of study drug 
3. Two independent readings at least 5 minutes apart  
4. All patients that come of treatment for reasons other than progressive disease will have a scan at the time of the End of Treatment visit  
5. MM-121 PK (for experimental arm patients only):  pre-dose and immediately after the end of the MM-121 infusion (+15 mins); 
6. MM-121 PK (for experimental arm patients only):  pre-dose  
7. All procedures should occur ±3 calendar days from scheduled date of visit 
8. Immunogenicity samples should be collected for experimental arm patients only prior to dosing. 
9. Disease evaluation per RECIST version 1.1.  
10. Evaluations may be performed + 1 week from the scheduled date of visit 
11. HRG testing will be performed during screening (pre-treatment) to confirm heregulin levels for enrollment.   
12. Should patients refuse or drop out of survival follow-up, attempts should be made to obtain any death information available via public records.  
13. Research tumor biopsies will be performed for all HRG+ patients that did not undergo a fresh biopsy for eligibility testing. The research biopsy must be performed prior to 
first dose and no systemic therapy should be received between collection of this tissue and dosing on this study. 
14. In the event a patient experiences an infusion reaction at any point in the study, an anti-MM-121 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 MM-121, an anti-MM-121 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. 
15. Serum for biomarkers should be collected prior to docetaxel dosing on week 1 of each cycle for all patients. 
16. End of treatment visit should be completed within 4 weeks of the last dose of study drug. 
17. Plasma for evaluation of docetaxel PK will be collected for 15 patients randomized to each of the following treatments:  MM-121 + docetaxel or docetaxel alone.  For Cycle 2 
Week1 only, plasma should be collected at the following timepoints relative to the start of the docetaxel infusion:  pre-infusion, post-infusion, 3 hours post start of infusion 
and 7 hours post-start of infusion. The window for each collection timepoint is (+ 15mins) 
18. All adverse and serious adverse events should be collected and reported from the time of informed consent through the first survival follow-up.  Adverse and serious adverse 
event collection and reporting for patients in both the Experimental and Control Arms should proceed as outlined in Section 9.1.3. 
19. All patient hospitalizations and/or hospital visits should be collected, whether or not associated with an adverse event. 
20. One reading prior to the start of the docetaxel infusion. 
 


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6.2 
Screening and Baseline Visit 
All procedures for screening and baseline are outlined in Section 6.1. The window for screening 
procedures begins after receipt of heregulin results.  For further descriptions of the clinical and 
laboratory assessments required, please refer to Section 7 and Section 8 respectively. 
6.2.1 RNA-ISH Heregulin Testing 
All patients must submit a tissue sample to the central lab for RNA-ISH testing of heregulin 
levels following signing the pre-screening informed consent form, as this will determine patient 
eligibility for treatment randomization and subsequent screening procedures. Tissue samples 
may be submitted from either: 1) archived tissue from previously completed standard of care 
tissue acquisition or 2) fresh tissue from a core needle biopsy (CNB), fine needle aspiration 
(FNA), thoracentesis or excisional 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 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. Samples obtained from a primary tumor, metastatic site or pleural effusion are 
acceptable. Upon receipt at the central lab, samples will be processed and analyzed at a central 
facility where they are scored by an independent 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. Pre-screening 
can take place at any time, including while the patient is receiving other systemic therapy. Any 
patient who scores positive (a score of >1+) for HRG mRNA will be eligible for the study and 
should sign the full study consent form before continuing with screening procedures. 
6.2.2 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 required on the sample requisition form in the Laboratory Manual.  
6.3 
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 ±3 days will apply to all visits, unless otherwise stated. 
6.4 
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 4 weeks of last dose of study drug. All End of Treatment 
procedures and assessments are outlined in Section 6.1. 
6.5 
Survival Follow-up 
Survival data will be collected via telephone or clinic visits every 2 months (±10 days) from the 
date of last treatment until death, loss to follow-up, withdrawal of consent, or study termination 
by the Sponsor. During the first survival follow-up, any adverse events should be collected. In 
addition, any new anti-cancer therapies and procedures should be collected and documented 
during every survival follow-up. All survival information will be captured using the electronic 


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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, until the first survival 
follow-up (2 months from the date of last treatment), and followed through to resolution as 
detailed in Section 9. 
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 Frederica 
method (QTcF). 
7.6 
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 


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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 6 weeks (±1 week) from randomization regardless of treatment 
schedule. In cases where there is a suspicion of disease progression prior to the next scheduled 
scan, an unscheduled assessment should take place. All patients that come off treatment for 
reasons other than progressive disease will have a scan at the time of the End of Treatment visit.  
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, and chloride), 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 during Screening and the End of Treatment 
visit 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 MM-121 PK samples 
For patients on the experimental arm (Arm A), blood samples will be collected to determine the 
levels of monoclonal antibodies that comprise MM-121. The serum PK analysis will be 
performed pre- and post-dose on Cycle 1, Week 1, and pre-dose for all subsequent MM-121 
infusions, as well as during the Cycle 1, Week 2 clinic visit, 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.  
For patients on Arm A (experimental arm), PK samples should be collected at the following 
time-points relative to the MM-121 infusion: 
Table 4: MM-121 PK Collection Time points for Arm A Patients 
MM-121 PK Sample 
Pre-infusion 
Post-infusion 
Cycle 1, Week 1 
X 
X 
Cycle 1, Week 2 
X* 
 
Cycle X, Week 1 
X 
 
*No C1W2 infusion; sample should be collected at any point during C1W2 clinic visit 


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8.5.2 Docetaxel PK samples 
To determine the levels of docetaxel, blood samples will be collected for 15 patients randomized 
to each of the following treatments:  MM-121 + docetaxel, or docetaxel alone.  For Cycle 2, 
Week1 only, plasma should be collected at the following time points relative to the start of the 
docetaxel infusion:  pre-infusion, post-infusion, 3 hours post-start of infusion, and 7 hours post-
start of infusion.  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. 
8.6 
Anti-MM-121 Immunogenicity 
Serum samples will be collected to determine the presence of an immunologic reaction to MM-
121 (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 NSCLC, these samples will be used to assess the mRNA and/or protein for 
clinically relevant biomarkers for NSCLC, including the PD-1 receptor, ErbB receptors, cMET, 
IGF-1R, and FGF receptor tyrosine kinases and their respective ligands (PD-L1, ErbB ligands, 
HGF, IGFs and FGFs). Efficacy outcomes considered for pre-specified mechanistic biomarker 
analysis will include OS, PFS, and ORR.  
8.7.1 Tumor Biopsy 
As described in Section 6.3, if archived tissue is available, it may be submitted in lieu of a fresh 
tissue sample for HRG testing. If this tissue is not available, patients can undergo a fresh tissue 
biopsy (core needle biopsy, fine needle aspiration, thoracentesis or excision biopsy) to determine 
eligibility and are also asked to submit a second pass core needle biopsy or second fine needle 
aspirate for research purposes if possible.  
In order to obtain fresh tissue from all patients enrolled, all patients that receive HRG results for 
eligibility based on testing of archived samples will also be required to undergo a fresh research 
biopsy (either FNA, core needle, thoracentesis or excision biopsy) prior to first dose. It is 
important that no systemic therapy is administered between collection of this tissue and dosing 
on this study.  An additional sample will not be requested from patients who underwent a fresh 
biopsy for eligibility testing. 
Directions for processing and shipping the tissue sample for heregulin testing can be found in the 
laboratory manual. 
8.7.2 Archived Tumor Samples 
If available, formalin-fixed paraffin embedded tumor samples (either a tumor block or freshly cut 
slides) obtained at the time of primary disease diagnosis will be collected to compare biomarker 
expression at the time of disease diagnosis to expression in the sample submitted for HRG 
testing. This sample is in addition to the sample submitted for HRG testing. Directions and 
requirements for processing and shipping the archived tumor samples can be found in the 
laboratory manual. 


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8.7.3 Serum Samples 
Serum samples will be collected at time points described in Section 6.1   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 MM-121 in NSCLC patients. In the event that there 
is remaining sample available after conducting these analyses, it will be used by the Sponsor for 
future analysis of biomarkers that may be mechanistically linked to MM-121 activity.  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. 
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 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. 


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9.1.2.1 
Progressive Disease 
Because of the natural history of non-small cell lung 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 
nor uniquely captured as an adverse event or serious adverse event. In the event however that the 
investigator is unsure whether or not an symptom/AE is a associated with progression of the 
underlying malignancy, the symptom/AE should be recorded and captured as a serious adverse 
event if it meets the appropriate seriousness criteria, following SAE reporting procedures 
outlined in Section 9.3Assessing and Documenting Adverse Events and Hospitalizations 
Adverse event assessment will begin in conjunction with informed consent. All adverse events 
occurring after signing informed consent should be captured on the adverse event page of the 
eCRF.  All serious adverse events are to be reported as outlined in Section 9.3. 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 heregulin negative patients, all adverse events, whether serious or not, will be described in 
the source documents and the adverse event page of the eCRF.  All new events, as well as those 
that worsen in intensity or frequency relative to baseline, which occur through the date of receipt 
of the HRG report, must be reported if they are related to any study procedure (i.e. tumor 
biopsy).    
For heregulin positive patients, all adverse events, whether serious or not, will be described in 
the source documents and the adverse event page of the eCRF.  All new events, as well as those 
that worsen in intensity or frequency relative to baseline, which occur through the first survival 
follow-up clinic visit or telephone call (2 months from the date of the last study treatment) 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 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) 


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• 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) 
9.1.3 Hospitalizations 
Information on patient hospitalizations and/or unscheduled hospital visits should be collected in 
the eCRF, whether or not associated with an adverse event. 
9.2 
Reporting Serious Adverse Events 
Serious adverse events (SAE) will not be reported for patients who only sign the pre-screening 
consent form unless the serious event is directly related to any study procedure (i.e. tumor 
biopsy). Serious adverse event reporting will begin in conjunction with the date of informed 
consent. 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 (MM-121 or docetaxel), 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 MM-121, and ≥133% of planned dose of 
docetaxel.  
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. 
9.3 
Determining the Severity and Relatedness of an Event 
9.3.1 Grading the Severity of an Adverse Event 
Each adverse event will be graded according to the NCI CTCAE V 4.03, which may be found at 
http://ctep.cancer.gov/reporting/ctc.html. For events not listed in the CTCAE, severity will be 


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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/Grade 1: an event not resulting in disability or incapacity and which resolves 
without intervention; 
• Moderate/Grade 2: an event not resulting in disability or incapacity but which requires 
intervention; 
• Severe/Grade 3: an event resulting in temporary disability or incapacity and which 
requires intervention; 
• Life-threatening/Grade 4: an event in which the patient was at risk of death at the time 
of the event 
• Fatal/Grade 5: an event that results in the death of the patient 
9.3.2 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 
9.3.3 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. 


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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 
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.  Descriptive statistics will be 
displayed in abbreviated treatment identifiers instead of MM-121+docetaxel, docetaxel alone, 
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 factor in 
the model including:  number of prior systemic therapies for locally advanced and/or metastatic 
disease (1 or 2).  Statistical significance will be determined by using a one-sided type I error of 
0.15.  A stratified Cox proportional hazards model will be used to estimate the hazard ratio. 
Approximately 61 PFS events are required to have at least 80% power to detect a 2 month 
improvement in median PFS over 3 months as compared between patients receiving the 
combination of MM-121 plus docetaxel versus docetaxel alone (i.e., hazard ratio ≤ 0.60), using a 
one-sided, stratified log-rank test at a significance level of 0.15 with patients randomized in a 2:1 
ratio.  Assuming an enrollment approximately 15 months in length, the required number of 61 
PFS events is estimated to be achieved at approximately 18 months. 
10.3 Analysis Populations 
Due to the adjusted entry criteria, patients randomized prior to this amendment will be 
maintained as evaluable for the primary efficacy analysis where applicable.  A thorough review 
of all patient level data will be performed on those already randomized.  Those patients meeting 
the new entry criteria will be eligible to be part of the primary efficacy analysis and may 
contribute to the total sample size of 80 patients enrolled under Version 4.0 of the protocol, as 
long as no major protocol violations exist which would exclude them from the per protocol 
population. Major protocol violations include those not meeting the new entry criteria, those with 
no baseline measurable lesions, and those patients that never received at least 1 dose of study 
drug.  The total number of patients randomized will not exceed the number needed to randomize 


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80 patients who qualify for the per protocol population of Version 4.0. It is estimated to be in the 
range of 110-150 patients.   
Patients that meet eligibility criteria but have existing major protocol violations which would 
exclude them from the per protocol population will be analyzed as part of a sensitivity analysis 
by pooling them with the per protocol population.  
Any patient randomized and not meeting the new entry criteria will be pooled with all other 
patients and analyzed as part of a sensitivity analysis population.    
All patients previously randomized under previous protocols will be used either as part of the 
primary efficacy analysis in the per protocol population or in some form of sensitivity analysis.  
All patients dosed will contribute to the safety population. 
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 and dosed patients.  The PP 
population is the primary efficacy population and will only include patients that meet all 
inclusion/exclusion criteria as defined in Protocol Version 4.0 and that are confirmed 
HRG positive based on centralized analysis of tissue collected after progression on the 
most recent line of therapy (pre-treatment tissue sample).  The PP will exclude those 
patients with major protocol violations, which will be defined in the SAP in more detail 
and assessed in an unbiased ongoing manner.  Primary considerations for exclusion will 
be those patients with no measurable baseline tumor, non-evaluated baseline non-target 
tumor assessments, and incomplete tumor evaluations.  Not all circumstances will result 
in exclusion, however a continual review of patient data will be performed to address 
data inconsistencies by the medical director, statistician, and clinical trial manager.  Data 
will be reviewed without knowledge of progression/non-progression. 
• Safety (SAF) population: The safety population includes patients receiving at least one 
dose of study medication. Patients will be analyzed by the treatment received and not by 
the treatment to which they were randomized.  All safety analyses will be performed on 
this population.  
• PK population: All treated patients with at least one PK assessment. 
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 
Progression-Free Survival (PFS) based on investigator assessment is the primary endpoint of the 
study. PFS is defined as the time from randomization to the first documented radiographical 
progression of disease using RECIST 1.1, or death from any cause, whichever comes first.  
Details of censorship will be thoroughly explained in the SAP.  The primary efficacy will be 
performed on the per protocol (PP) population using a stratified log-rank test. The Kaplan-Meier 


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method will be used to estimate median PFS and 70% CI for each treatment group.  A stratified 
Cox proportional hazards model will be used to estimate the hazard ratio and the corresponding 
70% confidence intervals.  Stratification factor include:  number of prior systemic therapies for 
locally advanced and/or metastatic disease (1 or 2).   
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.  The OS analysis will be performed using a stratified log-rank test.  The Kaplan-
Meier method will be used to estimate median OS for each treatment group. A stratified Cox 
proportional hazard model will be used to obtain an estimate hazard ratio and corresponding 95% 
confidence intervals.  OS will be analyzed using the same population and log-rank test as the 
PFS primary efficacy analysis.  Kaplan-Meier curves displaying median OS and stratified Cox 
proportional hazard models will be performed similarly as PFS. Various sensitivity analyses will 
be performed on PFS and OS which will be described in the SAP.  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. Sensitivity analysis will include various patient populations such as per 
protocol patients with all patients previously randomized, per protocol new amendment patients 
only, etc. 
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 and OS 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 proportional hazards model will be used to calculate hazard ratios and 95% 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.  The docetaxel safety 
run-in analysis will include all patients randomized during this portion of the study.   
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 


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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 
MM-121 or docetaxel.  Additional tabulations include serious adverse events (SAE), TEAE-
related to MM-121 or docetaxel 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 and ECG 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 and serum samples to assess potential 
associations with tumor response. These 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). PFS, ORR, and OS 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 MM-121 and docetaxel 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 
A regular review of safety data will be conducted by an independent Data Monitoring Committee 
(DMC) as outlined in the DMC charter. The DMC will consist of oncology and statistical 
experts, independent of the Sponsor. The charter of the DMC and the statistical analysis plan will 
be documented separately.  
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 
• 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 that is signed and 
dated.  
• A copy of the current medical license for the investigator and each sub-investigator. 


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• 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 
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. 


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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 
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. 


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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 will 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. 
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. 


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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 MM-121 
• 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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