Conditions: Solid Tumors ER/PR Positive Breast Cancer Triple Negative Breast Cancer Metastatic Breast Cancer With Active Brain Metastasis
Keywords: solid tumors Triple Negative Breast Cancer Colorectal Cancer MM-398 nanoliposomal irinotecan Ferumoxytol ER/PR positive Breast Cancer Pancreatic Cancer Ovarian Cancer Gastric Cancer Gastro-Esophageal Junction Adenocarcinoma Head and Neck Cancer TNBC
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 45
Healthy volunteers: no

Brief summary:
This is a Phase I study to understand the biodistribution of MM-398 and to determine the feasibility of using Ferumoxytol as a tumor imaging agent.

Detailed description:
This study is conducted over two phases.

Pilot Phase: This study will enroll approximately 12 patients, up to 20 in total in the Pilot Phase and 30 patients in the Expansion Phase. The first three patients that are enrolled in the Pilot Phase can have any solid tumor type; however subsequent patients must have Non-small cell lung cancer (NSCLC), Colorectal cancer (CRC), Triple negative breast cancer (TNBC), Estrogen Receptor/Progesterone Receptor (ER/PR) positive breast cancer, pancreatic cancer, ovarian cancer, gastric cancer, gastro-oesophageal junction adenocarcinoma or head and neck cancer. No more than three patients with ER/PR positive breast cancer can be enrolled in the Pilot Phase and similar restrictions may be placed on other tumor types to ensure a heterogeneous population.

Expansion Phase: The expansion will enroll patients with advanced metastatic breast cancer into three cohorts of 10 patients each depending on sub-type of breast cancer:

Cohort 1: ER and/or PR-positive breast cancer Cohort 2: TNBC Cohort 3: BC with active brain metastasis

Arms:
arm 1: Ferumoxytol 5 mg/kg IV at the rate of 1 mL/sec, given once on Day 1. MM-398 IV over 90 min on Days 1 and 15 of every 4 week cycle arm 2: Ferumoxytol 5 mg/kg IV at the rate of 1 mL/sec, given once on Day 1. MM-398 IV over 90 min dose 1 on Days 1 and 15 of every 4 week cycle Cohort 1: ER and/or PR-positive BC Cohort 2: TNBC Cohort 3: BC with active brain metastasis

Interventions: intervention 1: Ferumoxytol intervention 2: MM-398
Intervention descriptions: intervention 1: Ferumoxytol 5 mg/kg IV as a single bolus injection, given once. intervention 2: MM-398 IV over 90 min every 2 weeks, until progressive disease or intolerable toxicity

Protocol document:
Prot_001.pdf: 
 
 
 
 
 
MM-398-01-01-02: A Phase 1 Study in Patients Treated with MM-
398 (Nanoliposomal Irinotecan, nal-IRI,) to Determine Tumor Drug 
Levels and to Evaluate the Feasibility of Ferumoxytol Magnetic 
Resonance Imaging to Measure Tumor Associated Macrophages 
and to Predict Patient Response to Treatment 
 
IPSEN Bioscience, Inc. 
 
 
 
Version 6.0: 03Apr2017 
IND #: 102799 
EUDRA CT #: 2014-003673-42 
ClinicalTrials.gov ID: NCT01770353 
 
 
 
 
 
Sponsor: 
 
IPSEN BIOSCIENCE, Inc. 
650 East Kendall Street, 
Cambridge MA 02142 
USA 
Confidentiality Statement 
Persons supplied with this information must understand that it is strictly confidential. 
Information contained herin connot be disclosed, submitted for publication or used for any 
purpose other than that comtemplated herin without the sponsor’s prior written authorization.  
 


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Table of Contents 
List of Abbreviations ...................................................................................................................... 6 
1 
Synopsis .................................................................................................................................. 8 
2 
Background Information and Rationale ................................................................................ 16 
2.1 
MM-398 ......................................................................................................................... 17 
2.1.1 
MM-398 Pre-clinical Experience ............................................................................ 18 
2.1.2 
MM-398 Pre-clinical  Pharmacokinetics ................................................................ 18 
2.1.3 
Tumor Uptake and Local Tumor Activation of MM-398 by Macrophages ........... 20 
2.1.4 
MM-398 Clinical Experience ................................................................................. 23 
2.1.5 
MM-398 Safety in Humans .................................................................................... 26 
2.1.5.1 
Potential Toxicity of MM-398 in Humans ...................................................... 27 
2.1.6 
MM-398 PK in Humans.......................................................................................... 27 
2.2 
Ferumoxytol ................................................................................................................... 28 
2.2.1 
Use of Ferumoxytol as an Imaging Agent .............................................................. 29 
2.2.2 
Potential Toxicities of Ferumoxytol ....................................................................... 30 
2.2.3 
Interaction of Ferumoxytol and MM-398 ............................................................... 31 
2.3 
Summary of Study Rationale ......................................................................................... 34 
3 
Study Objectives ................................................................................................................... 35 
3.1 
Primary Objectives ......................................................................................................... 35 
3.2 
Secondary Objectives ..................................................................................................... 35 
3.3 
Exploratory Objectives ................................................................................................... 36 
4 
Study Design ......................................................................................................................... 36 
4.1 
Indications and Number of Patients ............................................................................... 36 
4.2 
Study Stages and Treatment Design .............................................................................. 36 
5 
Patient Selection and Discontinuation .................................................................................. 37 
5.1 
Inclusion Criteria ............................................................................................................ 37 
5.2 
Exclusion Criteria ........................................................................................................... 39 
5.3 
Patient Discontinuation .................................................................................................. 40 
5.4 
Patient Replacement ....................................................................................................... 41 
6 
Investigational Product and Study Treatment ....................................................................... 41 
6.1 
Description of MM-398 ................................................................................................. 41 
6.1.1 
Storage and Handling of MM-398 .......................................................................... 41 
6.1.2 
Packaging and Labeling of MM-398 ...................................................................... 41 
6.1.3 
Administration of MM-398..................................................................................... 41 
6.1.4 
Premedication Prior to MM-398 Administration .................................................... 42 
6.1.5 
Important Treatment Considerations After MM-398 Administration .................... 42 
6.1.5.1 
Diarrhea ........................................................................................................... 42 
6.1.5.2 
Neutropenia ..................................................................................................... 42 
6.1.5.3 
Hypersensitivity ............................................................................................... 43 
6.1.5.4 
Colitis/Ileus ...................................................................................................... 43 
6.1.5.5 
Thromboembolism........................................................................................... 43 
6.1.5.6 
Pregnancy ........................................................................................................ 43 
6.1.5.7 
Care of Intravenous Site .................................................................................. 43 
6.1.5.8 
Patients at Particular Risk ................................................................................ 43 
6.1.5.9 
Acute Infusion Associated Reactions .............................................................. 43 
6.1.5.10 
Other Potential Toxicities ................................................................................ 43 


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6.1.6 
Dose Reductions Due to Toxicity ........................................................................... 44 
6.1.6.1 
Hematologic Toxicities .................................................................................... 44 
6.1.6.2 
Non-hematologic Toxicities ............................................................................ 45 
6.1.6.3 
UGT1A1*28 Homozygous Patients ................................................................ 45 
6.1.7 
Management of Infusion Reactions to MM-398 ..................................................... 46 
6.2 
Description of Ferumoxytol ........................................................................................... 47 
6.2.1 
Storage and Handling of Ferumoxytol .................................................................... 47 
6.2.2 
Packaging and Labeling of Ferumoxytol ................................................................ 47 
6.2.3 
Administration of Ferumoxytol .............................................................................. 47 
6.2.4 
Important Treatment Considerations With Ferumoxytol ........................................ 48 
6.3 
Drug Accountability ....................................................................................................... 49 
6.4 
Concomitant Therapy ..................................................................................................... 49 
6.4.1 
Antiemetic Medications .......................................................................................... 50 
6.4.2 
Granulocyte Colony Stimulating Factors................................................................ 50 
6.4.3 
Therapy for Diarrhea............................................................................................... 50 
6.5 
Prohibited Therapy ......................................................................................................... 50 
7 
Study Procedures .................................................................................................................. 51 
7.1 
Clinical Procedures ........................................................................................................ 51 
7.1.1 
Medical History ...................................................................................................... 51 
7.1.2 
Physical Examination.............................................................................................. 51 
7.1.3 
Vital Signs ............................................................................................................... 51 
7.1.4 
ECOG Performance Score ...................................................................................... 51 
7.1.5 
ECG......................................................................................................................... 51 
7.1.6 
Disease Evaluation .................................................................................................. 51 
7.1.6.1 
Modified RECIST Criteria for Cohort 3.......................................................... 52 
7.1.6.2 
Criteria for Treatment Termination due to Progressive Disease ..................... 52 
7.2 
Laboratory Procedures ................................................................................................... 53 
7.2.1 
Complete Blood Count ........................................................................................... 53 
7.2.2 
Serum Chemistry .................................................................................................... 53 
7.2.3 
Biomarker Samples ................................................................................................. 53 
7.2.4 
Coagulation Profile ................................................................................................. 53 
7.2.5 
UGT1A1*28 ........................................................................................................... 53 
7.2.6 
Urinalysis ................................................................................................................ 53 
7.2.7 
Urine or Serum Pregnancy Test .............................................................................. 53 
7.2.8 
Pharmacokinetic Assessments ................................................................................ 53 
7.3 
Tissue Collection ............................................................................................................ 54 
7.3.1 
Fresh Tumor Biopsies ............................................................................................. 54 
7.3.1.1 
Pilot Phase Biopsies......................................................................................... 54 
7.3.1.2 
Expansion Phase Biopsies ............................................................................... 54 
7.3.2 
Archived Tumor Samples ....................................................................................... 54 
7.4 
Ferumoxytol Magnetic Resonance Imaging .................................................................. 55 
8 
Schedule of Assessments ...................................................................................................... 56 
8.1 
Pilot Phase (Closed) ....................................................................................................... 56 
8.2 
Expansion Phase ............................................................................................................. 57 
9 
Adverse Event Reporting ...................................................................................................... 59 
9.1 
Definitions ...................................................................................................................... 59 


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9.1.1 
Adverse Event ......................................................................................................... 59 
9.1.2 
Unexpected Adverse Event ..................................................................................... 59 
9.1.3 
Adverse Events of Special Interest ......................................................................... 59 
9.1.4 
Serious Adverse Event ............................................................................................ 59 
9.2 
Documenting Adverse Events ........................................................................................ 60 
9.3 
Reporting Serious Adverse Events ................................................................................. 60 
9.4 
Determining the Severity and Relatedness of Adverse Events ...................................... 61 
9.4.1 
Grading the Severity of an Adverse Event ............................................................. 61 
9.4.2 
Relatedness to Study Drug ...................................................................................... 61 
9.4.3 
Reporting and Follow-up of Pregnancy .................................................................. 62 
10 Data Management and Statistical Analysis ........................................................................... 62 
10.1 
Case Report Forms ..................................................................................................... 62 
10.2 
Data Quality Assurance .............................................................................................. 62 
10.3 
Statistical Analysis ..................................................................................................... 63 
10.4 
Study Populations ....................................................................................................... 63 
10.5 
Disposition and Baseline Characteristics ................................................................... 63 
10.6 
Efficacy Analysis ........................................................................................................ 63 
10.7 
Safety Analysis ........................................................................................................... 64 
10.8 
Biomarker Subgroup Analysis.................................................................................... 65 
10.9 
Pharmacodynamic Marker Analysis ........................................................................... 65 
10.10 
Pharmacodynamic Analysis ....................................................................................... 65 
10.11 
Sample Size and Statistical Hypothesis ...................................................................... 65 
11 Extension Phase .................................................................................................................... 66 
12 Study Administration ............................................................................................................ 66 
12.1 
Pre-study Documentation ........................................................................................... 66 
12.2 
Source Documents ...................................................................................................... 66 
12.3 
Trial Ethics ................................................................................................................. 66 
12.4 
Patient Informed Consent ........................................................................................... 67 
12.5 
Investigational Review Board .................................................................................... 67 
12.6 
Monitoring .................................................................................................................. 67 
12.7 
Confidentiality ............................................................................................................ 68 
12.8 
Confidentiality of Biomarker Samples ....................................................................... 68 
12.9 
Protocol Amendments ................................................................................................ 68 
12.10 
Publication .................................................................................................................. 69 
12.11 
Records Retention....................................................................................................... 69 
12.12 
Study Termination ...................................................................................................... 69 
13 Investigator Signature Page .................................................................................................. 71 
14 References ............................................................................................................................. 72 
 
 


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List of Tables 
Table 1: 
Summary of Completed Studies with MM-398 .......................................................... 24 
Table 2: 
Summary of On-going Studies with MM-398 ............................................................ 25 
Table 3: 
Summary of Grade 3 or Higher Adverse Events in PEP208 Study ............................ 26 
Table 4: 
Summary of Grade 3 or Higher Adverse Events in NAPOLI Study .......................... 27 
Table 5: 
MM-398 PK in Q3W Regimen (Irinotecan, Liposome + Free Drug) ........................ 28 
Table 6: 
MM-398 PK in Q3W Regimen (SN-38) ..................................................................... 28 
Table 7: 
MM-398 Dose Modifications for Neutrophil Count ................................................... 44 
Table 8: 
MM-398 Dose Modifications for Other Hematologic Toxicities ............................... 45 
Table 9: 
MM-398 Dose Modifications for Diarrhea ................................................................. 45 
Table 10: MM-398 Dose Modifications for Non-hematologic Toxicities Other Than Diarrhea, 
Asthenia and Grade 3 Anorexia .................................................................................. 45 
Table 11: Recommendations for Management of Chemotherapy Induced Diarrhea ................. 50 
Table 12: CNS Response Assessment for Cohort 3 .................................................................... 52 
Table 13: Summary of PK Timepoints in Treatment and Follow-up Phases ............................. 54 
Table 14: Summary of Expansion Phase MRI Scan Groups (Cohorts 1 and 2) ......................... 55 
Table 15: Expansion Phase Cohort 3 MRI Scan Time Points .................................................... 55 
Table 16: Probability to Detect an Adverse Event with N=12 Patients ...................................... 65 
List of Figures 
Figure 1: Summary of MM-398 PK Parameters in an HT-29 Xenograft Study. ....................... 19 
Figure 2: Macrophage Uptake by Liposomes and Tumor Activation. ....................................... 21 
Figure 3: Liposome Accumulation in Tumor Models ................................................................ 22 
Figure 4: Macrophage Depletion and Liposome Accumulation in a Tumor Bearing Mouse 
Model .......................................................................................................................... 23 
Figure 5: TAM Mediated Uptake of Ferumoxytol ..................................................................... 30 
Figure 6: Uptake of Liposomes by TAMS ................................................................................. 33 
Figure 7: Irinotecan and SN-38 Levels are Not Impacted by Ferumoxytol ............................... 34 
 
 


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List of Abbreviations  
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
ASCO 
American Society of Clinical Oncology 
BC 
Breast cancer 
BUN 
Blood urea nitrogen 
CES 
Carboxylesterase  
CL 
Clearance 
Cmax 
Maximum concentration 
CNS 
Central nervous system 
CRC 
Colorectal cancer 
CSF 
Colony-stimulating factor 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
ECHO 
Echocardiogram 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EPR 
Enhanced permeability and retention 
ER 
Estrogen Receptor 
FACS 
Fluorescence activated cell sorter 
FMX-MRI 
Ferumoxytol magnetic resonance imaging 
FMX 
Ferumoxytol 
5-FU 
5-Fluorouracil 
GCP 
Good Clinical Practice 
GEJ 
Gastroesophageal Junction 
GGT 
Gamma-glutamyl transferase 
GSF 
Growth stimulating factor 
G-CSF 
Granulocyte colony-stimulating factors 
HPLC 
High pressure liquid chromatography 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
Kilogram 
L 
Liter 
LV 
Leucovorin 
mg 
Milligram 
MRI 
Magnetic resonance imaging 
MUGA 
Multiple gated acquisition scan 
ng 
Nanogram 


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nm 
Nanometer 
NSCLC 
Non-small cell lung cancer 
PD 
Pharmacodynamic; or Progressive disease 
PET 
Positron emission tomography 
PK 
Pharmacokinetic 
PI 
Principal investigator 
PR 
Progesterone Receptor 
RECIST 
Response evaluation criteria in solid tumors 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
t1/2 
Half-life 
TOP-1 
Topoisomerase-1 
TAM 
Tumor associated macrophages 
TNBC 
Triple negative breast cancer 
ULN 
Upper limit of normal 
Vss 
Volume at steady state 
WBC 
White blood count 
 
 


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1 Synopsis 
Sponsor 
IPSEN BIOSCIENCE, Inc 
650 East Kendall Street, 
Cambridge MA 02142 - USA 
Protocol Title 
A Phase 1 Study in Patients Treated with MM-398 (Nanoliposomal Irinotecan, 
nal-IRI,) to Determine Tumor Drug Levels and to Evaluate the Feasibility of 
Ferumoxytol Magnetic Resonance Imaging to Measure Tumor Associated 
Macrophages and to Predict Patient Response to Treatment 
Protocol Number MM-398-01-01-02 
Phase of 
Development Phase 1 
Trial Locations USA 
Number of sites Multiple sites 
Primary  
Objectives  
Pilot Phase (Completed): 
In patients with non-small cell lung cancer (NSCLC), colorectal cancer (CRC), 
triple negative breast cancer (TNBC), ER/PR positive breast cancer, pancreatic 
cancer, ovarian cancer, gastric cancer, gastroesophageal junction (GEJ) 
adenocarcinoma or head and neck cancer, who are undergoing therapy with 
MM-398: 
 
To evaluate the feasibility of delayed ferumoxytol MRI (FMX-MRI) to 
identify tumor associated macrophages (TAM) 
 
To measure tumor levels of irinotecan and SN-38 
 
Expansion Phase:  
In patients with locally advanced or metastatic breast cancer: 
 
To further investigate the feasibility of ferumoxytol (FMX) quantitation in 
tumor lesions   
 
To characterize the relationship between ferumoxytol (FMX) tumor uptake 
and tumor response to MM-398 
Secondary 
Objectives 
All Phases: 
 
To characterize the safety profile of MM-398 in the presence of FMX  
 
To assess tumor response to treatment  
 
To characterize the pharmacokinetics (PK) of MM-398  
 
Pilot Phase (Completed): 
 
To estimate the correlations between FMX-MRI, TAM levels, and tumor 
levels of irinotecan and SN-38 with administration of MM-398 
 
To determine the value of FMX-MRI in directing tissue biopsy 
 
Expansion Phase: 
 
To characterize the efficacy of MM-398 in patients with locally advanced 
or metastatic breast cancer using key efficacy indicators such as objective 
response rate and clinical benefit rate 
 
To further characterize the safety profile of MM-398, in the presence of 
FMX, in patients with locally advanced or metastatic breast cancer 
 
To assess the association between deposition, as visualized by ferumoxytol 
imaging, and measures of efficacy 
 
To assess the analytical performance of FMX-MRI measurements and 
optimize FMX-MRI parameterization 


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Exploratory 
Objectives 
Pilot Phase (Completed): 
 
To estimate the correlations between potential pharmacodynamic markers 
(FMX-MRI, TAM, tumor irinotecan, tumor SN-38 levels) and safety 
 
To estimate the correlations between potential pharmacodynamic markers 
(FMX-MRI, TAM, tumor irinotecan, tumor SN-38 levels) and tumor 
response 
 
To characterize each tumor biopsy to permit multivariate comparative 
analyses between tumor characteristics, FMX-MRI signal and drug 
metabolite levels 
 
Expansion Phase: 
 
To evaluate a set of potential biomarkers from tumor tissue and blood 
samples for their ability to predict PK and/or response to MM-398 
treatment  
Study Design 
The Pilot Phase will enroll approximately 12 patients, up to 20 in total. The first 
three patients enrolled can have any solid tumor type; however subsequent 
patients must have NSCLC, CRC, TNBC, ER/PR positive breast cancer, 
pancreatic cancer, ovarian cancer, gastric cancer, gastroesophageal junction 
adenocarcinoma or head and neck cancer. No more than three patients with 
ER/PR positive breast cancer can be enrolled in the Pilot Phase and similar 
restrictions may be placed on other tumor types to ensure a heterogeneous 
population.  
 
An Expansion Phase will enroll cohorts of single indications of patients with 
locally advanced or metastatic breast cancer in 3 cohorts of 10 patients each 
depending on sub-type of breast cancer: 
 
Cohort 1: ER and/or PR-positive breast cancer  
Cohort 2: TNBC 
Cohort 3: breast cancer with active brain metastasis 
 
There are four stages to this study: 
 
Screening Period (-28 d): patients undergo screening assessments to 
determine if they are eligible for the study 
 
Ferumoxytol Period (Day 1 – Day 2): patients receive ferumoxytol (FMX) 
infusion and undergo required FMX-MRI scans and prior to receiving 
MM-398 
 
MM-398 Treatment Period (C1D1 – progression of disease): patients 
receive an MM-398 starting dose of 60 mg/m2 every 2 weeks which should 
be dose escalated to 80 mg/m2 every 2 weeks in subsequent doses 
depending on patient tolerance , other required assessments, and a post-
treatment biopsy 72 hours after first dose of MM-398 
 
Follow Up Period (+30 d from last dose): patients return to clinic 30 days 
following the last dose of MM-398 for final safety assessments 
 
MM-398 will be administered at a dose of 60 mg/m2 every two weeks and 
patients will be treated until disease progression or unacceptable toxicity. The 
dose of MM-398 should be escalated to 80 mg/m2 every two weeks depending 
on patient tolerance. 


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Estimated Number 
of Patients 
Between 12 and 20 patients will be enrolled in the Pilot Phase of this study. The 
Expansion phase will enroll up to 30 evaluable patients, in three cohorts of 
approximately 10 patients. The total enrollment for the study will be 
approximately 45 patients.  
Inclusion Criteria 
All Phases  
a) Pathologically confirmed solid tumors that have recurred or 
progressed following standard therapy, or that have not responded 
to standard therapy, or for which there is no standard therapy, or 
who are not candidates for standard therapy. Pathologically 
confirmed solid tumors that have recurred or progressed following 
standard therapy, or that have not responded to standard therapy, 
or for which there is no standard therapy, or who are not candidates 
for standard therapy.   
1. Pilot Phase:  the first three patients enrolled may have any solid 
tumor type, however patients subsequently enrolled into the Pilot 
phase must have one of the following tumor types: NSCLC, 
CRC, TNBC, ER/PR positive breast cancer, pancreatic cancer, 
ovarian cancer, gastric cancer, GEJ adenocarcinoma or head and 
neck cancer.  
2. Expansion Phase:  the following invasive breast cancer tumor 
sub-types are required:   
i. Cohorts 1 and 2 must be documented to be HER2 negative 
as outlined in the ASCO/CAP 2013 guidelines for HER2 
testing, defined by at least one of the following:  
 
HER2 immunohistochemistry (IHC) staining of 0 or 
1+,  
OR if HER2 IHC 2+ 
 
Negative by In-Situ Hybridization (ISH) based on 
defined as a  Single-probe average HER2 copy number 
<4.0 signals/cell 
 
OR Negative by Dual-probe ISH defined as a 
HER2/CEP17 ratio <2.0 with an average HER2 copy 
number <4.0 signals/cell 
ii. In addition, breast cancer patients must be able to be 
categorized into one of the following cohorts: 
 
Cohort 1: hormone receptor positive breast cancer 
patients with ER-positive and/or PR-positive tumors 
defined as ≥1%  of tumor nuclei that are 
immunoreactive for ER and/or PR and HER2 negative 
 
Cohort 2: triple negative breast cancer (TNBC) 
patients with ER-negative, PR-negative tumors defined 
as < 1%  of tumor nuclei that are immunoreactive for 
ER and PR and HER2 negative 
 
Cohort 3: Any sub-type of metastatic breast cancer and 
active brain metastases (see additional criteria o-r 
below)  


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b) Documented locally advanced or metastatic disease with at least 
two radiologically measurable lesions as defined by RECIST v1.1 
(except Expansion Phase Cohort 3, see inclusion criterion o below)  
c) ECOG performance status 0 or 1 
d) Bone marrow reserves as evidenced by: 
 
ANC > 1,500 cells/μl without the use of hematopoietic growth 
factors 
 
Platelet count > 100,000 cells/μl 
 
Hemoglobin > 9 g/dL 
e) Adequate hepatic function as evidenced by: 
 
Normal serum total bilirubin 
 
AST and ALT ≤ 2.5 x ULN (≤ 5 x ULN is acceptable if liver 
metastases are present) 
f) Adequate renal function as evidenced by serum creatinine ≤ 1.5 x 
ULN 
g) Normal ECG or ECG without any clinically significant findings  
h) Recovered from the effects of any prior surgery, radiotherapy or 
other anti-neoplastic therapy  
i) At least 18 years of age 
j) Able to understand and sign an informed consent (or have a legal 
representative who is able to do so) 
Expansion Phase additional inclusion criteria: 
k) Received at least one cytotoxic therapy in the locally advanced or 
metastatic setting, with exception of TNBC patients who 
progressed within 12 months of adjuvant therapy   
l) Received ≤ 5 prior lines of chemotherapy in the metastatic setting 
(no limit to prior lines of hormonal therapy in Cohort 1) 
m) Candidate for chemotherapy 
n) At least one lesion amenable to multiple pass core biopsy 
(exception: Cohort 3 patients) 
Expansion Phase Cohort 3 additional inclusion criteria: 
o) Radiographic evidence of new or progressive brain metastases after 
prior radiation therapy with at least one brain metastasis measuring 
≥ 1 cm in longest diameter on gadolinium-enhanced MRI (note: 
progressive brain lesions are not required to meet RECIST criteria 
in order to be eligible; extra-cranial metastatic disease is also 
allowed) 
p) Imaging following prior radiation is not consistent with pseudo-
progression in the judgment of treating clinician 
q) Neurologically stable as defined by: 
 
Stable or decreasing dose of steroids and anti-convulsants for at 
least 7 days prior to study entry 


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 
No clinically significant mass effect, hemorrhage, midline shift, or 
impending herniation on baseline brain imaging 
 
No significant focal neurologic signs and/or symptoms which 
would necessitate radiation therapy or surgical decompression in 
the judgment of the treating clinician 
r) No evidence of diffuse leptomeningeal disease on brain MRI or by 
previously documented cerebrospinal fluid (CSF) cytology. 
NOTE: discrete dural metastases are permitted. 
Exclusion Criteria 
1. Active central nervous system metastases, indicated by clinical 
symptoms, cerebral edema, or steroid requirement (applies to Pilot 
Phase and Expansion Phase Cohorts 1-2 only)   
2. Clinically significant gastrointestinal disorder including hepatic 
disorders, bleeding, inflammation, occlusion, or diarrhea > grade 1 
3. Have received irinotecan or bevacizumab (or other anti-VEGF therapy)  
within the last six months; and for Expansion Phase patients,  have 
received any prior treatment with a Topo1 inhibitor (irinotecan-derived 
or topotecan) 
4. History of any second malignancy in the last 3 years; patients with prior 
history of in-situ cancer or basal or squamous cell skin cancer are 
eligible.  Patients with a history of other malignancies are eligible if 
they have been continuously disease free for at least 3 years. 
5. Unable to undergo MRI due to presence of errant metal, cardiac 
pacemakers, pain pumps or other MRI incompatible devices. 
6. A history of allergic reactions to compounds similar to ferumoxytol as 
described in full prescribing information for ferumoxytol injection, or 
to other IV iron replacement products (e.g. parenteral iron, dextran, 
iron-dextran, or parenteral iron polysaccharide preparations);  
7. Documented history of multiple drug allergies 
8. Known hypersensitivity to any of the components of MM-398, or other 
liposomal products 
9. Concurrent illnesses that would be a relative contraindication to trial 
participation such as active cardiac or liver disease.  
 
Severe arterial thromboembolic events (myocardial infarction, 
unstable angina pectoris, stroke) less than 6 months before 
inclusion 
 
NYHA Class III or IV congestive heart failure, ventricular 
arrhythmias or uncontrolled blood pressure  
10. Active infection or an unexplained fever > 38.5°C during screening 
visits or on the first scheduled day of dosing (at the discretion of the 
investigator, patients with tumor fever may be enrolled), which in the 
investigator’s opinion might compromise the patient’s participation in 
the trial or affect the study outcome 


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11. Prior chemotherapy administered within 3 weeks, or within a time 
interval less than at least 5 half-lives of the agent, whichever is longer, 
prior to the first scheduled day of dosing in this study 
12. Received radiation therapy in the last 14 days 
13. Evidence of Iron overload as determined by:  
 
Fasting transferrin saturation of >45 % and/or 
 
Serum ferritin levels >1000 ng /ml 
14. Treated with parenteral iron in the previous 4 weeks 
15. HIV-positive patients on combination antiretroviral therapy or other 
conditions requiring treatment where there is a potential for 
ferumoxytol to have negative pharmacokinetic interactions 
16. Any other medical or social condition deemed by the Investigator to be 
likely to interfere with a patient’s ability to sign informed consent, 
cooperate and participate in the study, or interfere with the 
interpretation of the results 
17. Pregnant or breast feeding; females of child-bearing potential must test 
negative for pregnancy at the time of enrollment based on a urine or 
serum pregnancy test. Both male and female patients of reproductive 
potential must agree to use a reliable method of birth control, during 
the study and for 3 months following the last dose of study drug. 
Length of Study 
Patients will be treated until disease progression, intolerable toxicity, or at the 
discretion of the treating physician.  A follow up clinic visit is required 30 days 
after last dose to complete the final safety assessments. 
Study Treatments 
A single dose of 5 mg/kg of ferumoxytol will be administered at Day 1 as an IV 
infusion in 50-200 mL of 0.9% sodium chloride or 5% dextrose over a 
minimum period of 15 minutes following dilution.  The total single dose will 
not exceed 510 mg, the maximum approved single dose of ferumoxytol. 
 
MM-398 monotherapy will be administered by intravenous (IV) infusion over 
90 minutes at a dose of 60 mg/m2 every two weeks. The dose of MM-398 
should be escalated to 80 mg/m2 in subsequent doses depending on patient 
tolerance. 
Investigational 
Products 
MM-398 is irinotecan (also known as CPT-11) encapsulated in a nanoliposomal 
drug delivery system.  It will be supplied in sterile, single-use vials containing 
10 mL of MM-398 at a concentration of 5 mg/mL. MM-398 must be stored 
refrigerated at 2 to 8°C, with protection from light. 
 
Ferumoxytol is an iron replacement product indicated for the treatment of iron 
deficiency anemia in adult patients with chronic kidney disease. Although not 
an approved indication, ferumoxytol has been used as an MR contrast agent in 
various indications and healthy volunteers and will be utilized as such in this 
study. Ferumoxytol (30 mg/mL) is available for intravenous infusion in single 
use vials. Each vial contains 510 mg of elemental iron in 17 mL.  Ferumoxytol 
must be stored at controlled room temperature (20° to 25°C). 
Statistical Analyses Between 12 and 20 patients will be enrolled in the Pilot Phase of this study, and 
approximately 30 patients in three Expansion Phase cohorts. 


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The safety population will include all patients receiving at least one dose of 
MM-398 or ferumoxytol.  The efficacy evaluable population includes all 
patients receiving at least one dose of MM-398.  The pharmacodynamic 
evaluable population includes all efficacy evaluable patients with the following:  
a) pre-treatment FMX-MRI scan(s) and b) radiological scans at 8 weeks.  The 
pharmacokinetic population includes patients receiving at least one dose of 
MM-398 and blood samples adequately collected at the predefined points. 
 
No formal hypothesis testing will be performed in the pilot or expansion phases 
of this study.  Descriptive statistics will be calculated to summarize categorical 
and continuous parameters.  Time to event parameters will be presented 
graphically using Kaplan-Meier estimates. 
 
Safety analyses (adverse events and laboratory analyses) will be performed 
using the safety population.  Adverse events will be reported in the most current 
version of MedDRA.  Tabular summaries will be presented for all adverse 
events, pre-treatment adverse events, treatment-emergent adverse events 
(TEAE), serious adverse events, and deaths, TEAE-related to MM-398 or 
ferumoxytol and TEAE Grade 3/4. Laboratory data will be presented by cycle.  
Abnormal laboratory values will be assessed using all available data and 
toxicity grading will be assigned according to NCI CTCAE toxicity scale, 
where possible.  
 
Tumor evaluation will be measured according to Response Evaluation Criteria 
In Solid Tumors (RECIST) version 1.1 for non-CNS disease, or according to 
modified RECIST criteria as defined in this protocol for CNS disease.  Tumor 
evaluations will be characterized according to best overall response (BOR), 
duration of response (DOR), progression-free survival (PFS), and clinical 
benefit rate (CR, PR, or SD ≥ 24 weeks). Objective response rate (ORR) and 
BOR will be summarized using frequency and percentage. PFS will be 
described using Kaplan-Meier methods.    
 
FMX uptake will be summarized as a continuous parameter.  Box and whisker 
plots will be displayed for FMX uptake.  The relationship between FMX uptake 
and tumor response will be evaluated using various parameters and methods. 
Relationships may be explored as appropriate.  Additionally, informal Fisher’s 
exact test will be used to investigate dichotomous FMX cut-points as related to 
ORR.  Other graphical procedures may be implemented to explore the 
relationship between FMX and efficacy response.       
 
Spearman pairwise correlations will be computed between the following 
measurements:  
 
FeMRI levels 
 
Tumor associated macrophage levels 
 
Tumor irinotecan levels 
 
Tumor SN-38 levels 
 
Graphical and regression methods will be used to explore potential relationships 
among correlated measurements. In addition, relationships between 


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pharmacodynamics markers and efficacy response will be evaluated in an 
exploratory manner. 
 
PK parameters will be derived from the blood PK samples and will be analyzed 
using descriptive statistics, including the median, mean and 95% confidence 
intervals around parameter estimates by dose level.  All PK parameters will 
include Cmax, Tmax, AUC (area under the concentration curve), clearance, 
volume of distribution at steady state (Vdss), and the terminal elimination half-
life.  Estimation of the pharmacokinetic parameters will be performed using 
standard non-compartmental methods.   
Sample Size 
Justification 
No formal hypothesis testing will be performed for this study.  The Pilot Phase 
will enroll 12-20 patients in a variety of indications, while the Expansion Phase 
will enroll approximately 30 patients with metastatic breast cancer within 3 
cohorts. Although no formal sample size calculation was performed for either 
study phase, the anticipated response rate in the HER2 negative Expansion 
Phase is estimated around 29% [36]. 


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2 Background Information and Rationale 
MM-398 is irinotecan encapsulated in a nanoliposomal delivery system.  Nanoliposome delivery 
reduces systemic exposure and increases drug accumulation within a tumor. Tumor associated 
macrophages (TAMs) appear to play a key role in the deposition, retention and activation of 
MM-398 within the tumor microenvironment.  Ferumoxytol is an approved therapy that is 
indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney 
disease; however a growing number of cancer patients without iron deficiency are being 
administered ferumoxytol as an imaging agent to visualize macrophage content and vasculature 
[1], [2]. This pilot study will evaluate the feasibility of measuring TAMs by utilizing 
ferumoxytol MRI (FMX-MRI) as an imaging agent and will also measure corresponding MM-
398 metabolite drug levels, and their correlation.  If successful, future studies will correlate 
macrophage profiling using FMX-MRI as a potential predictive biomarker for patients treated 
with MM-398.   
To maximize the information from this study, patients that are most likely to achieve the 
objectives of the study will be enrolled.  Although the first three patients enrolled in the study 
can have any solid tumor, subsequent patients will be limited to a subset of indications. Selection 
of these indications is based on the expected higher levels of tumor-associated macrophages, the 
potential sensitivity to irinotecan based on clinical experience and/or the presence of the pro-
drug converting carboxyl esterase enzymes (CES) and the amenability to imaging and biopsy 
collection. These indications include colorectal cancer (CRC), non-small cell lung cancer 
(NSCLC), triple negative breast cancer (TNBC), estrogen receptor and/or progesterone receptor 
(ER/PR) positive breast cancer, pancreatic cancer, ovarian cancer, gastric cancer, 
gastroesophageal junction (GEJ) adenocarcinoma and head and neck cancer.  No more than three 
patients with ER/PR positive breast cancer can be enrolled in the Pilot Phase of the study and 
similar restrictions may be placed on other tumor types to ensure a heterogeneous population at 
study end. 
Merrimack Pharmaceuticals’ tumor microarray analysis of patient samples showed that both 
colorectal CRC and NSCLC have a significant subset with higher levels of the CD68 marker for 
tumor associated macrophages. This is in agreement with published findings reviewed by 
Heusinkveld and van der Burg (2011) [24]. This review also provides supportive information on 
the presence of tumor-associated macrophages in other indications, including ovarian, gastric 
and pancreatic cancers. Head and neck cancer has been shown to achieve high deposition of 
pegylated liposomes in an imaging study by Harrington et al. (2001) [25] and contains many 
immune cells, including phagocytic dendritic cells and macrophages (reviewed in [26, 27]). In-
house profiling of human primary xenografts showed high CES enzyme activity (measured by 
tumors ability to convert irinotecan to SN-38) in CRC and NSCLC patient tumor samples.  
Analysis of the gene expression of CES1, CES2 and topoisomerase 1 (TOP1) demonstrated high 
expression of TOP1 and CES2 particularly in breast cancer, as well as the mammary ductal 
carcinoma subtype.  These higher expression levels were also seen in TNBC samples.  
The use of irinotecan is well established in CRC as a single agent or in combination with 5-
FU/LV in the first and second line [3].  Irinotecan has demonstrated efficacy in advanced 
NSCLC in a phase 3 setting both as a monotherapy and when combined with cisplatin [4].  
Similarly, Nogami et al (2012) reported that in a phase II study the combination of irinotecan and 
amrubicin was effective in patients with relapsed NSCLC [5]. Combinations of cetuximab with 
irinotecan have shown promising responses particularly in TNBC [6] and more recently also in 


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gastroesophageal cancer [28, 29, 30]. Topoisomerase I inhibitors such as topotecan and 
irinotecan also provide very effective and tolerable treatment options for recurrent ovarian cancer 
[31]. Further, irinotecan has demonstrated efficacy in metastatic breast cancer [32, 33], and 
although not specifically approved for this indication, irinotecan is commonly used to treat 
patients with anthracycline and taxane pre-treated metastatic breast cancer [34].  
In order to characterize MM-398 efficacy in the Expansion Phase of the study, as well as to 
explore the potential correlation between ferumoxytol (FMX) tumor uptake and tumor response 
to MM-398, cohorts of patients with a single indication will be enrolled. The Expansion Phase of 
the study will focus on patients with metastatic breast cancer stratified into cohorts of ER/PR 
positive breast cancer, TNBC, and patients with active brain metastases. In addition to having 
high unmet medical need and sensitivity to irinotecan based on clinical experience, preclinical 
studies in breast cancer models have demonstrated activity of pro-drug converting CES enzymes 
(unpublished data) as well as efficacy of MM-398 [35]. 
2.1 
MM-398 
MM-398 (also known as PEP02) is irinotecan (also known as CPT-11) encapsulated in a 
nanoliposome drug delivery system. 
The active ingredient of MM-398 injection is irinotecan.  Irinotecan is a member of the 
topoisomerase I inhibitor class of drugs and is a semi-synthetic and water soluble analog of the 
naturally-occurring alkaloid, camptothecin.  Topoisomerase I inhibitors work to arrest 
uncontrolled cell growth by preventing the unwinding of DNA and therefore preventing 
replication.  The pharmacology of irinotecan is complex, with extensive metabolic conversions 
involved in the activation, inactivation, and elimination of the drug [7], [8], [9]. Irinotecan is a 
pro-drug that is converted by nonspecific carboxylesterases into a 100-1000 fold more active 
metabolite, SN-38 [10]. SN-38 is cleared via glucuronidation, for which major pharmacogenetic 
differences have been shown, and biliary excretion. These drug properties contribute to the 
marked heterogeneities in efficacy and toxicity observed clinically with irinotecan [11], [12]. 
Hence, drug carrier technologies represent a rational strategy to improve the pharmacokinetics 
and biodistribution of irinotecan while protecting it from premature metabolism.  
MM-398 employs a novel intraliposomal drug stabilization technology for encapsulation of 
irinotecan into long-circulating liposome-based nanoparticles with high drug load and high in 
vivo stability. 
The stable nanoliposome formulation of irinotecan has several attributes that may provide an 
improved therapeutic index.  The controlled and sustained release should improve activity of this 
schedule-dependent drug by increasing duration of exposure of tumor tissue to drug, an attribute 
that allows it to be present in a higher proportion of cells during the more sensitive S-phase of 
the cell cycle.  The long circulating pharmacokinetics, high intravascular drug retention in the 
liposomes, and enhanced permeability and retention (EPR) effect may potentially result in site-
specific drug delivery to solid tumors.  Stromal targeting results from the subsequent depot 
effect, where liposomes accumulating in TAMs release the active drug and convert it locally to 
the substantially more cytotoxic SN-38.  The preferentially local bioactivation should result in 
reduced exposure to potential sites of toxicity and increased exposure to neighboring cancer cells 
within the tumor.  In addition, since SN-38 is not recognized by P-glycoprotein, a drug 
transporter that plays an important role in acquired drug resistance, MM-398 is likely to be active 
in tumors resistant to other standard chemotherapies. 


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Similar to other nanoparticles, MM-398 is a relatively large molecule measuring approximately 
100 nm, and as such is not expected to diffuse easily into tumors in the same way as smaller 
molecules. It is therefore critical to understand the tracking, uptake and processing of MM-398 in 
the tumor micro environment in order to deliver the optimal therapeutic dose to the tumor. 
2.1.1 MM-398 Pre-clinical Experience 
MM-398 has been shown in pre-clinical settings to have a broad spectrum of activity in a wide 
range of solid tumors including colon, pancreatic, gastric, cervical, non-small cell lung, small 
cell lung, ovarian, thyroid, and breast cancers, as well as glioma, Ewing’s sarcoma, and 
neuroblastoma, often with a high degree of anti-tumor activity against resistant or difficult to 
treat cancer models. Nanoliposomal irinotecan, MM-398, and immunoliposomal irinotecan 
showed potent antitumor activity, including durable tumor regressions, and were markedly 
superior to the equivalent dose of free drug in a bioluminescent-based orthotopic xenograft 
pancreatic model [13].  
2.1.2 MM-398 Pre-clinical  Pharmacokinetics 
The pharmacokinetic (PK) properties of MM-398 were evaluated in an HT-29 colon 
subcutaneous xenograft model. Tumor bearing mice were injected with different doses of MM-
398 (5, 10, 20 mg/kg) and following a single injection, plasma and tissue samples were collected 
at various time points (1, 4, 8, 24, 48, 72, 168 hours). HPLC analysis was used to measure the 
levels of the irinotecan and its metabolite SN-38 in these samples.  The PK profile of MM-398 
was compared with that of free irinotecan (at 10 and 40 mg/kg). 
Both irinotecan and SN-38 are cleared very rapidly (within 8 hours) from the plasma following 
free irinotecan administration. However, MM-398 clearance is considerably slower with a half-
life of approximately 48 hours as shown in Figure 1A; as >90% of irinotecan is encapsulated 
throughout in the plasma, irinotecan levels are reflective of MM-398 concentration. SN-38 
plasma exposure is also greater though Cmax levels are reduced following MM-398 
administration, suggesting the advantage of the irinotecan liposomal formulation in prolonging 
exposure and half-life (Figure 1B). Both irinotecan and SN-38 accumulate in tissues for extended 
time (at least 1 week after MM-398 administration). Also, the accumulation was observed to be 
dose-dependent (Figure 1C). When compared to accumulation in other organs, there were 
relatively higher levels of prolonged accumulation in the tumor compared to normal tissue where 
the metabolites are at very low levels after 48 hours (Figure 1D).   
 


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Figure 1: Summary of MM-398 PK Parameters in an HT-29 Xenograft Study 
A. 
 
B. 
 
 
C. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D. 
 
 
 
Plasma irinotecan (A) and SN-38 (B) levels following free irinotecan and MM-398 
administrations. (C) Intratumor levels of irinotecan and SN-38 levels following a single MM-398 
(20 mg/kg) dose. (D) Prolonged accumulation of SN-38 (~168 h) seen in tumor compared to other 
organs (~48 h). 


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Activation of irinotecan to SN-38 by the liver is the primary path for SN-38 tumoral 
accumulation when free irinotecan is administered. In contrast, these data suggest that 
accumulation of MM-398 in the tumor and subsequent liposome breakdown and local conversion 
of irinotecan to SN-38 is responsible for the enhanced tumor exposure of SN-38 when MM-398 
is administered. Current research is focused on identifying cell types located in the tumor 
responsible for liposomal breakdown and activation of MM-398.  
2.1.3 Tumor Uptake and Local Tumor Activation of MM-398 by Macrophages 
Tumor associated macrophages are a highly phagocytic cell type known to phagocytize 
liposomes.  They express one of the carboxylesterase enzymes that are responsible for activation 
of the pro-drug irinotecan to the active SN-38 metabolite, making them a prime candidate for 
participating in the processing of MM-398 in the tumor [14].   
Merrimack first determined whether macrophages take up liposomes using an in vitro cell based 
assay. Fluorescence activated cell sorter (FACS) analysis (Figure 2A) was performed to quantify 
the differential uptake of labeled (DiI5) liposomes (20 μg/ml, 24h) across multiple cell lines 
(macrophages and tumor cells). Relatively higher uptake was seen in phagocytic cell lines 
(J774.1, Raw264.7, THP-1, U937) compared to tumor cell lines (HT29, CT26, Hela). One of the 
macrophage cell lines, U937, was selected to test whether human macrophages can convert 
irinotecan to SN-38 when exposed to either free irinotecan or liposomal MM-398. This human 
monocytic cell line was differentiated into macrophages with phorbol-12-myristate-13-acetate to 
measure liposome uptake and drug conversion. Microscopy showed intracellular uptake of DiI5-
labelled liposomes by macrophages (Figure 2B; blue: nucleus, red: liposomes). The cells were 
also incubated with either free irinotecan or MM-398 for 24 hours and the SN-38 released in the 
media was measured by high pressure liquid chromatography (HPLC) analysis (Figure 2C).  A 
2-fold increase in SN-38 levels released in the media was seen in the presence of macrophages as 
compared to the absence of macrophages. The data suggested high uptake of liposomes by 
macrophages and their ability to activate irinotecan. 


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Figure 2: Macrophage Uptake by Liposomes and Tumor Activation  
A. 
B. 
 
C. 
 
(A) FACS analysis comparing uptake of labeled (DiI5) liposomes by macrophages and tumor 
cells. (B). Human macrophage cell line U937 shows intracellular uptake of DiI5 label liposomes 
(red); nucleus (blue). (C) HPLC analysis to measure SN-38 levels in media when either irinotecan 
or MM-398 is incubated for 24 h in presence and absence of macrophages (U937 cells). 
The ability of TAM’s to phagocytize liposomes using ex-vivo FACS analysis was also measured. 
A number of tumor bearing mice models were injected with labeled (DiI5-liposomes) and tumors 
were collected 24 hour post injection. The tumors were digested, and FACS analysis was 


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performed to quantify the DiI5 signal in different cell populations (tumor cells, myeloid cells, 
macrophages). In all models macrophages captured the largest share of the overall liposomal 
accumulation in the tumor (Figure 3). 
Figure 3: Liposome Accumulation in Tumor Models 
 
Macrophages take up the largest share of liposomes in various tumor models as assessed by ex-
vivo flow cytometry. Myeloid cells are CD45+CD11b+, while macrophages are also F4/80+ 
(N=4). 
To confirm that MM-398 was predominantly phagocytized by TAM’s compared to tumor cells, 
tumor bearing mice were pre-treated with anti-CSF-1 antibody to deplete TAM’s, this antibody 
inhibits colony stimulating growth factor (CSF-1), which recruits macrophages [15]. Following 
TAM depletion, the mice were then injected with DiI5 labeled liposomes to measure the relative 
uptake of liposomes by various cell populations within the tumor. Ex-vivo FACS analysis 
confirmed the depletion of macrophages (Figure 4A), resulting in the expected robust decrease in 
the liposome accumulation associated with the macrophage cell population (Figure 4B). 


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Figure 4: Macrophage Depletion and Liposome Accumulation in a Tumor Bearing Mouse 
Model 
 
(A) Ex-vivo FACS analysis of tumors from mice without and with depletion of macrophages 
showing depletion of tumor associated macrophages. (B)  Reduction of liposomal accumulation in 
the depleted macrophage cell population. Depletion also reduces the overall liposomal load in the 
HT-29 tumors. 
2.1.4 MM-398 Clinical Experience 
Six clinical studies of MM-398 have been completed to date, with approximately 385 patients 
across multiple tumor types exposed to various dosing regimens (Table 1). Additionally, five 
studies are currently underway and actively recruiting patients across multiple tumor types 
(Table 2). 
 
 


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Table 1: Summary of Completed Studies with MM-398 
Study 
PEP0201 
PEP0202 
PEP0203 
PEP0206 
PEP0208 
NAPOLI-1 
Tumor Type 
Solid tumors 
Cervical  
Solid Tumors 
Gastric 
Pancreas 
Pancreas 
Phase 
1 
1 
1 
2 
2 
3 
Study design 
Open label, dose 
escalation 
Open label, dose 
escalation 
Open label, dose 
escalation 
Open label, 3 
arm study 
comparing MM-
398, docetaxel 
and irinotecan 
(44 patients/arm) 
Open label, 
single arm 
Randomized comparison 
of MM-398 and MM-
398+ 5-FU/LV vs a 
common control of 5-
FU/LV 
Number of 
Patients treated 
with MM-398 
11 
6 
16 
44  
40 
151 (monotherapy) 
117 (combination) 
Dosing 
Frequency 
Q3W 
Q3W 
Q3W 
Q3W 
Q3W 
Q3W (monotherapy) 
Q2W (combination) 
Dose Level 
(mg/m2) 
60 (n = 1) 
120 (n = 6) 
180 (n = 4) 
60 (n = 3) 
80 (n = 3) 
60 (n = 3) 
80 (n = 6) 
100 (n = 5) 
120 (n = 2) 
120 
120 
120 (monotherapy) 
80 (combination) 
Combination 
No 
Cisplatin 
5FU/LV 
No 
No 
5FU/LV 
Combination 
dose 
--- 
60 mg 
2000/500 mg/m2 
--- 
--- 
2400/400 mg/m2 
Key results 
MTD identified 
as 120 mg/m2 
Study 
terminated due 
to protocol 
violation 
MTD identified 
as 80 mg/m2 
Similar safety 
profile across 
irinotecan and 
MM-398 arms; 
6 responses in 
MM-398 arm 
met primary 
endpoint 
(7.3 month 
mOS, 13.6% 
ORR) 
Median survival 
of 5.2 months 
Combination arm 
achieved median OS 6.1 
months, 1.9 month 
improvement over 
control arm   
(HR=0.67;  p-
value=0.012) 
 
Q2W combination arm 
performed better than 
Q3W monotherapy (OS 
6.1 vs 4.9 months) 


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Table 2: Summary of On-going Studies with MM-398 
Study 
UCSF 8603 
PIST-CRC-01 
PEPCOL 
UCSF 13-12025 
SPOC 2012-001 
DOUBLIRI C13-4 
MM-398-07-02-03 
Tumor Type 
Glioma 
Colorectal 
Colorectal 
Glioma 
Pediatric Solid 
Tumors 
Colorectal 
Pancreatic 
Phase 
1 
1 
2 
1 
1 
1 
2 
Study 
Design 
Open label, dose 
escalation 
Open label, 
dose escalation 
Compariso
n of MM-
398 + 
5FU/LV + 
avastin 
versus 
FOLFIRI + 
avastin 
Open label, dose 
escalation using 
convection-
enhanced 
delivery for 
direct tumoral 
injection 
Open label, dose 
escalation 
Open label, dose 
escalation. MM-
398 + irinotecan  
Comparison of 
MM-398 + 
5FU/LV with or 
without oxaliplatin 
versus nab-
Paclitaxel + 
gemcitabine 
Dosing 
Frequency 
Q3W 
Q2W 
Q2W 
Single dose 
Q3W 
Q2W 
Q2W 
Dose Level 
(mg/m2) 
HTZa 
60 (n = 3) 
90 (n = 5) 
WTb 
120 (n = 6) 
180 (n = 4) 
240 (n = 3) 
80 (n = 6) 
90 (n = 6) 
100 (n = 6) 
80 
 
Dose 
20 mg 
40 mg 
60 mg 
80 mg 
Tumor 
Volum
e 1-4 
cm3 
1-4 
cm3 
2-5 
cm3 
2-6 
cm3 
60 (n = 1) 
90 
120 
150 
180 
210 
MM-398  
60 (n = 3-6)  
80 (n = 3-6) 
 
80 
Combination 
No 
No 
5FU/LV 
No 
Cyclophosphamide 
Irinotecan  
5FU/LV 
± Oxaliplatin 
Combination 
Dose 
--- 
--- 
2400/400 
mg/m2 
(5FU/LV) 
5 mg/kg 
(avastin) 
--- 
250 mg/m2 
90 or 120 
mg/m2 
(Irinotecan) 
 
2400/400 mg/m2 
(5FU/LV) 
60 or 85 mg/m2 
(oxaliplatin) 
125/1000 mg/m2 
(nab-Pac/Gem) 
Current 
Status 
MTD identified for 
HTZ; escalation 
ongoing for WT 
Enrollment 
completed in 
final cohort 
Enrollment 
ongoing 
Enrollment 
ongoing 
Enrollment ongoing 
Enrollment ongoing 
Enrollment ongoing 
a Heterozygous for UGT1A1*28 
b Wildtype for UGT1A1*28 


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2.1.5 MM-398 Safety in Humans 
The clinical safety profile of MM-398 is consistent with that seen with free irinotecan.  Diarrhea 
is a frequent adverse event, while hematological toxicity is around 30%.   
The overall safety profile of MM-398 is presented in detail in the related Investigator Brochure.  
In a phase 2 pancreatic cancer study (PEP0208), MM-398 was generally well tolerated, with 
patients receiving 5 cycles of treatment on average.  Infection was the most common SAE.  
There were three deaths (7.5%) that occurred within 30 days of treatment, which were of an 
infectious nature and related to neutropenia. A total of 28 patients (70%) experienced at least one 
treatment-emergent Grade 3 or higher adverse event (Common Terminology Criteria for Adverse 
Events (CTCAE) version 3.0); neutropenia was the most common adverse event (30%), possibly 
related to prior therapy with gemcitabine.  Abdominal pain, asthenia, anemia, hyponatremia, 
diarrhea and infection occurred in > 10% of patients.  Table 3 provides a summary of the adverse 
events (AEs) observed in this study. 
Table 3: Summary of Grade 3 or Higher Adverse Events in PEP208 Study 
Adverse Event 
N (%) 
Adverse Event 
N (%) 
Neutropenia 
12 (30%) 
Thrombocytopenia 
2 (5%) 
Abdominal pain/discomfort 
7 (17.5%) Ulcer 
2 (5%) 
Fatigue/Asthenia 
8 (20%) 
Encephalopathy 
1 (2.5%) 
Anemia 
8 (20%) 
Febrile Neutropenia 
1 (2.5%) 
Hyponatremia 
7 (17.5%) Hemorrhage 
1 (2.5%) 
Diarrhea 
6 (15%) 
Heartburn 
1 (2.5%) 
Infection 
6 (15%) 
AST elevated 
1 (2.5%) 
Anorexia 
4 (10%) 
Hypoalbuminemia 
1 (2.5%) 
Nausea 
4 (10%) 
BUN elevated 
1 (2.5%) 
GGT elevated 
5 (12.5%) Hypoglycemia 
1 (2.5%) 
Hyperglycemia 
3 (7.5%) 
Confusion 
1 (2.5%) 
Hyperbilirubinemia 
3 (7.5%) 
Pancytopenia 
1 (2.5%) 
Vomiting 
3 (7.5%) 
Liver abscess 
1 (2.5%) 
Alkaline Phosphatase elevated 
2 (5%) 
Lymphopenia 
1 (2.5%) 
Ascites 
2 (5%) 
Pleural effusion 
1 (2.5%) 
Aspiration Pneumonia 
1 (2.5%) 
ALT elevated 
1 (2.5%) 
Hyperuricemia 
2 (5%) 
 Deep Vein Thrombosis 
1 (2.5%) 
Hypokalemia 
2 (5%) 
Obstruction 
1 (2.5%) 
Pain 
2 (5%) 
Dyspnea 
1 (2.5%) 
Additionally, the following safety data is available from a recently concluded Phase III study in 
pancreatic cancer (NAPOLI-1) comparing MM-398 + 5-Fluorouracil/Leucovorin (5-FU/LV), or 
MM-398 monotherapy, with 5-FU/LV alone (see Table 4). 
 
 


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Table 4: Summary of Grade 3 or Higher Adverse Events in NAPOLI Study 
Grade ≥ 3 Non-hematologic AEs in > 5% 
Patients, %a  
MM-398+5-FU/LV 
80 mg/m2 q2w 
(N=117) 
MM-398 
120 mg/m2 q3w 
 (N=147) 
5-FU/LV 
(N=134) 
   Fatigue 
14 
6 
4 
   Diarrhea 
13 
21 
5 
   Vomiting 
11 
14 
3 
   Nausea 
8 
5 
3 
   Asthenia 
8 
7 
7 
   Abdominal pain 
7 
8 
6 
   Decreased appetite 
4 
9 
2 
   Hypokalemia 
3 
12 
2 
   Hypernatremia 
3 
6 
2 
Grade  ≥3 Hematologic AEs Based on 
Laboratory Values, %a,b 
 
 
 
   Neutrophil count decreased    
20 
16 
2 
   Hemoglobin decreased 
6 
7 
5 
   Platelet count decreased 
2 
1 
0 
a Per CTCAE Version 4 
b Includes only patients who had at least one post-baseline assessment 
2.1.5.1 
Potential Toxicity of MM-398 in Humans 
It has been shown in animal and human pharmacokinetics studies that once irinotecan is released 
from the MM-398 liposomes, the conversion of irinotecan to SN-38 is similar to that of the 
unencapsulated irinotecan.  Because the active pharmaceutical ingredient in MM-398 is 
irinotecan, the safety profile is anticipated to be similar.  In addition to the adverse events noted 
in Table 3 and Table 4 above, additional treatment related adverse effects may be observed with 
further experience.  For a description of the adverse effects of irinotecan please refer to the full 
prescribing information [16].  
2.1.6 MM-398 PK in Humans 
The pharmacokinetic profile of MM-398 single agent was investigated in a phase I clinical study 
(PEP0201) in patients at 60, 120 or 180 mg/m2 and in a phase II clinical trial in gastric cancer 
patients (PEP0206) at 120mg/m2. Plasma levels of total irinotecan, SN-38 and encapsulated 
irinotecan were measured in these studies. 
The peak serum concentrations of total irinotecan (Cmax) ranged from 48-79 μg/ml for 
120 mg/ m2 of MM-398, which was approximately 50 fold higher than 125mg/ m2 free 
irinotecan.  The total irinotecan half-life (t1/2) for MM-398 ranged from 21 to 48 hours which 
was approximately 2-3 fold higher than 125 mg/ m2 of free irinotecan.  Overall total irinotecan 
exposure at one week (AUC 0–T) ranged from 1200- 3000 (μg*h/ml) at a dose of 120 mg/ m2 of 
MM-398, approximately 50-100 fold higher than 300mg/ m2 of free irinotecan. In contrast, SN-
38 Cmax levels at 120 mg/ m2 of MM-398 ranged from 9 to 17 ng/ml, which was approximately 
50% less than free irinotecan at 125 mg/ m2.  Overall exposure of SN-38 at one week (AUC 0-T) 
ranged from 474 to 997 ng*/ml and was only 1-2 fold higher than achieved by free irinotecan at 
300 mg/ m2. For both SN-38 and total irinotecan, AUC increases less than proportionally with 
dose of MM-398. The PK parameters of encapsulated irinotecan almost matched that of total 
irinotecan indicates that most of irinotecan remained encapsulated in the liposomes during 


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circulation.  The MM-398 PK parameters are not significantly changed when combined with 5-
FU/LV. Table 5 and Table 6 below summarize the PK findings in previous studies of MM 398.   
Table 5: MM-398 PK in Q3W Regimen (Irinotecan, Liposome + Free Drug) 
Study 
PEP0203 
PEP0201 
PEP0206 
Camptosar®  
Package Insert 
Drug 
MM-398 
Camptosar® 
Dose  
(mg/m2) 
60 
(n=3) 
80 
(n=6) 
100 
(n=4) 
120 
(n=2) 
120 
(n=6) 
180 
(n=4) 
120  
(n=37) 
300 
(n=27) 
125 
(n=64) 
340 
(n=6) 
Cmax 
(μg/mL) 
28.93  
(± 15.75) 
29.16  
(± 5.24) 
44.06 
(± 7.65) 
47.94 
(± 16.24) 
79.4 
(± 13.9) 
102 
(± 17.6) 
60.8 
(± 36.6) 
4.3 
(± 1.2) 
1.66 
(± 0.797) 
3.392 
(± 0.874) 
t1/2 (h) 
24.02 
(± 16.8) 
32.09 
(± 18.2) 
48.11 
(± 17.4) 
30.65 
(± 5.32) 
29.5 
(± 17.2) 
22.2 
(± 11.5) 
21.2 
(± 18.3) 
7.7 
(± 4.4) 
5.8 
(± 0.7) 
11.7 
(± 1.0) 
AUC0-T  
(μg•h/mL) 
1,047 
(± 1,156) 
1,116 
(± 810) 
2,193 
(± 1,017) 
1,177 
(± 308) 
2,835 
(± 1,817) 
1,945  
(± 1,029) 
1,651.5 
(± 1,412) 
24.2 
(± 7.7) 
10.2 
(± 3.27) 
20.60 
(± 6.03) 
AUC0- 
(μg•h/mL) 
1,114 
(± 1,270) 
1,211 
(± 924) 
2,472 
(± 1,261) 
1,261 
(± 500) 
2,963 
(± 1,947) 
1,963 
(± 1,035) 
1,812.2 
(± 1,602) 
26.2  
(± 9.0) 
- 
- 
Cl 
(L/h/m2) 
0.1249 
(± 0.1058) 
0.1164 
(± 0.0949) 
0.0547 
(± 0.0358) 
0.1033 
(± 0.0409) 
0.0591  
(± 0.0367) 
0.119 
(± 0.0703) 
0.191  
(± 0.260) 
12.9 
(± 4.7) 
13.3 
(± 6.01) 
13.9 
(± 4.0) 
Vss 
(L/m2) 
2.6 
(± 1.44) 
2.93 
(± 0.60) 
2.63 
(± 0.49) 
3.16 
(± 0.38) 
1.8 
(± 0.771) 
1.97 
(± 0.342) 
2.23 
(± 0.69) 
98.5 
(± 29.0) 
110 
(± 48.5) 
234 
(± 69.6) 
Note:  AUC0-T is defined as T = 24 hours for Camptosar® package insert, T= 49.5 hours for Camptosar in the PEP0206 
study and T = 169.5 hours for MM-398. Arithmetic mean and standard deviation are shown. Results are shown as 
arithmetic mean ± standard deviation. 
Table 6: MM-398 PK in Q3W Regimen (SN-38) 
Study 
PEP0203 
PEP0201 
PEP0206 
Camptosar®  
Package Insert 
Drug 
MM-398 
Camptosar® 
Dose 
(mg/m2) 
60 
n=3 
80 
(n=6) 
100 
(n=4) 
120 
(n=2) 
120 
(n=6) 
180 
(n=4) 
120  
(n=37) 
300 
(n=27) 
125 
(n=64) 
340 
(n=6) 
Cmax 
(μg/mL) 
7.02 
(± 5.64) 
7.98 
(± 4.39) 
7.39 
(± 1.68) 
16.64 
(± 9.36) 
9.2 
(± 3.5) 
14.3 
(±6.16) 
8.79 
(± 8.68) 
44.1 
(±28.2) 
26.3 
(± 11.9) 
56.0 
(± 28.2) 
t1/2 (h) 
183.81 
(± 172.3) 
53.75 
(± 15.6) 
73.41 
(± 18.3) 
26.23 
(± 6.53) 
75.4 
(± 43.8) 
58.0 
(± 32.8) 
88.8 
(± 114.6) 
22.8 
(± 10.9) 
10.4 
(± 3.1) 
21.0 
(± 4.3) 
AUC0-T 
(µg•h/mL) 
367.40 
(± 227) 
354.77 
(± 145) 
551.40 
(± 381.8) 
367.60 
(± 155.7) 
710 
(± 395) 
1,160 
(± 969) 
467 
(± 310) 
361 
(± 125) 
229 
(± 108) 
474 
(± 245) 
AUC0- 
(µg•h/mL) 
1,373.3 
(± 1,119) 
502.15 
(± 153) 
844.28 
(± 444) 
474.00 
(± 209) 
997 
(± 680) 
1,420 
(± 1,134) 
879 
(± 1,426) 
440 
(± 162) 
- 
- 
Note: AUC 0-T is defined as T = 24 hours for Camptosar® package insert, T= 49.5 hours for Camptosar® in the 
PEP0206 study and T = 169.5 hours for MM-398. Results are shown as arithmetic mean ± standard deviation. 
The pharmacokinetic parameters of total irinotecan and SN-38 following the administration of 
80 mg/m2 MM-398 in the Pilot Phase of this protocol (n=13) are consistent with these previous 
observations. For total irinotecan, peak plasma concentrations were ~38.12 μg/ml with an 
elimination half-life of 24.45 h. Overall exposure at one week was 1,356 h∙µg/mL. For SN-38, 
peak plasma concentrations were ~3.04 ng/ml. Overall exposure at one week was 179 h∙ng/mL. 
These summary statistics are given as geometric means. 
2.2 
Ferumoxytol 
Ferumoxytol (Feraheme™- AMAG Pharmaceuticals, Inc.) is a small (17-31 nm in diameter), 
non-stoichiometric magnetite (superparamagnetic iron oxide), coated with polyglucose sorbitol 


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carboxymethylether, nanoparticle.  It is approved to treat iron deficiency anemia in patients with 
chronic renal failure.  It is also used experimentally as an imaging agent in cancer patients [17].  
2.2.1 Use of Ferumoxytol as an Imaging Agent 
One of the properties of ferumoxytol is its prolonged residence time within the intravascular 
space, due to an average particle size of approximately 30 nm and slow clearance from the blood 
stream.  When performing MRI studies in patients given this agent for the treatment of their 
anemia, angiographic images can be obtained up to 24 hours post injection. This enhancement of 
the intravascular space following ferumoxytol administration has provided a novel approach to 
imaging pathologic conditions that involve the vascular tree, such as in stroke, vascular 
malformations, chronic renal disease and tumor vascularity, even in patients without kidney 
disease [18]. In addition, this agent has been used in patients with CNS malignancies to measure 
tumor vascularity and the response to chemotherapy [19]. FDA has designated this agent as an 
orphan drug for brain tumor imaging.  
An interesting feature of this agent is that delayed MRI, after 24-72 hours post injection, results 
in visualization of inflammatory cells in tissue due to the eventual leakage of the agent into the 
interstitial space, followed by uptake of the nanoparticles into macrophages [15], [20], [21], [22]. 
There is early evidence that shows that TAMs take up ferumoxytol leading to distinctive signal 
changes which can be detected on MRI. Specifically, delayed ferumoxytol signal has been 
shown to cause T2* susceptibility-related signal loss (so-called T2*-signal hypo- enhancement) 
on T2*-weighted Gradient-Echo (GRE) images and T1 hyper-enhancement due to T1-shortening 
on heavily T1-weighted images in glioblastoma multiforme and in chronic renal insufficiency.  
This signal change correlates with the TAM population.  Preclinical studies in mice have 
supported the possibility of utilizing ferumoxytol for MRI of TAM’s [15].   Anti-CSF-1 antibody 
was used to deplete TAM’s as evidenced by reduction in the number of CD68 positive cells 
(Figure 5A). A decreased MRI signal following depletion of macrophages was observed, further 
supporting TAM-mediated uptake of ferumoxytol (Figure 5B). 


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Figure 5: TAM Mediated Uptake of Ferumoxytol 
A. 
B. 
(A) IHC images confirm the depletion of macrophages (CD68 cells (red)) in the MMTV-PyMT 
spontaneous metastatic mouse model with anti-CSF-1 antibody. (B) Ferumoxytol-enhanced MRI 
signal is reduced in the MMTV-PyMT spontaneous metastatic mouse model at 24 hours in mice 
treated with anti-CSF-1 antibody [15]. 
2.2.2 Potential Toxicities of Ferumoxytol 
The US package insert dated 03/2015 ferumoxytol lists the following warnings and precautions:  
hypersensitivity reactions, hypotension, iron overload and ability to affect the diagnostic 
capability of MRI.   
Across three randomized clinical trials that enrolled 605 patients treated with ferumoxytol, the 
following adverse events were reported by ≥ 1% of patients treated with ferumoxytol: nausea, 
dizziness, hypotension, peripheral edema, headache, edema, vomiting, abdominal pain, chest 
pain, cough, pruritus, pyrexia, back pain, muscle spasms, dyspnea and rash [17].   
Because adverse reactions are reported voluntarily from a population of uncertain size, it is not 
always possible to reliably estimate their frequency or establish a causal relationship to drug 
exposure. 
In the initial clinical trials of Feraheme (ferumoxytol), conducted predominantly in patients with 
chronic kidney disease, serious hypersensitivity reactions were reported in 0.2 percent (3/1,726) 
of patients receiving Feraheme. Other adverse reactions potentially associated with 
hypersensitivity (e.g., pruritus, rash, urticaria or wheezing) were reported in 3.7 percent 
(63/1,726) of these patients. In other trials that did not include patients with chronic kidney 
disease, moderate to severe hypersensitivity reactions, including anaphylaxis, were reported in 
2.6 percent (26/1,014) of patients treated with Feraheme.  


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The following serious adverse reactions have been reported from the post-marketing experience 
with Feraheme: fatal, life-threatening, and serious anaphylactic-type reactions, 
cardiac/cardiorespiratory arrest, clinically significant hypotension, syncope, unresponsiveness, 
loss of consciousness, tachycardia/rhythm abnormalities, angioedema, ischemic myocardial 
events, congestive heart failure, pulse absent, and cyanosis. These adverse reactions have usually 
occurred within 30 minutes after the administration of Feraheme. Reactions have occurred 
following the first dose or subsequent doses of Feraheme. 
All IV iron products carry a risk of potentially life-threatening allergic reactions. At the time of 
the US approval of Feraheme in 2009, this risk was described in the Warnings and Precautions 
section of the drug label. 
Additionally, since its approval, cases of serious hypersensitivity, including death, have been 
reported for Feraheme.  In a post- marketing analysis performed by the FDA, a search of the 
FDA Adverse Event Reporting System database identified 79 cases of anaphylactic reactions 
associated with Feraheme administration, reported from the time of approval to June 30, 2014. 
Of the 79 cases, 18 were fatal, despite immediate medical intervention and emergency 
resuscitation attempts. The 79 patients ranged in age from 19 to 96 years. Nearly half of all cases 
reported that the anaphylactic reactions occurred with the first dose of Feraheme. Approximately 
75 percent (60/79) of the cases reported that the reaction began during the infusion or within 
5 minutes after administration completion. Frequently reported symptoms included cardiac 
arrest, hypotension, dyspnea, nausea, vomiting, and flushing. Of the 79 cases, 43 percent (34/79) 
of the patients had a medical history of drug allergy, and 24 percent had a history of multiple 
drug allergies. 
Based on the FDA evaluation, the prescribing instructions and other label information were 
updated to include a Boxed Warning that describes these serious risks and recommendation for 
use, described further in section 6.2.4. 
2.2.3 Interaction of Ferumoxytol and MM-398 
Despite early encouraging studies with ferumoxytol in patients, little is known about the optimal 
conditions and timing of FMX-MRI to measure TAM. For example, the number of TAMs, 
timing of MRI imaging and dose of ferumoxytol infusion for optimal signal-to-noise ratios has 
yet to be determined. Furthermore, it is not known what specific tumor types or histologies 
would favor ferumoxytol imaging or what the impact tumor micro- or macro-environment would 
have on the ability to detect TAM signal on MRI.  Pre-clinical studies with MM-398 have 
elucidated the role of TAMs in MM-398 intracellular tumoral accumulation a key step in the 
processing MM-398 into SN-38.  As a consequence of this mechanism of action, there is a desire 
to have a way to reliably measure TAMs in a non-invasive manner. FMX-MRI may provide one 
such technique for addressing the role of TAMs in the treatment response to MM-398 and 
similar liposomal compounds. Thus, a pilot study is warranted to evaluate the role of FMX-MRI 
in detecting a TAM signal and correlating it to MM-398 accumulation and activation.   
Preclinical studies with MM-398 suggest that TAMs are a dominant cell type internalizing MM-
398, a key step in processing MM-398 into tumoral SN-38. TAMs also take up ferumoxytol 
which provides contrast when performing MRI of tumors. In this clinical study, we plan to image 
patients with metastatic tumors using ferumoxytol as the MRI contrast, followed by treatment 
with MM-398. Thus it was critical to evaluate whether ferumoxytol might have a negative 
impact on uptake of MM-398 by TAM’s.  


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To determine the interaction between ferumoxytol and MM-398, we performed studies in HT-29 
colon xenografts. Tumor bearing mice were injected with ferumoxytol, and 24 hours later with 
either labeled (DiI5) liposomes to assess liposome distribution (Figure 5) or MM-398 to measure 
tumor metabolite levels (Figure 7). Both flow cytometry and IHC analysis were performed to 
evaluate intratumoral localization of liposomes (Figure 6A) and alterations in overall tumor DiI5 
liposome uptake (Figure 6B). We observed predominant uptake of DiI5 liposomes by tumor 
associated macrophages (CD11b+ cells) when compared to tumor cells (EPCAM+). Further, 
ferumoxytol (20 mg/kg or 50 mg/kg) did not alter the overall DiI5 liposome uptake. We also 
observed a spatial correlation between the intratumor accumulation of liposomes (Figure 6C) and 
the ferumoxytol signal within tumors (Figure 6D). 


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Figure 6: Uptake of Liposomes by TAMS 
A. 
B. 
C. 
D. 
HT-29 tumor bearing mice were injected with ferumoxytol followed by DiI5 liposomes. FACS 
analysis data showed no effect of ferumoxytol (Fe) on overall DiI5 liposome uptake in either 
EpCAM+ tumor cells or CD11b+ myeloid cells (A). The mean fluorescence intensity (MFI) of 
DiI5 liposomes was higher in CD11b+ myeloid cells and remained unaltered by ferumoxytol as 
compared to MFI in EPCAM+ tumor cells (B).  (C)  IHC analysis shows clear spatial correlation 
between the intratumor liposomes (red) accumulation and ferumoxytol staining (Prussian blue 
staining) within the tumors (D) 
The pharmacokinetic analysis performed using HPLC revealed unaltered levels of both 
irinotecan and SN-38 in plasma (Figure 7A and Figure 7B) and HT-29 tumors (Figure 7C and 
Figure 7D) following ferumoxytol exposure. These data clearly suggested that ferumoxytol could 
be used for MRI without impacting the deposition or local activation of MM-398. 
 
 


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Figure 7: Irinotecan and SN-38 Levels are Not Impacted by Ferumoxytol 
 
Effects of ferumoxytol on the PK profile of MM-398 in mice in plasma (A, B) and tumor (C, D). 
2.3 
Summary of Study Rationale 
In this study, we propose to use FMX-MRI in patients being treated with MM-398 to both 
determine the imaging parameters that could be applied to future clinical trials and to better 
define the appropriate strategy for incorporating ferumoxytol in TAM imaging for MM-398 
studies. Having a biomarker for TAMs would further assist in understanding TAM-tumor 
biology interactions and provide insight into which treatments may rely upon or be impeded by 
these inflammatory cells.  Additionally, as the size of ferumoxytol is relatively large (17-31 nm), 
the delivery of ferumoxytol to the tumor microenvironment may serve as a surrogate for the 
tumor delivery and deposition of MM-398 liposomes. Therefore, the Expansion Phase will 
evaluate FMX-MRI and tumor lesion ferumoxytol signal as a tool for predicting response to 
treatment with MM-398 in patients with locally advanced or metastatic breast cancer.   
An important goal of the Expansion Phase of this study is to assess multi-institutional feasibility 
of imaging with FMX-MRI with the purpose of correlating clinical activity in a specific patient 
population with uptake of ferumoxytol as measured by MRI. Advanced breast cancer has been 
selected for the study based on published clinical data on irinotecan and preliminary evidence of 
clinical activity with MM-398 as described below. 
Irinotecan has a distinct mechanism of action from other drugs commonly used to treat patients 
with metastatic breast cancer and limited cross-resistance [32]. Irinotecan is used to treat patients 
with advanced breast cancer with single agent response rates of 5-23% [38]. Results for single 
agent irinotecan signal the need for both an improved irinotecan-based agent as well as 
biomarker strategy to identify patients likely to respond. We believe that MM-398 and FMX-


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MRI have potential to fill this role. In previous clinical studies (PEP0201, PEP0203) 6 patients 
with metastatic breast cancer have been treated with MM-398, alone or in combination with 5-
FU/LV. Two patients achieved stable disease and 1 patient achieved a partial response as best 
response.    
3 Study Objectives 
3.1 
Primary Objectives 
Pilot Phase (Completed) 
In patients with NSCLC, CRC, TNBC, ER/PR positive breast cancer, pancreatic cancer, ovarian 
cancer, gastric cancer, GEJ adenocarcinoma or head and neck cancer, who are undergoing 
therapy with MM-398: 
 
To evaluate the feasibility of delayed ferumoxytol MRI (FMX-MRI) to identify tumor 
associated macrophages (TAMs) 
 
To measure tumor levels of irinotecan and SN-38  
Expansion Phase: 
In patients with locally advanced or metastatic breast cancer: 
 
To further investigate the feasibility of ferumoxytol (FMX) quantitation in tumor lesions   
 
To characterize the relationship between ferumoxytol (FMX) tumor uptake and tumor 
response to MM-398  
3.2 
Secondary Objectives 
All Phases: 
 
To characterize the safety profile of MM-398 in the presence of FMX  
 
To assess tumor response to treatment 
 
To characterize the pharmacokinetics (PK) of MM-398 
Pilot Phase (Completed): 
 
To estimate the correlations between FMX-MRI, TAM levels, and tumor levels of 
irinotecan and SN-38 with administration of MM-398 
 
To determine the value of FMX-MRI in directing tissue biopsy 
Expansion Phase: 
 
To characterize the efficacy of MM-398 in patients with locally advanced or metastatic 
breast cancer using key efficacy indicators such as objective response rate and clinical 
benefit rate  
 
To assess the association between deposition, as visualized by ferumoxytol imaging, and 
measures of efficacy 
 
To further characterize the safety profile of MM-398, in the presence of FMX, in patients 
with metastatic breast cancer  
 
To assess the analytical performance of FMX-MRI measurements and optimize FMX-
MRI parameterization 


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3.3 
Exploratory Objectives 
Pilot Phase (Completed): 
 
To estimate the correlations between potential pharmacodynamic (PD) markers (FMX-
MRI, TAM, tumor irinotecan, tumor SN-38 levels) and safety 
 
To estimate the correlations between potential PD markers (FMX-MRI, TAM, tumor 
irinotecan, tumor SN-38 levels) and tumor response 
 
To characterize each tumor biopsy to permit multivariate comparative analyses between 
tumor characteristics, FMX-MRI signal and drug metabolite levels 
Expansion Phase: 
 
To evaluate a set of potential biomarkers from tumor tissue and blood samples for their 
ability to predict PK and/or response to MM-398 treatment 
4 Study Design 
4.1 
Indications and Number of Patients 
This study will enroll approximately 12 patients, up to 20 in total in the Pilot Phase. The first 
three patients that are enrolled in this phase can have any solid tumor type; however subsequent 
patients must have NSCLC, CRC, TNBC, ER/PR positive breast cancer, pancreatic cancer, 
ovarian cancer, gastric cancer, gastroesophageal junction adenocarcinoma or head and neck 
cancer. No more than three patients with ER/PR positive breast cancer can be enrolled in the 
Pilot Phase and similar restrictions may be placed on other tumor types to ensure a 
heterogeneous population. 
These indications were selected based on data suggesting that these tumor types have high levels 
of CD68 (tumor associated macrophages) and carboxylesterase enzyme (CES) activity or high 
levels of deposition, any of which may correlate to MM-398 response.  
An Expansion Phase will enroll cohorts of single indications of patients with locally advanced or 
metastatic breast cancer, in 3 cohorts: 
Cohort 1: ER and/or PR-positive breast cancer  
Cohort 2: TNBC 
Cohort 3: BC with active brain metastasis 
The total enrollment for the study will be approximately 45 patients. 
4.2 
Study Stages and Treatment Design 
There are four stages to this study, defined as periods: 
 
Screening Period (-28d):  patients undergo screening assessments to determine if they are 
eligible for the study 
 
Ferumoxytol (FMX) Period (Day 1 – Day 2):  patients receive ferumoxytol (FMX) 
infusion and undergo required FMX-MRI scans prior to receiving MM-398. 
 
MM-398 Treatment Period (C1D1 – progression of disease):  patients receive an MM-
398 dose of 60 mg/m2 every 2 weeks, which should be dose escalated to 80 mg/m2 every 2 
weeks in subsequent doses depending on patient tolerance, other required assessments, and 
undergo a post-treatment (MM-398) multiple pass core biopsy 


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 
Follow Up Period (+30d from last dose):  patients return to clinic 30 days following the 
last dose of MM-398 for final safety assessments 
For all enrolled patients, a single dose of 5 mg/kg of ferumoxytol will be administered at Day 1 
during the ferumoxytol period by intravenous infusion in 50-200 mL of 0.9% sodium chloride or 
5% dextrose over a minimum period of 15 minutes following dilution.  The total single dose will 
not exceed 510mg, the maximum approved single dose of ferumoxytol. 
MM-398 will be administered by intravenous (IV) infusion over 90 minutes at a dose 
of60 mg/m2 every two weeks. The MM-398 period (C1D1) should begin within 7 days of the 
ferumoxytol infusion. The dose of MM-398should be escalated to 80 mg/m2 every two weeks 
depending on patient tolerance. 
All patients will be treated until disease progression (see section 7.1.6.2) or unacceptable 
toxicity. 
Enrollment and Treatment 
Between 12 and 20 patients will be enrolled in this the Pilot Phase of the study. The Expansion 
Phase will enroll up to 30 evaluable patients, in three cohorts. The total enrollment for the study 
will be approximately 45 patients. 
Patients receiving ferumoxytol and not completing all assessments and/or those who do not have 
evaluable FMX MR images, may still proceed to the MM-398 treatment phase; however 
additional patients may be enrolled to ensure that adequate MRI data are collected to achieve the 
objectives of the study. In addition, in order to be considered evaluable from a pharmacodynamic 
standpoint for the Expansion Phase, patients must have received MM-398 and completed at least 
one CT scan at the 8-week post-treatment time point. 
5 Patient Selection and Discontinuation 
5.1 
Inclusion Criteria 
For inclusion into the study, patients must have/be: 
All Phases  
a) Pathologically confirmed solid tumors that have recurred or progressed following 
standard therapy, or that have not responded to standard therapy, or for which there is no 
standard therapy, or who are not candidates for standard therapy   
1. Pilot Phase (Completed):  the first three patients enrolled may have any solid 
tumor type, however patients subsequently enrolled into the Pilot phase must have 
one of the following tumor types: NSCLC, CRC, TNBC, ER/PR positive breast 
cancer, pancreatic cancer, ovarian cancer, gastric cancer, GEJ adenocarcinoma or 
head and neck cancer.  
2. Expansion Phase:  the following invasive breast cancer tumor sub-types are 
required:   
i. Cohorts 1 and 2 must be documented to be HER2 negative as outlined in 
the ASCO/CAP 2013 guidelines for HER2 testing, defined by at least one 
of the following:  
 HER2 immunohistochemistry (IHC) staining of 0 or 1+,  


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OR if HER2 IHC 2+ 
 Negative by In-Situ Hybridization (ISH) based on defined as a  
Single-probe average HER2 copy number <4.0 signals/cell 
 OR Negative by Dual-probe ISH defined as a HER2/CEP17 ratio 
<2.0 with an average HER2 copy number <4.0 signals/cell 
ii. In addition, breast cancer patients must patients must be  
 Cohort 1: hormone receptor positive breast cancer patients with 
ER-positive and/or PR-positive tumors defined as ≥1% of tumor 
nuclei that are immunoreactive for ER and/or PR and HER2 
negative 
 Cohort 2: triple negative breast cancer (TNBC) patients with ER-
negative, PR-negative tumors defined as <1% of tumor nuclei that 
are immunoreactive for ER and PR and HER2 negative 
 Cohort 3: Any sub-type of metastatic breast cancer and active brain 
metastases (see additional criteria o-r below)  
b) Documented metastatic disease with at least 1 radiologically measurable lesion as defined 
by RECIST v1.1 (except Cohort 3, see inclusion criterion o below)  
c) ECOG performance status 0 or 1 
d) Bone marrow reserves as evidenced by: 
 ANC > 1,500 cells/μl without the use of hematopoietic growth factors 
 Platelet count > 100,000 cells/μl 
 Hemoglobin > 9 g/dL 
e) Adequate hepatic function as evidenced by: 
 Normal serum total bilirubin 
 AST and ALT ≤ 2.5 x ULN (≤ 5 x ULN is acceptable if liver metastases are present) 
f) Adequate renal function as evidenced by serum creatinine ≤ 1.5 x ULN 
g) Normal ECG or ECG without any clinically significant findings  
h) Recovered from the effects of any prior surgery, radiotherapy or other anti-neoplastic 
therapy  
i) At least 18 years of age 
j) Able to understand and sign an informed consent (or have a legal representative who is 
able to do so) 
Expansion Phase additional inclusion criteria: 
k) Received at least one cytotoxic therapy in the metastatic setting, with exception of TNBC 
patients who progressed within 12 months of adjuvant therapy   
l) Received ≤ 5 prior lines of chemotherapy in the metastatic setting (no limit to prior lines 
of hormonal therapy in Cohort 1) 
m) Candidate for chemotherapy 
n) At least one lesion amenable to multiple pass biopsy (exception: Cohort 3 patients) 


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Expansion Phase Cohort 3 additional inclusion criteria: 
o) Radiographic evidence of new or progressive brain metastases after prior radiation therapy 
with at least one brain metastasis measuring ≥ 1 cm in longest diameter on gadolinium-
enhanced MRI (note: progressive brain lesions are not required to meet RECIST criteria in 
order to be eligible; extra-cranial metastatic disease is also allowed) 
p) Imaging following prior radiation is not consistent with pseudo-progression in the 
judgment of treating clinician 
q) Neurologically stable as defined by: 
 Stable or decreasing dose of steroids and anti-convulsants for at least 7 days prior to 
study entry 
 No clinically significant mass effect, hemorrhage, midline shift, or impending 
herniation on baseline brain imaging 
 No significant focal neurologic signs and/or symptoms which would necessitate 
radiation therapy or surgical decompression in the judgment of the treating clinician 
r) No evidence of diffuse leptomeningeal disease on brain MRI or by previously documented 
cerebrospinal fluid (CSF) cytology-NOTE: discrete dural metastases are permitted. 
5.2 
Exclusion Criteria 
Patients must meet all the inclusion criteria listed above and none of the following exclusion 
criteria: 
18. Active central nervous system metastases, indicated by clinical symptoms, cerebral edema, or 
steroid requirement (applies to Pilot Phase and Expansion Phase Cohorts 1-2 only)  
s) Clinically significant gastrointestinal disorder including hepatic disorders, bleeding, 
inflammation, occlusion, or diarrhea > grade 1 
t) Have received irinotecan or bevacizumab (or other anti-VEGF therapy) within the last six 
months; and for Expansion Phase patients, have received any prior treatment with a Topo1 
inhibitor (irinotecan-derived or topotecan) 
u) History of any second malignancy in the last 3 years; patients with prior history of in-situ 
cancer or basal or squamous cell skin cancer are eligible.  Patients with a history of other 
malignancies are eligible if they have been continuously disease free for at least 3 years. 
v) Unable to undergo MRI due to presence of errant metal, cardiac pacemakers, pain pumps 
or other MRI incompatible devices 
w) A history of allergic reactions to compounds similar to ferumoxytol as described in full 
prescribing information for ferumoxytol injection, or to other IV iron replacement products 
(e.g. parenteral iron, dextran, iron-dextran, or parenteral iron polysaccharide preparations) 
x) Documented history of allergies to multiple drugs 
y) Known hypersensitivity to any of the components of MM-398, or other liposomal products 
z) Concurrent illnesses that would be a relative contraindication to trial participation such as 
active cardiac or liver disease  
 
Severe arterial thromboembolic events (myocardial infarction, unstable angina 
pectoris, stroke) less than 6 months before inclusion 


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 
NYHA Class III or IV congestive heart failure, ventricular arrhythmias or 
uncontrolled blood pressure  
19. Active infection or an unexplained fever > 38.5°C during screening visits or on the first 
scheduled day of dosing (at the discretion of the investigator, Patients with tumor fever may be 
enrolled), which in the investigator’s opinion might compromise the patient’s participation in 
the trial or affect the study outcome 
20. Prior chemotherapy administered within 3 weeks, or within a time interval less than at least 5 
half-lives of the agent, whichever is longer, prior to the first scheduled day of dosing in this 
study 
21. Received radiation therapy in the last 14 days 
22. Evidence of Iron overload as determined by:  
 
Fasting transferrin saturation of >45 % and/or 
 
Serum ferritin levels >1000 ng /ml 
23. Treated with parenteral iron in the previous 4 weeks 
24. HIV-positive patients on combination antiretroviral therapy or other conditions requiring 
treatment where there is a potential for ferumoxytol to have negative pharmacokinetic 
interactions 
25. Any other medical or social condition deemed by the Investigator to be likely to interfere with 
a patient’s ability to sign informed consent, cooperate and participate in the study, or interfere 
with the interpretation of the results 
26. Pregnant or breast feeding; females of child-bearing potential must test negative for pregnancy 
at the time of enrollment based on a urine or serum pregnancy test. Both male and female 
patients of reproductive potential must agree to use a reliable method of birth control, during 
the study and for 3 months following the last dose of study drug. 
5.3 
Patient Discontinuation 
Patients may withdraw or be withdrawn from the study at any time and for any reason.  Some 
possible reasons for early withdrawal include, but are not limited to the following:   
 
Progressive neoplastic disease 
 
The patient experiences an adverse event which, in the opinion of the Investigator, 
precludes further participation in the trial 
 
Clinical and/or symptomatic deterioration 
 
Development of an intercurrent medical condition or need for concomitant treatment that 
precludes further participation in the trial 
 
Noncompliance with the protocol  
 
Withdraws consent  
 
The Investigator removes the patient from the trial in the best interests of the patient 
 
Study termination by the Sponsor 
 
Use of prohibited concomitant medications 
 
Lost to follow up 
If a patient withdraws from the trial, attempts should be made to contact the patient to determine 
the reason(s) for discontinuation.   


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All procedures and evaluations required by the 30 day follow up visit should be completed when 
a patient is discontinued.  All patients who discontinue the trial as a result of an adverse event 
must be followed until resolution or stabilization of the adverse event.  
5.4 
Patient Replacement 
The following patients will not be considered pharmacodynamically evaluable for the Expansion 
Phase of the study and may be replaced at the discretion of the Sponsor. 
 
Patients who do not complete all study procedures during the FMX phase and/or who do 
not have evaluable FMX MR images 
 
Patients who discontinue the study early, prior to completing the 8-week disease 
evaluation  
6 Investigational Product and Study Treatment 
6.1 
Description of MM-398 
MM-398 is irinotecan (also known as CPT-11) encapsulated in a nanoliposomal drug delivery 
system in the form of the sucrose octasulfate salt of irinotecan.  It will be supplied as sterile, 
single-use vials containing 10 mL of MM-398 at a concentration of 5 mg/mL. The vials contain a 
0.5 mL excess to facilitate the withdrawal of the label amount from each vial. 
6.1.1 Storage and Handling of MM-398 
MM-398 must be stored refrigerated at 2 to 8°C, with protection from light.  Light protection is 
not required during infusion.  MM-398 must not be frozen.  Responsible individuals should 
inspect vial contents for particulate matter before and after they withdraw the drug product from 
a vial into a syringe.  They must contact the Sponsor or its designee if they notice a problem with 
the study drug.  
MM-398 must be diluted prior to administration.  The diluted solution is physically and 
chemically stable for 4 hours at room temperature (15-30°C), but it is preferred to be stored at 
refrigerated temperatures (2-8°C), and protected from light. The diluted solution must not be 
frozen.  Because of possible microbial contamination during dilution, it is advisable to use the 
diluted solution within 24 hours if refrigerated (2-8°C), and within 4 hours if kept at room 
temperature (15-30°C). 
6.1.2 Packaging and Labeling of MM-398 
Twenty vials of MM-398 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 local regulatory 
requirements. 
6.1.3 Administration of MM-398 
MM-398 will be administered by intravenous (IV) infusion over 90 minutes at a dose 
of60 mg/m2 every two weeks.  The dose of MM-398 should be escalated to 80 mg/m2 every two weeks 
depending on patient tolerance. The first cycle Day 1 is a fixed day; subsequent doses should be 
administered on the first day of each cycle +/- 2 days. 
Prior to administration, the appropriate dose of MM-398 must be diluted in 5% Dextrose 
Injection solution (D5W) to a final volume of 500 mL. Care should be taken not to use any 


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diluents other than D5W or 0.9% sodium chloride USP, to a final volume of 500 mL.  MM-398 
can be administered using standard intravenous administration bags and tubing.  
The actual dose of MM-398 to be administered will be determined by calculating the patient’s 
body surface area (BSA) at the beginning of each cycle.  A +/- 5% variance in the calculated 
total dose will be allowed for ease of dose administration. Since MM-398 vials are single use 
vials, site staff must not store any unused portion of a vial for future use and must discard all 
unused portions of the product.  
If a patient experiences an infusion reaction, or any adverse event deemed as related by the 
investigator to ferumoxytol, MM-398 should be held until the event is grade 1 or resolved.  
6.1.4 Premedication Prior to MM-398 Administration 
All patients must be premedicated prior to MM-398 infusion with standard doses of 
dexamethasone and a 5-HT3 antagonist or other anti-emetics according to standard institutional 
practices for irinotecan administration.  Atropine may be prescribed prophylactically for patients 
who experienced acute cholinergic symptoms in the previous cycles. 
6.1.5 Important Treatment Considerations After MM-398 Administration 
Data from previous MM-398 studies does not show any unexpected toxicity when compared to 
the active ingredient, irinotecan, which has been studied extensively. The warnings and 
precautions for the use of irinotecan and the treatment procedures for managing those toxicities 
are provided below.  
6.1.5.1 
Diarrhea 
Irinotecan can induce both early and late forms of diarrhea that appear to be mediated by 
different mechanisms.  Early diarrhea (occurring during or shortly after infusion of irinotecan) is 
cholinergic in nature.  It is usually transient and only infrequently severe.  It may be 
accompanied by symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, 
flushing, and intestinal hyper-peristalsis that can cause abdominal cramping.  For patients who 
experienced early cholinergic symptoms during the previous cycle of MM-398, prophylactic 
administration of atropine will be given at the discretion of the investigator. 
Late diarrhea (generally occurring more than 24 hours after administration of irinotecan) can be 
life threatening since it may be prolonged and may lead to dehydration, electrolyte imbalance, or 
sepsis.  Late diarrhea should be treated promptly with loperamide, and octreotide should be 
considered if diarrhea persists after loperamide, as described in section 6.4.3 (Therapy for 
Diarrhea).  Loss of fluids and electrolytes associated with persistent or severe diarrhea can result 
in life threatening dehydration, renal insufficiency, and electrolyte imbalances, and may 
contribute to cardiovascular morbidity. The risk of infectious complications is increased, which 
can lead to sepsis in patients with chemotherapy-induced neutropenia.  Patients with diarrhea 
should be carefully monitored, given fluid and electrolyte replacement if they become 
dehydrated, and given antibiotic support if they develop ileus, fever, or severe neutropenia.    
6.1.5.2 
Neutropenia 
Deaths due to sepsis following severe neutropenia have been reported in patients treated with 
irinotecan.  Neutropenic complications should be managed promptly with antibiotic support.  G-
CSF may be used to manage neutropenia at the investigator’s discretion, provided it is 
administered within parameters specified in section 6.4.2.  Patients, who are known to have 


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experienced Grade 3 or 4 neutropenia while receiving prior anti-neoplastic therapy, should be 
monitored carefully and managed as outlined in section 6.1.6.1 
6.1.5.3 
Hypersensitivity 
Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been 
observed.  Suspected drugs should be withheld immediately and aggressive therapy should be 
given if hypersensitivity reactions occur. 
6.1.5.4 
Colitis/Ileus 
Cases of colitis complicated by ulceration, bleeding, ileus, and infection have been observed.  
Patients experiencing ileus should receive prompt antibiotic support.  
6.1.5.5 
Thromboembolism 
Thromboembolic events have been observed in patients receiving irinotecan- containing 
regimens; the specific cause of these events has not been determined.  
6.1.5.6 
Pregnancy 
The pregnancy category of irinotecan is D.  Women of childbearing potential should be advised 
to avoid becoming pregnant while receiving treatment with irinotecan.  If a pregnancy is 
reported, treatment should be discontinued.  The patient should be withdrawn from the study, 
and the pregnancy should be followed until the outcome becomes known. 
6.1.5.7 
Care of Intravenous Site 
Care should be taken to avoid extravasation, and the infusion site should be monitored for signs 
of inflammation.  Should extravasation occur, flushing the site with sterile saline and 
applications of ice are recommended.  
6.1.5.8 
Patients at Particular Risk 
In clinical trials of the weekly schedule of irinotecan, it has been noted that patients with 
modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) have had a 
significantly greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia than those 
with bilirubin levels that were less than 1.0 mg/dL (50.0% [19/38] versus 17.7% [47/226]; 
p < 0.001).  Patients with abnormal glucuronidation of bilirubin, such as those with Gilbert's 
syndrome, may also be at greater risk of myelosuppression when receiving therapy with 
irinotecan.  
6.1.5.9 
Acute Infusion Associated Reactions 
Acute infusion-associated reactions characterized by flushing, shortness of breath, facial 
swelling, headache, chills, back pain, tightness of chest or throat, and hypotension have been 
reported in a small number of patients treated with liposome drugs.  In most patients, these 
reactions generally resolve within 24 hours after the infusion is terminated.  In some patients, the 
reaction resolves by slowing the rate of infusion.  Most patients who experienced acute infusion 
reactions to liposome drugs are able to tolerate further infusions without complications. 
6.1.5.10 
Other Potential Toxicities 
MM-398, the liposomal formulation of irinotecan is different from irinotecan in unencapsulated 
formulation, so there is a potential for toxicities other than those caused by irinotecan.  All 
patients should be monitored closely for signs and symptoms indicative of drug toxicity, 


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particularly during the initial administration of treatment. QTc prolongation that occurs in the 
setting of diarrhea induced electrolyte imbalance should be treated by with appropriate 
electrolyte repletion. Once the underlying abnormality is corrected and the ECG abnormalities 
have reversed, treatment may continue under careful monitoring and with appropriate dose 
modification for diarrhea as described above. 
6.1.6 Dose Reductions Due to Toxicity 
The toxicity of each cycle must be recorded prior to the administration of a subsequent cycle and 
graded according to the NCI CTCAE (Version 4.02).  All dose reductions should be based on the 
worst preceding toxicity. 
Dosing may be held for up to 2 weeks from the occurrence to allow for recovery from toxicity 
related to the study treatment.  If the time required for recovery from toxicity is more than 
2 weeks, the patient should be discontinued from the study, unless the patient is benefiting from 
the study treatment, in which case the patient’s continuation on study should be discussed 
between Investigator and Sponsor regarding risks and benefits of continuation.   
If a patient’s dose is reduced during the study due to toxicity, it should remain reduced for the 
duration of the study; dose re-escalation to an earlier dose is not permitted.  Any patient who has 
2 dose reductions and experiences an adverse event that would require a third dose reduction 
must be discontinued from study treatment.  
6.1.6.1 
Hematologic Toxicities 
Prior to each MM-398 dosing, patients must have: 
 
ANC ≥ 1500/mm3 
 
Platelet count ≥ 100,000/mm3 
Treatment should be delayed to allow sufficient time for recovery, and upon recovery, treatment 
should be administered according to the guidelines in the tables below.  If the patient had febrile 
neutropenia, the ANC must have resolved to ≥ 1500/mm3 and the patient must have recovered 
from infection. 
Table 7: MM-398 Dose Modifications for Neutrophil Count 
Worst 
CTCAE 
Grade 
ANC 
Levels 
(cells/mm3) 
Modification 
Occurrence 
MM-398 adjustment in 
patients receiving 60 
mg/m2 (and have not been  
escalated to 80 mg/m2) 
MM-398 adjustment in 
patients receiving 80 
mg/m2 (if dose escalated  
from 60 mg/m2) 
Grade 1 or 2 
1000-1999 
Any 
Same as previous dose 
Same as previous dose 
Grade 3 or 4 
<1000 
First 
50 mg/m2 
60 mg/m2 
Second 
40 mg/m2 
50 mg/m2 
Third 
Discontinue from MM-398 
Discontinue from MM-398 


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Table 8: MM-398 Dose Modifications for Other Hematologic Toxicities 
Worst 
CTCAE 
Grade 
Modification 
Occurrence 
MM-398 adjustment in  
patients receiving 60 mg/m2  
(and have not been  
escalated to 80 mg/m2) 
MM-398 adjustment in  
patients receiving 80 mg/m2 
(if dose escalated  
from 60 mg/m2) 
Grade 1 or  2 
Any 
Same as previous dose 
Same as previous dose 
Grade 3 or 4 
First 
50 mg/m2 
60 mg/m2 
Second 
40 mg/m2 
50 mg/m2 
Third 
Discontinue from MM-398 
Discontinue from MM-398 
6.1.6.2 
Non-hematologic Toxicities   
Treatment should be delayed until diarrhea resolves to < Grade 1, and for other Grade 3 or 4 
non-hematological toxicities, until they resolve to Grade 1 or baseline.  Guidelines for dose 
adjustment of MM-398 for drug related diarrhea and other Grade 3 or 4 non-hematological 
toxicities are provided below. 
Table 9: MM-398 Dose Modifications for Diarrhea 
Worst 
CTCAE 
Grade 
Modification 
Occurrence 
MM-398 adjustment in  
patients receiving 60 mg/m2  
(and have not been  
escalated to 80 mg/m2) 
MM-398 adjustment in  
patients receiving 80 mg/m2 
(if dose escalated  
from 60 mg/m2) 
Grade 1 or 2 
Any 
Same as previous dose 
Same as previous dose 
Grade 3 or 4 
First 
50 mg/m2 
60 mg/m2 
Second 
40 mg/m2 
50 mg/m2 
Third 
Discontinue from MM-398 
Discontinue from MM-398 
Table 10: MM-398 Dose Modifications for Non-hematologic Toxicities Other Than 
Diarrhea, Asthenia and Grade 3 Anorexia 
Worst CTCAE 
Grade 
Modification 
Occurrence 
MM-398 adjustment in  
patients receiving 60 mg/m2  
(and have not been  
escalated to 80 mg/m2) 
MM-398 adjustment in  
patients receiving 80 mg/m2 
(if dose escalated  
from 60 mg/m2) 
Grade 1 or 2 
Any 
Same as previous dose 
Same as previous dose 
Grade 3 or 4 (except 
nausea and vomiting) 
First 
50 mg/m2 
60 mg/m2 
Second 
40 mg/m2 
50 mg/m2 
Third 
Discontinue from MM-398 
Discontinue from MM-398 
Grade 3 or 4 nausea 
and/or vomitinga 
First 
50 mg/m2 
60 mg/m2 
Second 
40 mg/m2 
50 mg/m2 
Third 
Discontinue from MM-398 
Discontinue from MM-398 
a For Grade 3 or 4 nausea and vomiting, dose reduce only if they occur despite optimal anti-emetic therapy 
6.1.6.3 
UGT1A1*28 Homozygous Patients 
Patients will be tested for UGT1A1*28 status at screening.  The result of the test is not required 
prior to the initial dose of MM-398.  Both the starting dose and dose modifications for toxicities 
will be the same for all patients regardless of UGT1A1*28 genotype. 


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6.1.7 Management of Infusion Reactions to MM-398 
Infusion reactions will be defined according to the National Cancer Institute CTCAE (Version 
4.02) definition of an allergic reaction/hypersensitivity as defined below: 
Grade 1: Transient flushing or rash, drug fever < 38° C (< 100.4°F); intervention not 
indicated 
Grade 2: Intervention or infusion interruption indicated; responds promptly to symptomatic 
treatment (e.g., antihistamines, NSAIDS, narcotics); prophylactic medications 
indicated for <= 24 hrs. 
Grade 3:  Symptomatic bronchospasm, with or without urticaria; parenteral intervention 
indicated; allergy-related edema/angioedema; hypotension 
Grade 4:  Life-threatening consequences; urgent intervention indicated 
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 650 mg orally, 
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 diphenhydramine hydrochloride 50 mg 
IV, dexamethasone 10 mg IV, and acetaminophen 650 mg orally. 
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-398 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-398 will be permitted 
For patients who experience a Grade 1 or Grade 2 infusion reaction, future infusions may be 
administered at a reduced rate (over 120 minutes), at the discretion of the Investigator.   
For patients who experience a second grade 1 or 2 infusion reaction, administer dexamethasone 
10 mg IV.  All subsequent infusions should be premedicated with diphenhydramine 
hydrochloride 50 mg IV, dexamethasone 10 mg IV, and acetaminophen 650 mg orally or as per 
institutional guidelines. 


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6.2 
Description of Ferumoxytol 
Ferumoxytol is an iron replacement product indicated for the treatment of iron deficiency anemia 
in adult patients with chronic kidney disease.  Although not approved as an indication, 
ferumoxytol has also been used as an imaging agent in cancer patients and will be utilized as 
such in this study as opposed to an iron replacement product.   
6.2.1 Storage and Handling of Ferumoxytol 
Ferumoxytol must be stored at controlled room temperature (20° to 25°C [68° to 77°F]). 
Excursions to 15° – 30°C (59° – 86°F) are permitted. 
6.2.2 Packaging and Labeling of Ferumoxytol 
Ferumoxytol (30 mg/mL) is available for intravenous injection in single use vials. Each vial 
contains 510 mg of elemental iron in 17 mL. Ferumoxytol will be provided to the patient by the 
hospital pharmacy commercial supply or by individual patient prescription. 
6.2.3 Administration of Ferumoxytol 
A single dose of ferumoxytol will be administered at Day 1 by intravenous infusion.  This dosing 
schedule is less intense than the approved label, which recommends two doses of 510 mg 3 to 
8 days apart; however, since ferumoxytol is being used as imaging agent in this study as opposed 
to a replacement product for iron deficiency, a lower dose is more appropriate.  
Dosing will be calculated according to patient weight at 5 mg/kg.  The total single dose will not 
exceed 510 mg, the maximum approved single dose of ferumoxytol.  Care should be taken to 
review and follow the ferumoxytol package insert for safety precautions.  
Do not administer ferumoxytol by undiluted IV injection. This product should be diluted per 
label instructions.  Ferumoxytol should only be administered as an IV infusion in 50-200 mL of 
0.9% sodium chloride or 5% dextrose over a minimum period of 15 minutes following dilution.  
Administer while patient is in a reclined or semi-reclined position. Patients should be closely 
monitored for signs and symptoms of serious allergic reactions, including monitoring blood 
pressure and pulse during administration and for at least 30 minutes following each infusion as 
per the ferumoxytol label instructions. 
If a patient experiences an adverse reaction of grade 2 or above that is related to ferumoxytol, 
dosing of MM-398 should be held until the event is grade 1 or completely resolved.  Any grade 2 
or higher reactions possibly related to ferumoxytol should be reported to the study sponsor 
within 24 hours of administration.  
Additional Information for Health Care Professionals  
 
 Fatal and serious hypersensitivity reactions including anaphylaxis have occurred in 
patients receiving ferumoxytol. Initial symptoms may include hypotension, syncope, 
unresponsiveness, and cardiac/cardiorespiratory arrest with or without signs of rash.  
 
All intravenous (IV) iron products carry a risk of anaphylaxis; therefore, these products 
should be administered only in patients who require IV iron therapy. Ferumoxytol is only 
approved for use in adults with iron-deficiency anemia in the setting of chronic kidney 
disease.  
 
Ferumoxytol is contraindicated in patients with a history of hypersensitivity to 
ferumoxytol or any other IV iron product.  


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 
Only administer ferumoxytol and other IV iron products when personnel and therapies 
are immediately available for the treatment of anaphylaxis and other hypersensitivity 
reactions.  
 
Patients with a history of multiple drug allergies may have a greater risk of anaphylaxis 
with parenteral iron products. Carefully consider the potential risks and benefits before 
administering ferumoxytol to these patients.  
 
Elderly patients 65 years of age and older with multiple or serious comorbidities who 
experience hypersensitivity reactions or hypotension or both following administration of 
ferumoxytol may have more severe outcomes.  
 
Advise patients to immediately report any signs and symptoms of hypersensitivity that 
may develop during and following ferumoxytol administration, such as respiratory 
distress, hypotension, dizziness or lightheadedness, edema, rash, or itching. Advise 
patients to seek immediate medical attention if these signs and symptoms occur.  
 
Allow at least 30 minutes between administration of ferumoxytol and administration of 
other medications that could potentially cause serious hypersensitivity reactions or 
hypotension or both, such as chemotherapeutic agents or monoclonal antibodies.  
6.2.4 Important Treatment Considerations With Ferumoxytol  
Iron levels will be measured in the blood prior to ferumoxytol administration. As currently 
recommended by the American Association of liver Disease, screening for iron overload is 
diagnosed by measuring a fasting morning transferrin saturation ≥ 45% (ratio of serum iron 
divided by the serum total iron binding capacity and expressed as a percentage).  A ferritin level 
of 1000 ng/ml is likely to be also associated with organ damaging levels of iron.  Both 
measurement of transferrin saturation and serum ferritin can be altered by inflammation as 
occurs in malignancy, and may be difficult to interpret.  Actual tissue measurement of liver iron 
is the gold standard for diagnosing iron overload but is associated with some morbidity.  Careful 
interpretation of iron test preferably with an expert is recommended. 
For this protocol, a specific Adverse Event of Special Interest (AESI) includes notification and 
collections of any hypersensitivity reactions associated with the administration of ferumoxytol 
and will follow Serious Adverse Event notification procedures.  Hypersensitivity reaction reports 
including anaphylaxis/ anaphylactoid reactions should include individual signs and symptoms, 
time to onset, time to resolution and any intervention or medication given for the treatment 
thereof.   
Additional Information for Health Care Professionals  
 
Fatal and serious hypersensitivity reactions including anaphylaxis have occurred in 
patients receiving ferumoxytol. Initial symptoms may include hypotension, syncope, 
unresponsiveness, and cardiac/cardiorespiratory arrest with or without signs of rash.  
 
All intravenous (IV) iron products carry a risk of anaphylaxis; therefore, these products 
should be administered only in patients who require IV iron therapy. Ferumoxytol is only 
approved for use in adults with iron-deficiency anemia in the setting of chronic kidney 
disease.  
 
Ferumoxytol is contraindicated in patients with a history of hypersensitivity to 
ferumoxytol or any other IV iron product.  


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 
Only administer ferumoxytol and other IV iron products when personnel and therapies 
are immediately available for the treatment of anaphylaxis and other hypersensitivity 
reactions.  
 
Patients with a history of multiple drug allergies may have a greater risk of anaphylaxis 
with parenteral iron products. Carefully consider the potential risks and benefits before 
administering ferumoxytol to these patients.  
 
Elderly patients 65 years of age and older with multiple or serious comorbidities who 
experience hypersensitivity reactions or hypotension or both following administration of 
ferumoxytol may have more severe outcomes.  
 
Advise patients to immediately report any signs and symptoms of hypersensitivity that 
may develop during and following ferumoxytol administration, such as respiratory 
distress, hypotension, dizziness or lightheadedness, edema, rash, or itching. Advise 
patients to seek immediate medical attention if these signs and symptoms occur.  
 
Allow at least 30 minutes between administration of ferumoxytol and administration of 
other medications that could potentially cause serious hypersensitivity reactions or 
hypotension or both, such as chemotherapeutic agents or monoclonal antibodies. 
6.3 
Drug Accountability 
The Investigator and investigational site staff are responsible for maintaining an accurate 
inventory and accounting of MM-398.  A record of all vials of study drug received and 
administered will be maintained on an investigational drug inventory form provided by the 
Sponsor.  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 
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. 
At each monitoring visit, 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.  
At the conclusion of the study, the monitor will package and ship all unused vials of study drug 
back to Sponsor for destruction.  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. 
6.4 
Concomitant Therapy 
All concurrent medical conditions and complications of the underlying malignancy will be 
treated at the discretion of the Investigator according to acceptable local standards of medical 
care.  Patients should receive analgesics, antiemetics, antibiotics, anti-pyretics, and blood 
products as necessary. Glucocorticoids and anti-seizure medication is permitted for patients with 
brain metastases (Expansion Phase Cohort 3; see restrictions on anti-convulsants in section 6.5 


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below). Although warfarin-type anticoagulant therapies are permitted, careful monitoring of 
coagulation parameters is imperative, in order to avoid complications of any possible drug 
interactions.  All concomitant medications, including transfusions of blood products, will be 
recorded on the appropriate case report form.  
Guidelines for treating certain medical conditions are discussed below; however, institutional 
guidelines for the treatment of these conditions may also be used.  The concomitant therapies 
that warrant special attention are discussed below. 
6.4.1 Antiemetic Medications 
Dexamethasone and a 5-HT3 blocker (e.g., ondansetron or granisetron) will be administered to 
all patients as premedications unless contraindicated for the individual patient.  Antiemetics will 
also be prescribed as clinically indicated during the study period. 
6.4.2 Granulocyte Colony Stimulating Factors 
Use of granulocyte colony-stimulating factors (G-CSF) is permitted to treat patients with 
neutropenia or neutropenic fever; prophylactic use of G-CSF will be permitted only in those 
patients who have had at least one episode of grade 3 or 4 neutropenia or neutropenic fever while 
receiving study therapy or have had documented grade 3 or 4 neutropenia or neutropenic fever 
while receiving prior anti-neoplastic therapy. 
6.4.3 Therapy for Diarrhea 
Acute diarrhea and abdominal cramps, developing during or within 24 hours after MM-398 
administration, may occur as part of a cholinergic syndrome.  The syndrome will be treated with 
atropine.  Prophylactic or therapeutic administration of atropine should be considered in patients 
experiencing cholinergic symptoms during the study.  
Diarrhea can be debilitating and on rare occasions is potentially life-threatening. Diarrhea should 
be managed according to institutional guidelines, or according to the guidelines developed by an 
ASCO panel for treating chemotherapy-induced diarrhea, abstracted below [23].     
Table 11: Recommendations for Management of Chemotherapy Induced Diarrhea 
Clinical Presentation 
Intervention 
Diarrhea, any grade 
Oral loperamide (2 mg every 2 hours for irinotecan induced 
diarrhea): continue until diarrhea-free for  12 hours 
Diarrhea persists on loperamide for 
> 24 hours 
Oral fluoroquinolone x 7 days 
Diarrhea persists on loperamide for 
> 48 hours 
Stop loperamide; hospitalize patient; administer IV fluids 
ANC < 500 cells/L, regardless of 
fever or diarrhea  
Oral fluoroquinolone (continue until resolution of neutropenia) 
Fever with persistent diarrhea, even 
in the absence of neutropenia 
Oral fluoroquinolone (continue until resolution of fever and 
diarrhea) 
6.5 
Prohibited Therapy 
The following drugs are noted in the irinotecan prescribing information as interacting with 
irinotecan: St. John’s Wort, CYP3A4 inducing anticonvulsants (phenytoin, phenobarbital, and 
carbamazepine), ketoconazole, itraconazole, troleandomycin, erythromycin, diltiazem and 


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verapamil.  Treatment with these agents and any other that interact with irinotecan, should be 
avoided wherever possible.  
Thus, the following therapies are not permitted during the trial: 
 
Other anti-neoplastic therapy, including cytotoxics, targeted agents, endocrine therapy or 
other antibodies  
 
Potentially curative radiotherapy; palliative radiotherapy is permitted 
 
Any other investigational therapy is not permitted 
7 Study Procedures 
7.1 
Clinical Procedures 
7.1.1 Medical History 
Medical history will include all pertinent prior medical conditions, surgeries or other medical 
procedures.   
7.1.2 Physical Examination 
Physical examination will include a careful assessment of all body systems, including the skin; 
central and peripheral nervous system; eyes, ears, nose and throat; respiratory and cardiovascular 
systems; abdomen and extremities.  Particular attention should be made to areas of possible 
neoplastic involvement.   
7.1.3 Vital Signs 
Vital signs will include weight, resting blood pressure, pulse, respiratory rate and temperature.   
7.1.4 ECOG Performance Score 
The Eastern cooperative oncology group (ECOG) Performance Score will be obtained by the PI 
or his/her designee by questioning the patient about their functional capabilities.   
7.1.5 ECG 
A 12 lead ECG will include a description of the cardiac rate, rhythm, interval durations and an 
overall impression. 
7.1.6 Disease Evaluation 
Tumor response will be evaluated according to the Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 or modified RECIST criteria (for CNS disease only; Cohort 3), to 
establish disease progression by computed tomography (CT) or MRI. At baseline, all Expansion 
Phase patients with extracranial disease will also have a standard fluorodeoxyglucose (18F-FDG) 
positron emission tomography (PET)/CT scan in order to identify lesions that are metabolically 
active; follow-up PET/CT scans are not required. 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. Patients in Cohort 3 with both CNS and non-CNS disease will have 
separate evaluations of each disease type.  Investigators should select target and non-target 
lesions in accordance with RECIST v1.1 guidelines, or modified RECIST criteria as specified 
below for brain lesions. Follow up measurements and overall response should also be in 
accordance with these guidelines, unless otherwise specified below (Cohort 3 only). 


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7.1.6.1 
Modified RECIST Criteria for Cohort 3 
Tumor response for CNS disease will be evaluated according to modified RECIST criteria as 
described previously [37], and as specified below. A maximum of five target lesions (≥ 5 mm in 
size of long axis, with at least one lesion measuring ≥ 1 cm) will be identified at baseline, with 
the remaining lesions followed as non-target lesions. Selection of necrotic or cystic lesions as 
target lesions should be avoided if other solid lesions are present. All target lesions should be 
measured for each follow-up disease evaluation, even if lesion size decreases to < 5 mm. If a 
lesion is too small to measure, a default value of 3 mm should be used. Table 12 describes the 
definition of response for CNS disease only; non-CNS disease will be assessed separately 
according to RECIST v1.1. 
Table 12: CNS Response Assessment for Cohort 3 
Response 
Definition 
Complete Response (CR) 
Disappearance of all target and non-target lesions; or lesions do not show 
any gadolinium enhancement and are completely necrotic 
Partial Response (PR) 
≥ 30% decrease in the sum longest dimension (LD) of target lesions 
(taking as reference 
the baseline sum diameters) and an absolute decrease of at least 5 mm in at 
least one target lesion; non-target lesions do not meet the criteria for PD 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study; non-target lesions do not meet the criteria for PD 
Progressive Disease (PD) 
≥ 20% increase in the sum LD of target lesions (taking as reference the 
smallest sum on study, including the baseline sum if that is the smallest on 
study) and an absolute increase in size of at least 5 mm in at least one 
target lesion, or the appearance of one or more new lesions of at least 6 
mm in size; and/or growth of non-target lesion(s) sufficient to determine 
unequivocal progression 
7.1.6.2 
Criteria for Treatment Termination due to Progressive Disease 
Pilot Phase and Expansion Phase patients in Cohorts 1 and 2 will be discontinued from study 
treatment due to progressive neoplastic disease, assessed by RECIST v1.1 as described in section 
7.1.6 above. Patients in Expansion Phase Cohort 3 will have CNS and non-CNS disease assessed 
separately. Patients in Cohort 3 should be discontinued from study treatment for radiographic 
evidence of progressive disease (PD) in the CNS (see Table 12), however, patients may stay on 
study treatment at the Investigator’s discretion for the following reasons: 
 
Radiographic evidence of non-CNS PD only (no evidence of CNS PD) 
 
Symptomatic progression of CNS disease (without radiographic evidence of PD) 
If there is evidence that a patient in Expansion Phase Cohort 1 or Cohort 2 experiences PD yet 
has also derived clear clinical benefit from study treatment, then the Investigator, Medical 
Monitor and Sponsor may review the specifics of the case at the request of the Investigator.  
Such a patient may remain on study if the consensus judgment is that continued treatment is in 
the patient’s best interest.   


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7.2 
Laboratory Procedures 
7.2.1 Complete Blood Count 
A complete blood count will include a white blood count (WBC) and differential, hemoglobin, 
hematocrit and platelet count. 
7.2.2 Serum Chemistry 
Serum chemistry will include electrolytes (sodium, potassium, chloride and bicarbonate), BUN, 
serum creatinine, glucose, bilirubin, AST, ALT, alkaline phosphatase, lactate dehydrogenase, 
uric acid, total protein, albumin, calcium, magnesium and phosphate.  Iron levels (ferritin, iron 
and transferrin saturation) will be measured at the screening visit, at the time of the first MM-398 
dose of Cycle 2 (first additional cycle) and at the 30 Day Follow-up visit.  
7.2.3 Biomarker Samples 
Whole blood and plasma will be collected to potentially identify factors that may correlate with 
tumor response, sensitivity or resistance to MM-398, and MM-398 PK.  Examples of potential 
analyses include cytokine levels (e.g. MCSF1, and IL-6), growth factors (e.g. IGF1 and EGFR 
family receptors and ligands), enzyme levels (e.g. MMP9).  
7.2.4 Coagulation Profile 
A coagulation profile will include a partial thromboplastin time and an international normalized 
ratio.   
7.2.5 UGT1A1*28 
A whole blood sample will be collected from all patients at baseline to test for UGT1A1*28 
allele status. The result is not needed prior to the initial dose of MM-398. Both the starting dose 
and dose modifications for toxicities will be the same for all patients regardless of UGT1A1*28 
genotype, as described in section 6.1.6.3. 
7.2.6 Urinalysis 
A urinalysis will include descriptions of color and clarity; pH; specific gravity; and analyses of 
blood, glucose, ketones and total protein. A microscopic examination of the urine, to include 
WBC, RBC, bacteria and casts will be performed if the urinalysis is abnormal. 
7.2.7 Urine or Serum Pregnancy Test 
A urine or serum pregnancy test will be obtained for all females of childbearing potential.  
Exempt female patients will include those who have undergone a bilateral oophorectomy or 
hysterectomy or who are menopausal (defined as absence of a menstrual cycle for at least 
12 consecutive months). 
7.2.8 Pharmacokinetic Assessments  
Plasma samples will be collected to determine the levels of MM-398 and SN-38.  Additional 
analytes which may impact the pharmacokinetics of MM-398 may also be measured from this 
sample. Directions for processing and shipping the PK plasma samples can be found in the study 
manual. The PK time points outlined in Table 13 below will be drawn during Cycles 1-3. 


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Table 13: Summary of PK Timepoints in Treatment and Follow-up Phases 
Sample 
Time-point (Cycles 1-3) 
Window 
1 
Immediately prior to MM-398 infusion on Day 1 
-5 mins 
2 
At the end of the MM-398 infusion 
+5 mins 
3 
+2 hours after the completion of the MM-398 infusion 
±30 mins 
4 
+ 48 hours after the completion of the MM-398 infusion  
±24 hours 
5 
+168 hours/7 days after the completion of the MM-398 infusion 
±24 hours 
6 
Immediately prior to MM-398 infusion on D15 
-24 hours 
7 
30 day follow up visit 
--- 
7.3 
Tissue Collection 
7.3.1 Fresh Tumor Biopsies 
7.3.1.1 
Pilot Phase Biopsies 
Two biopsies will be collected on Day 4 of the ferumoxytol phase and two biopsies will be 
collected three days after the first dose of MM-398.   
On Day 4 of the ferumoxytol phase, the lesion(s) selected for biopsy will be based on the results 
of the FMX-MRI obtained on Days 1, 2 and 4. The first core biopsy will be in the region of the 
tumor that shows the greatest signal change based on FMX-MRI and the second core biopsy will 
be taken from the region that shows the least signal change based on FMX-MRI.   
On Cycle 1 Day 4 of the MM-398 Treatment phase, the lesion(s) selected for biopsy will be 
based on the results of the FMX-MRI obtained on Days 1, 2 and 4 of the ferumoxytol phase. The 
post-treatment biopsies will be collected from a previously non-biopsied lesion.  The first core 
biopsy will be in the region of the tumor that shows the greatest signal change on either the T2* 
or T1 sequences, based on FMX-MRI.  The second core biopsy will be taken from the region 
that shows the least signal change based on FMX-MRI, avoiding obvious areas of necrosis.  
7.3.1.2 
Expansion Phase Biopsies 
A Post-treatment core biopsy must be collected at 72 h (+/- 1 day) after the C1D1 administration 
of MM-398. Any lesion that is amenable to a safe multi-pass core biopsy procedure may be 
selected. Expansion Phase patients in Cohort 3 with central nervous system (CNS) disease only 
are not required to undergo biopsy; however patients in Cohort 3 with non-CNS disease will be 
required to submit a biopsy sample, if a core biopsy can be safely obtained from a site of 
extracranial disease. Three passes should be obtained with the first two passes snap frozen and 
the third pass, if available, formalin fixed; See Laboratory Manual for details on processing and 
handling of the biopsy samples. Frozen samples will be used to measure tumor drug (CPT-11) 
and metabolite (SN-38) levels in order to further establish the mechanism of action of MM-398 
and evaluate the relationship with tumor ferumoxytol levels as measured by FMX-MRI.  
Formalin fixed samples may be used to explore potential markers of sensitivity and resistance to 
irinotecan other pharmacodynamic markers related to activity of MM-398. 
7.3.2 Archived Tumor Samples 
Archived tumor blocks or unstained FFPE slides containing tumor tissue, prepared at the time of 
initial diagnosis and at the time of metastasis (if available) will be collected from each patient. 
Archived paraffin blocks may be used if available and will be returned to the site upon sectioning 
by sponsor or sponsor designated central lab. Samples will be used to explore potential markers 


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of sensitivity and resistance to irinotecan, including but not limited to the following: DNA 
damage repair pathways (e.g. Topo1, BRCA1/2, and SLFN11), growth factor pathways (IGF1 
and EGFR family receptors and ligands), and factors involved in CPT-11 conversion to SN-38 
(e.g. macrophage content and CES activity).  
7.4 
Ferumoxytol Magnetic Resonance Imaging 
It is anticipated that the MRI parameters will need to be optimized in patients that are enrolled at 
the beginning of the study and/or in the Expansion Phase, in order to assess any correlations 
between FMX-MRI signal and TAMs, pharmacodynamic markers, or tumor response.  A 
detailed FMX-MRI protocol is included in the study imaging manual, but briefly, each patient 
will be required to undergo their FMX-MRIs on the same scanner to reduce inter-scan 
variability.  Each MRI study will be evaluated for image quality and signal characteristics of 
tumors and reference tissue on T1-, T2- and T2*- weighted sequences. Once a completed set of 
images from each patient has been received, the images will be loaded onto the viewing 
workstation for qualitative review and then sent to a quantitative lab for analysis.  
During the Expansion Phase, multiple MR images will be collected on Day 1-Day 2 of the 
ferumoxytol period, at various time points depending on the scan group to which the patient is 
assigned. The body areas to be scanned will be determined by the location of the patient’s 
disease; detailed instructions are described in the study imaging manual. All patients will have a 
baseline image acquired prior to the ferumoxytol infusion, and either a second successive image 
(baseline repeat; Scan Group 1) or a second image occurring 1-4 h after the end of ferumoxytol 
administration (Scan Groups 2 and 3). All patients will return on Day 2 for a 24 hour (16-24 h 
window) FMX-MRI using the same protocol and sequences as on Day 1. Patients enrolled into 
Scan Groups 1 and 2 will require one additional scan either at 24 h or 2 weeks, for a total of 4 
scans. Patients will be assigned in an alternating fashion to Scan Groups 1 and 2 before 
enrollment into Scan Group 3 begins. See Table 14 below for additional details on scan groups 
and required time points. 
Table 14: Summary of Expansion Phase MRI Scan Groups (Cohorts 1 and 2) 
Scan 
Group 
Na 
Baseline 
Baseline 
(repeat) 
1-4 h 
24 h 
(16-24 h) 
24 h 
(repeat) 
2 wk (+/- 1 Day) 
Baseline 
1 
5 
X 
X 
 
X 
 
X 
2 
5 
X 
 
X 
X 
X 
 
3 
10 
X 
 
X 
X 
 
 
a Enrollment into Scan Groups 1 and 2 may be increased at the discretion of the Sponsor, in the event that any of 
the images are not evaluable, or it is determined that more information is needed from the additional scan time 
points. In this case, enrollment into Scan Group 3 will be decreased by a corresponding number of patients. 
Table 15: Expansion Phase Cohort 3 MRI Scan Time Points 
Scan 
Group 
N 
Baseline Baseline 
(repeat) 
1-4 h 
24 h 
(16-24 h) 
24 h 
(repeat) 
2 wk (+/- 1 Day) 
Baseline 
4 (cohort 3) 
10 
Xa 
 
Xb 
Xa 
 
 
a Patients with extra-cranial disease will have MRIs of two body areas at baseline and 24 h: one brain scan and 
one body scan (body scan will capture the majority of the patient’s extra-cranial disease; see imaging manual 
for details) 
b Brain scan only will be completed at this time point 


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8 Schedule of Assessments 
8.1 
Pilot Phase (Closed) 
PILOT PHASE SCHEDULE OF ASSESSMENTS REMOVED (MM-398-01-01-02 Version 
3.0).  This portion of the trial has been completed and the schedule of assessments has been 
removed from this version of the protocol to reduce confusion during operation of Expansion 
phase.  


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8.2 
Expansion Phase 
Procedure 
Screening 
Period 
Ferumoxytol 
(FMX)Period 
MM-398 Treatment Period 
Follow Up 
Period 
-28d 
Day 1 
Day 2 
Cycle 123, 2, and 3 
Additional Cycles  
(every 1 month)28 
Every 8w 
after 1st dose 
+30d22 
D1 
D3 
D8 
D15 
D1 
D15 
Informed consent 
X1 
 
 
 
 
 
 
 
 
 
 
Medical history 
X1 
 
 
 
 
 
 
 
 
 
 
Demographics 
X1 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X2 
 
 
X 
 
 
 
X 
 
 
X 
Vital signs 
X2 
X3 
 
X 
 
X 
X 
X 
X 
 
X 
ECOG PS 
X2 
 
 
X 
 
 
 
X 
 
 
X 
CBC 
X2 
 
 
X 
 
X 
X 
X 
X 
 
X 
Serum chemistry21 
X2,16 
 
 
X 
 
X 
X 
X16 
X 
 
X16 
UGT1A1*28 
X1,17 
 
 
 
 
 
 
 
 
 
 
Coagulation profile21 
X2 
 
 
X 
 
 
 
X 
 
 
X 
Urinalysis 
X2 
 
 
 
 
 
 
 
 
 
X 
Pregnancy test 
X2 
 
 
 
 
 
 
 
 
 
X 
ECG 
X1,4 
 
 
 
 
 
 
 
 
 
X4 
FMX-MRI 
 
X5 
X6 
 
 
 
X7 
 
 
 
 
Ferumoxytol infusion 
 
X25 
 
 
 
 
 
 
 
 
 
Tumor biopsy8 
 
 
 
 
X9 
 
 
 
 
 
 
Archived tissue10 
X 
 
 
 
 
 
 
 
 
 
 
Plasma for PK 
 
 
 
X11 
X12 
X13 
X14 
 
 
 
X 
Biomarker analysis18,21 
 
 
 
X14 
 
 
 
X 
 
 
X 
Concomitant meds 
X1 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
MM-398 dosing15 
 
 
 
X 
 
 
X 
X 
X 
 
 
AE reporting 
Continuous Monitoring 
Disease evaluation 
X1,24 
 
 
 
 
 
 
 
 
X20 
X19 
1 Procedures to be completed within 28 days of ferumoxytol dose 
2 Procedures to be completed within 7 days of ferumoxytol dose 
3 Body weight to be collected within 7 days of ferumoxytol dose 
4 Two independent readings at least 1 minute apart 
5 Procedure completed at Cycle 2 only 
6 One reading prior to the start of the MM-398 infusion and one reading post infusion of MM-398 is required 
7 Two FMX-MRI collected as outlined in section 7.4 and Table 14 and Table 15 
8 One MRI at 24 h (16-24 hour window) except Scan Group 2, who will undergo 2 repeat scans at the 24 h timepoint 
9 For Scan Group 1 only, one MRI scan will be performed during Cycle 1 only (±1 day) 


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10 Biopsy required for Cohorts 1 and 2, as well as Cohort 3 patients with extracranial disease that can be safely biopsied 
11 Post-Treatment Biopsy collected 72h post C1D1 MM-398 infusion 
12 Collection of archived tumor block or paraffin embedded slides, if available 
13 Samples collected at the following timepoints on C1D1 of the MM-398 Treatment Phase: just prior to the MM-398 infusion (-5 mins); at the end of  the 
MM-398 infusion (+5 mins); +2 hours after the completion of the MM-398 infusion (±30 mins);  
14 Sample collected +48 hours after the completion of the MM-398 infusion (±24 hours) 
15 Sample collected +168 hours/7 days after the completion of the MM-398 infusion (±24 hours) 
16 Sample obtained just prior to dosing with MM-398 (-24 hour window)  
17 MM-398 administration should occur ±2 days from scheduled date of administration 
18 In addition to normal labs, iron levels will be measured at the screening visit, at the time of the first MM-398 dose of Cycle 2 (first additional cycle) and at 
the 30 Day Follow-up visit. 
19 Result not required prior to enrollment in the study., but patients positive for UGT1A1*28 Both the starting dose and dose modifications for toxicities will 
be the same for all patients regardless of UGT1A1*28 genotype, may have future doses reduced as described in section 6.1.6.3 
20 Blood will be collected for biomarker analyses 
21 Unless completed in the prior 6 weeks 
22 Disease evaluations should be done every 8 weeks (± 7 days) after 1st dose  
23 Visit for samples should be obtained ± 2 days from scheduled date of collection 
24 The 30-Day Follow-Up visit should occur 30 days (± 7 days) after last dose  
25 The Cycle 1 Day 1 visit should occur within 7 days of ferumoxytol infusion 
26 In addition to contrast-enhanced CT and/or MRI, 18F-FDG PET/CT scan required at baseline only (patients with extracranial disease only) 
27 Administer while patient is in a reclined or semi-reclined position. Patients should be closely monitored for signs and symptoms of serious allergic 
reactions, including monitoring blood pressure and pulse during administration and for at least 30 minutes following the infusion as per the ferumoxytol 
label instructions. Ferumoxytol administration outlined in section 6.2.3. 


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9 Adverse Event Reporting 
9.1 
Definitions 
9.1.1 Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign, including abnormal laboratory findings, symptoms, or diseases temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.  Worsening of a medical condition for which the efficacy of the study drug is 
being evaluated will not be considered an adverse event.  
9.1.2 Unexpected Adverse Event 
An unexpected adverse event is one for which the nature or severity of the event is not consistent 
with the applicable product information, e.g., the Investigator’s Brochure. 
9.1.3 Adverse Events of Special Interest 
For this protocol the collection of Adverse Events of Special Interest (AESI) will be reported 
following serious adverse event reporting procedures as described below.   
For this protocol, a specific AESI includes notification and collections of hypersensitivity 
reactions associated with the administration of ferumoxytol and will follow Serious Adverse 
Event notification procedures.  Hypersensitivity reaction reports including 
anaphylaxis/anaphylactoid reactions should include individual signs and symptoms, time to 
onset, time to resolution and any intervention or medication given for the treatment thereof.   
9.1.4 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 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly or birth defect 
 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed above.  Examples of such events are intensive 
treatment in an emergency room for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; or development of drug dependency or 
drug abuse. 
The term “severe” is often used to describe the intensity (severity) of an event; the event itself 
may be of relatively minor medical significance (such as a severe headache).  This is not the 
same as “serious”, which is based on patient/event outcome or action criteria usually associated 
with events that pose a threat to a patient’s life or functioning.    


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Death due to disease progression is not considered an SAE and should not be recorded as such. 
Death due to disease progression should be recorded on the appropriate form in the electronic 
data capture system. If the primary cause of death is something other than disease progression, 
then the death should be reported as an SAE with the primary cause of death as the event term, as 
death is typically the outcome of the event, not the event itself. 
9.2 
Documenting Adverse Events 
SAE reporting will begin on the date the patient provides informed consent to participate in the 
study. Treatment-emergent adverse event reporting will begin as of the administration of 
ferumoxytol. The Investigator should elicit information regarding the occurrence of adverse 
events through open-ended questioning of the patient, physical examination and review of 
laboratory results.   
All adverse events, whether serious or not, will be recorded in the source documents and the 
adverse event page of the case report form (except as noted below).  All new events, as well as 
those that worsen in intensity or frequency relative to baseline, which occur after first 
administration of study drug through 30 days following the last dose of study drug, must be 
recorded.  Adverse events should be followed through resolution, where possible. Adverse 
events that are ongoing at the time of treatment discontinuation should be followed through the 
30 day follow up assessment. However, new adverse events considered by the Investigator to be 
related to MM-398 or ferumoxytol, must be reported any time the Investigator becomes aware of 
such an event, even if this occurrence is more than 30 days after the last dose of study drug.  
Laboratory, vital signs 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 
 
Action taken: none; change in the study drug administration (e.g., temporary interruption 
in dosing); drug treatment required; non-drug treatment required; hospitalization or 
prolongation of hospitalization required (complete serious adverse event page); 
diagnostic procedure performed; patient discontinued from the study (complete Final 
Visit Section of the case report form) 
 
Outcome:  resolved without sequelae; resolved with sequelae; event resolving; event 
ongoing; patient died (notify the Sponsor immediately, and complete the Serious Adverse 
Event page and the Final Visit section of the case report form) 
9.3 
Reporting Serious Adverse Events 
All fatal or life-threatening adverse events or adverse event of special interest (AESI) must be 
reported to the medical monitor immediately by telephone or e-mail.  Within 24 hours of 
knowledge of the event, the Serious Adverse Event Form must be faxed to the appropriate 
contact 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. Source documentation of 


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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 MM-398, even if asymptomatic or not fulfilling a 
seriousness criterion, the overdose is to be reported to the Sponsor immediately (within 1 
working day) using the AE and SAE forms. Overdose of MM-398 will be defined as ≥ 133% of 
planned dose. 
All other serious adverse events must be reported to the appropriate contact within 24 hours of 
becoming aware of the event by phone, e-mail or fax. The Serious Adverse Event Form must 
also be faxed to the appropriate contact 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 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 
Institutional Review Board (IRB). 
9.4 
Determining the Severity and Relatedness of Adverse Events 
9.4.1 Grading the Severity of an Adverse Event 
Each adverse event will be graded according to the NCI CTCAE Version 4.02, which may be 
found at http://ctep.cancer.gov/reporting/ctc.html.  For events not listed in the CTCAE, severity 
will be designated as mild, moderate, severe or life threatening or fatal which correspond to 
Grades 1, 2, 3, 4 and 5, respectively on the NCI CTCAE, with the following definitions: 
 
Mild: an event not resulting in disability or incapacity and which resolves without 
intervention;  
 
Moderate: an event not resulting in disability or incapacity but which requires 
intervention;  
 
Severe: an event resulting in temporary disability or incapacity and which requires 
intervention;  
 
Life-threatening: an event in which the patient was at risk of death at the time of the 
event 
 
Fatal: an event that results in the death of the patient 
9.4.2 Relatedness to Study Drug 
The Investigator must attempt to determine if there exists reasonable possibility that an adverse 
event is related to the use of the study drug, according to the following guidelines:   
The Investigator must attempt to determine if an adverse event is in some way related to the use 
of the study drug. This relationship should be described as follows: 


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 
Unlikely:  The event is clearly due to causes distinct from the use of the study drug, such 
as a documented pre-existing condition, the effect of a concomitant medication a new 
condition which, based on the pathophysiology of the condition, and the pharmacology of 
the study drug, would be unlikely related to the use of the study drug 
 
Possible:  The event follows a reasonable temporal sequence from administration of the 
study drug and the event follows a known response pattern to the study drug BUT the 
event could have been produced by an intercurrent medical condition which, based on the 
pathophysiology of the condition, and the pharmacology of the study drug, would be 
unlikely related to the use of the study drug or the event could be the effect of a 
concomitant medication 
 
Probable: The event follows a reasonable temporal sequence from administration of the 
study drug and the event follows a known response pattern to the study drug AND the 
event cannot have been reasonably explained by an intercurrent medical condition which 
or the event cannot be the effect of a concomitant medication 
 
Definite:  The event follows a reasonable temporal sequence from administration of the 
study drug, the event follows a known response pattern to the study drug and based on 
the known pharmacology of the study drug, the event is clearly related to the effect of the 
study drug 
 
Unknown:  Based on the evidence available, causality cannot be ascribed  
9.4.3 Reporting and Follow-up of Pregnancy 
Patients who become pregnant while on study must immediately discontinue MM-398, and the 
pregnancy must be immediately reported to the medical monitor.  Pregnancies occurring up to 
90 days after the completion of the study medication must also be reported to the Sponsor.   
The Investigator should inform the patient of the risks of continuing with the pregnancy and the 
possible effects on the fetus. Monitoring of the patient should continue until conclusion of the 
pregnancy. 
In the event of a pregnancy occurring in the partner of a male patient participating in the study, 
the pregnant partner should be requested to report the pregnancy to the Sponsor. The partner 
should also be informed of the risks of continuing with the pregnancy, the possible effects on the 
fetus, and be followed until conclusion of the pregnancy. 
10 Data Management and Statistical Analysis 
10.1 Case Report Forms 
All data for the patients recruited for the trial will be entered onto electronic case report forms 
(eCRFs) via an Electronic Data Capture system provided by the Sponsor.  The following 
information for the patients who screen-failed will be entered into the database: screening visit 
date, informed consent form, demographics, eligibility, adverse events, concomitant medication 
and procedures, and overall study termination. Only authorized staff may enter data onto the 
eCRFs. If an entry error is made, the corrections to the eCRFs will be made according to eCRF 
guidelines by an authorized member of the site staff.    
10.2 Data Quality Assurance 
Electronic CRFs will be checked for correctness against source document data by the Sponsor’s 
monitor. If any entries into the eCRF are incorrect or incomplete, the monitor will ask the 
Investigator or the study site staff to make appropriate corrections, and the corrected eCRF will 


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again be reviewed for completeness and consistency. Any discrepancies will be noted in the CRF 
system by means of electronic data queries. Authorized site staff will be asked to respond to all 
electronic queries according to the eCRF guidelines. 
10.3 Statistical Analysis 
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 maintained by the 
Sponsor.  The SAP may modify the analysis outlined in the protocol; however, any major 
modifications of the primary endpoint and/or its analysis will also be reflected in a protocol 
amendment. 
No formal hypothesis testing will be performed in the Pilot or Expansion Phases of this study.  
Descriptive statistics will be calculated to summarize categorical and continuous parameters.  
Parameters will be reported by cohort and overall, according to Pilot and Expansion Phase.  
When appropriate, the Pilot and Expansion study phases may be pooled.  At the minimum, 
categorical parameters will be summarized by frequency and percentage, while continuous 
parameters will be summarized by n, mean, standard deviation, median, minimum and 
maximum.  Time-to-event parameters will be graphically displayed using Kaplan-Meier 
estimates.  Median event times and 2-sided 95% confidence intervals will be reported on the 
graphs.  Two-sided 95% confidence intervals (CI) may be displayed for some other parameters.  
All analyses will be performed in SASv9.2 or higher. No interim analysis will be performed. 
A cycle is defined as 28 days in length starting with Cycle 1 Day 1 as the first dose date of MM-
398.  Data will be analyzed according to the cycle in which it actually occurred.   
10.4 Study Populations 
The Pilot and Expansion Phases will be analyzed according to safety and efficacy parameters.  
Similar constraints will be applied according to study phase. 
 
The safety population will include all patients receiving at least one dose of MM-398 or 
ferumoxytol.  Depending upon patients receiving MM-398 and not ferumoxytol and vice 
versa, the safety population may be expanded in order to not dilute any adverse event rate 
 
The efficacy evaluable population includes all patients receiving at least one dose of 
MM-398.  
 
The pharmacodynamic evaluable population includes all efficacy evaluable patients with 
the following:  a) pre-treatment FMX-MRI scan(s) and b) radiological scans at 8 weeks. 
 
The pharmacokinetic population includes patients receiving at least one dose of MM-398 
and blood samples adequately collected at the predefined points. 
10.5 Disposition and Baseline Characteristics 
Study populations (enrolled, safety, efficacy evaluable, pharmacodynamics evaluable, PK) will 
be summarized and displayed as frequencies.  Disposition of patients will be tabulated as those 
discontinued MM-398 and reason for discontinuation.  Demographic and baseline characteristics 
will be summarized.  Medical history and prior medications will be tabulated as well.   
10.6 Efficacy Analysis 
Tumor evaluation will be measured according to Response Evaluation Criteria In Solid Tumors 
(RECIST) version 1.1 (Cohort 1 and 2, and non-CNS disease for Cohort 3) or modified RECIST 


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as defined in section 7.1.6.1 (CNS disease; Cohort 3 only).  Best Overall Response (BOR) is 
defined as the best response as recorded from the start of MM-398 until disease progression.  
Objective Response Rate (ORR) is defined as the proportion of patients with a BOR 
characterized as either a Complete Response (CR) or Partial Response (PR) relative to the total 
number of evaluable patients.  Exact 95% confidence intervals based on the binomial distribution 
will be reported.    
Clinical benefit rate is defined as the proportion of patients with a BOR characterized as a CR, 
PR, or Stable Disease (SD) ≥ 24 weeks.  Proportion of patients relative to the total number of 
evaluable patients will be reported with exact 95% confidence intervals based on the binomial 
distribution.  
Duration of Response (DR) is defined as the time from first documentation of response (CR or 
PR whichever occurs first) to the date of disease progression or to death due to any cause, 
whichever occurs first.   
Progression-free survival (PFS) is defined as the time from first dose of MM-398 to the date of 
radiologic disease progression by RECIST per Investigator or death due to any cause, whichever 
occurs first.  Rules for declaring PFS events versus censors will be described in the SAP.   
A waterfall plot will be used to display BOR with maximum percent decrease in target lesion and 
FMX uptake value at 24 hours. 
FMX uptake (ug/mL and/or %ID/kg) will be summarized as a continuous parameter.  Absolute 
and change from baseline will be summarized.  The number of target lesions decreasing, staying 
the same, increasing relative to FMX uptake with various thresholds will be summarized by 
frequency and percent according to cycle.   Box and whisker plots will be displayed for FMX 
uptake by time point. The relationship between FMX uptake at 1-4 hours and/or 24 hours with 
tumor response will be evaluated using various parameters and methods.  Relationships may be 
explored as appropriate.  Additionally, informal Fisher’s exact test will be used to investigate 
dichotomous FMX cutpoints as related to ORR.  Other graphical procedures may be 
implemented to explore the relationship between FMX and efficacy response. 
10.7 Safety Analysis 
Safety analyses (adverse events and laboratory analyses) will be performed using the safety 
population.  Adverse events will be reported by Sponsor’s current MedDRA version.  Adverse 
event coding will be performed to the lowest level term.  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-398 or ferumoxytol, serious adverse events 
(SAE), TEAE-related to MM-398 or ferumoxytol 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.   
Toxicity grading will be assigned according to NCI CTCAE when possible.  Absolute laboratory 
values will be summarized by visit.  Maximum and minimum change from baseline laboratory 
data will be summarized.  Baseline will be the last measurement taken prior to the first study 
drug administration of MM-398.  Frequency and percent of abnormal laboratory values (L/ULN, 
2*L/ULN) will be assessed.  Shift to most severe toxicity grade will be summarized.  


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Vital signs will be tabulated for the change from baseline by timepoint.  Additional analyses may 
be performed as described in detail within the SAP. 
10.8 Biomarker Subgroup Analysis 
Biomarker subgroup analyses will be analyzed for efficacy parameters (ORR, percent change in 
target lesion size, and PFS or as appropriate).  Graphical displays will be performed when 
appropriate. 
10.9 Pharmacodynamic Marker Analysis 
Spearman pairwise correlations will be computed between the following measurements obtained 
from the Pilot Phase of the study:  
 
FMX-MRI levels 
 
Tumor associated macrophage levels 
 
Tumor irinotecan levels 
 
Tumor SN-38 levels 
Graphical and regression methods will be used to explore potential relationships among 
correlated measurements. In addition, relationships between pharmacodynamics markers and 
efficacy response will be evaluated in an exploratory manner in both the Pilot Phase and 
Expansion phases of the study. 
10.10 Pharmacodynamic Analysis 
Pharmacokinetic parameters will be derived from the blood PK samples and will be analyzed 
using descriptive statistics, including the median, mean and 95% confidence intervals around 
parameter estimates by dose level.  All PK parameters will include Cmax, Tmax, AUC (area 
under the concentration curve), clearance, volume of distribution at steady state (Vdss), and the 
terminal elimination half-life.  Estimation of the pharmacokinetic parameters will be performed 
using standard non-compartmental methods.   
10.11 Sample Size and Statistical Hypothesis 
No formal hypothesis testing will be performed for this study, therefore the Pilot and Expansion 
Phases are not appropriately powered to detect statistical differences.  The Pilot Phase will enroll 
between 12 and 20 patients with various indications, while the Expansion Phase will enroll 
approximately 30 metastatic breast cancer patients across 3 cohorts.   
For the Pilot Phase, Table 16 provides some probabilities of observing a particular adverse event.   
Table 16: Probability to Detect an Adverse Event with N=12 Patients 
True Event Rate 
Probability to Observe  
at Least 1 Event 
Probability to Observe  
More than 1 Event 
0.05 
0.46 
0.12 
0.10 
0.72 
0.34 
0.15 
0.86 
0.56 
0.20 
0.93 
0.73 
0.25 
0.97 
0.84 
The Expansion Phase ORR is estimated to be around 29% with a 95% confidence interval (14.6-
46.3) [36].  Other studies showed similar response rates ranges ranging from 5-32% [33].  


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Hypothesizing a true ORR of 30%, the probability of at least 14 responses of 30 evaluable 
patients would be 0.04.  The probability of at least 13 responses would be 0.084. 
11 Extension Phase 
Following fulfillment of analysis requirements, the Sponsor may elect to reduce follow-up to 
minimally required safety collection.  Patients will be followed per standard of care to assess for 
safety and the required visits in the schedule of assessments are no longer applicable.  All AEs 
meeting SAE reporting requirements or AESI for which the investigator feels are of greater 
incidence or severity than presented in the IB must be submitted as per section 9.3. 
12 Study Administration 
12.1 Pre-study Documentation 
Prior to initiating the trial, the Investigator will provide to the Sponsor or designee 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  
 
A copy of the current medical license for the Investigator and each sub-Investigator 
 
A letter from the IRB 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) 
 
A copy of the IRB-approved informed consent document 
 
The current IRB membership list for the reviewing IRB, or the multiple project assurance 
number from the Federal Wide Assurance program (www.ohrp.osophs.dhhs.gov). 
 
A signed Investigator Protocol Agreement 
 
A completed financial disclosure form for the Investigator and all sub-Investigators 
 
A current laboratory certification for the reference laboratory and curriculum vitae of the 
laboratory director 
 
A list of current laboratory normal values for the reference laboratory  
12.2 Source Documents 
The Investigator will maintain records separate from the eCRFs in the forms 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 as supporting 
documentation for serious adverse events will be de-identified to preserve confidentiality. 
12.3 Trial Ethics 
The study will be performed according to the principles of the Declaration of Helsinki 
(http://www.wma.net/e/policy/b3.htm), the International Conference on Harmonization Guidance 


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on Good Clinical Practice and the requirements of the US FDA regarding the conduct of human 
clinical trials. 
12.4 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.  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 will be given a copy of the signed, dated and witnessed document (the witness signature 
is only required for cases that fit the criteria for needing a witnessed signature).  The provision of 
informed consent will be documented in the medical record.   
12.5 Investigational Review Board 
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.  
The IRB should be duly constituted according to local regulatory requirements.  Approval must 
be in the form of a letter signed by the Chairperson or the Chairperson’s designee, must be on 
official stationary and must include the protocol by name and/or by designated number.  If an 
Investigator is a member of the IRB, then 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 of any SAEs 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 a final summary of the 
results of the trial at the conclusion of the trial.  
12.6 Monitoring 
A clinical monitor will make regularly scheduled trips to the investigational site to review the 
progress of the trial.  The actual frequency of monitoring trips will depend on the enrollment rate 
and performance at each site.  The Investigator will allow the Sponsor or designee 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.  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 with the principles of Good Clinical Practice; 
completion of case report forms; source data verification; study drug accountability and storage; 
facilities and staff. 
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 the above, representatives of the FDA may review the conduct or results of the 
study at the investigational site. The Investigator must promptly inform the Sponsor of any audit 


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requests by health authorities, and will provide the Sponsor with the results of any such audits 
and with copies of any regulatory documents related to such audits. 
In accordance with HIPAA and associated privacy regulations, a patient’s authorization to use 
personally identifiable health information may be required for 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.    
12.7 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.   
12.8 Confidentiality of Biomarker Samples 
Blood 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 for a maximum of 5 years after study completion. At that time, 
any remaining samples will be destroyed. At the time of informed consent, patients will be able 
to refuse long-term storage of these remaining samples. If long-term storage is refused, any 
remaining samples will be destroyed following the initial specified analyses.  Similarly, patients 
may withdraw approval at any time by submitting a written request to their 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 long-term storage may be used by the Sponsor for future 
research. The results from these exploratory analyses may not necessarily be shared with the 
Investigators or the participating patients. 
12.9 Protocol Amendments 
The protocol will only be amended with the consent of the Sponsor and the IRB.  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 their IRB and such amendments will only be implemented after approval of 
the requisite IRB.  All amendments will also be submitted to the FDA 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 the local IRB or EC 
and the Sponsor will immediately notify local regulatory authorities.  


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12.10   Publication 
As the Study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, first presentation or publication of the results of the Study shall be made 
only as part of a publication of the results obtained by all sites performing the Protocol. 
However, if no multicenter publication has occurred within twelve (12) months of the 
completion of this Study at all sites, the Investigator shall have the right to publish or present 
independently the results of this patient to the review procedure set forth herein. The Investigator 
shall provide the Sponsor with a copy of any such presentation or publication derived from the 
Study for review and comment at least forty-five (45) days in advance of any presentation or 
submission for publication. In addition, if requested by the Sponsor, any presentation or 
submission for publication shall be delayed for a limited time, not to exceed ninety (90) days, to 
allow for filing of a patent application or such other measures as the Sponsor deems appropriate 
to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The 
Sponsor shall not use the name(s) of the Investigator and/or the Collaborators in advertising or 
promotional material or publication without having received his/her and/or their prior written 
consent(s). 
The Sponsor or its designee has the right at any time to publish the results of the Study. 
12.11   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 
correspondence, Sponsor correspondence, etc.) for 2 years following the date that the last 
marketing application for the study drug is approved, 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.  
12.12   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 


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 
Safety concerns 
 
Drug supply or manufacturing issues 
 
The Sponsor’s decision to modify or discontinue the development MM-398 
 
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 their IRB if the study is suspended or terminated. 


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Proprietary and Confidential 
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13 Investigator Signature Page 
I have read this protocol and agree that it contains all necessary details for carrying out the study 
as described. I will conduct this study as outlined herein, including all statements regarding 
confidentiality. I will make a reasonable effort to complete the study within the time designated. 
I will provide copies of the protocol and access to all information furnished by the Sponsor to 
study personnel under my supervision. I will discuss this material with them to ensure that they 
are fully informed about the drug and the study. I will identify study personnel conducting study 
specific procedures and appropriately document their training and/or delegated responsibilities. I 
understand that the study may be terminated or enrollment suspended at any time by the Sponsor, 
with or without cause, or by me if it becomes necessary to protect the best interests of the 
patients in the study. 
I agree to conduct this study in full accordance with all applicable regulations and Good Clinical 
Practice (GCP). 
 
 
_________________________________ 
 
 
 
_______________________ 
Signature of Investigator 
 
 
 
 
 
Date 
 
 
________________________________ 
 
 
 
 
 
Print Name of Investigator 
 
 
 
 
 
 
 
 
 
_______________________________ 
 
 
 
______________________ 
On behalf of the Sponsor 
 
 
 
 
 
 
Date 
 
 
 
 Oncology and Endocrinology 
Global Drug Development, R&D 
IPSEN  
 
 
 
PPD
PP


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14 References 
[1] 
Weinstein JS, Varallyay CG, Dosa E, et al. Superparamagnetic iron oxide nanoparticles: 
diagnostic magnetic resonance imaging and potential therapeutic applications in neurooncology 
and central nervous system inflammatory pathologies, a review. Journal of cerebral blood flow 
and metabolism. 2010;30(1):15–35. 
[2] 
Dósa E, Tuladhar S, Muldoon LL, et al. MRI using ferumoxytol improves the 
visualization of central nervous system vascular malformations. Stroke: A Journal of Cerebral 
Circulation. 2011;42(6):1581–1588.  
[3]  
Cunningham, D.  Stage IV NSCLC combinations of platinum with irinotecan have shown 
efficacy. The Oncologist. 2001: (4): 17-23. 
[4] 
Negoro S, Masuda N, Takada Y, et al. Randomised phase III trial of irinotecan combined 
with cisplatin for advanced non-small-cell lung cancer. British Journal of Cancer. 
2003;88(3):335–41.  
[5]  
Nogami, N, Hotta K, Segawa Y, et al.  Phase II study of irinotecan and amrubicin in 
patients with relapsed non-small cell lung cancer: Okayama Lung Cancer Study Group Trial 
0402.  Acta Oncologica.  2012; 51 (6): 768-773. 
[6] 
O'Shaughnessy J, Weckstein D, Vukelja S, et al. Preliminary results of a randomized 
phase II study of weekly irinotecan/carboplatin with or without cetuximab in patients with 
metastatic breast cancer (abstract 308). Breast Cancer Res Treat. 2007;106(suppl 1):S32. 
[7] 
Innocenti F, Kroetz DL, Schuetz E, et al. Comprehensive pharmacogenetic analysis of 
irinotecan neutropenia and pharmacokinetics. Journal of clinical oncology. 2009;27(16):2604–
14.  
[8] 
Mathijssen RHJ, Alphen RJV, Verweij J, et al. Clinical Pharmacokinetics and 
Metabolism of Irinotecan Clinical Pharmacokinetics and Metabolism of Irinotecan (CPT-11 ). 
2001:2182–2194. 
[9] 
Bellanti F, Kågedal B, Della Pasqua O. Do pharmacokinetic polymorphisms explain 
treatment failure in high-risk patients with neuroblastoma? European journal of clinical 
pharmacology. 2011;67 Suppl 1:87–107.  
[10] 
Kawato, Y et al. Intracellular Roles of SN-38, a Metabolite of the Campthothecin 
Derivative CPT-11, in the Antitumor Effect of CPT-11. Cancer Res 1991; 51:4187-4194. 
[11] 
Garcia-Carbonero, R and Supko, J.G. Current Perspectives on the Clinical Experience, 
Pharmacology, and Continued Development of the Camptothecins. Clin Cancer Res 2002; 
8:641-661. 
[12] 
Vanhoefer, U et al. Irinotecan in the Treatment of Colorectal Cencer: Clinical Overview. 
J Clin Oncol. Vol 19, No 5 (March 1), 2001:1501-1518.  
[13] 
Tsai C et al. Nanovector-based therapies in advanced pancreatic cancer.  J Gastrointest 
Oncol 2011; 2: 185-194. 
[14] 
Zschunke F, Salmassi a, Kreipe H, et al. cDNA cloning and characterization of human 
monocyte/macrophage serine esterase-1. Blood. 1991;78(2):506–12.  


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[15] 
Daldrup-Link HE, Golovko D, Ruffell B, et al. MRI of tumor-associated macrophages 
with clinically applicable iron oxide nanoparticles. Clin Cancer Res. 2011;17(17):5695–704.  
[16] 
Irinotecan Hydrochloride U.S. Package Insert. 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm 
[17] 
Feraheme (ferumoxytol) U.S. Package Insert. 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm 
[18] 
Li W, Tutton S, Vu AT et al.  First-pass contrast-enhanced magnetic resonance 
angiography in humans using ferumoxytol, a novel ultrasmall superparamagnetic iron oxide 
(USPIO)-based blood pool agent. J Magn Reson Imaging. 2005; 21:46-52 
[19] 
Neuwelt EA, Varallyay CG, Manninger S, et al.  The potential of ferumoxytol 
nanoparticle magnetic resonance imaging, perfusion, and angiography in central nervous system 
malignancy: a pilot study. Neurosurgery.  2007; 60(4):601-11 
[20] 
Muldoon LL, Varallyay CG, Kraemer DF, et al.  Trafficking of superparamagnetic iron 
oxide particles (Combidex) from brain to lymph nodes in the rat.  Neuropathology and Applied 
Neurobiology.  2004; 30(1): 70-79. 
[21] 
Rausch M, Sauter A, Fröhlich  J et al.  Dynamic patterns of USPIO enhancement can be 
observed in macrophages after ischemic brain damage. Magnetic Resonance Medicine.  2001; 
46: 1018–1022.  
[22] 
Hasan DM, Mahaney KB, Magnotta VA, et al.  Macrophage imaging within human 
cerebral aneurysms wall using ferumoxytol-enhanced MRI: a pilot study.  Arteriscler Thromb 
Vasc Biol 2012; 32(4):1032-1038. 
[23] 
Benson AB, et al. Recommended Guidelines for the Treatment of Cancer Treatment-
Induced Diarrhea . J Clin. Oncol. 2004; 22:2918-2926. 
[24] 
Heusinkveld, M, & Van der Burg, SH Identification and manipulation of tumor 
associated macrophages in human cancers. J Transl Med 2011; 9(1), 216-229. 
[25] 
Harrington, KJ, Mohammadtaghi, S, Uster, PS et al. Effective targeting of solid tumors in 
patients with locally advanced cancers by radiolabeled pegylated liposomes. Clin Cancer Res 
2001; 7(2), 243–54. 
[26] 
Duray, A, Demoulin, S, Hubert, P et al. Immune suppression in head and neck cancers: a 
review. Clin Dev Immunol 2010; 2010(i), 701657.  
[27] 
Kross, KW, Heimdal, JH, & Aarstad, HJ. Mononuclear phagocytes in head and neck 
squamous cell carcinoma. European archives of oto-rhino-laryngology 2010; 267(3), 335–44.  
[28]  
Wöll, E, Greil, R, Eisterer, W et al. Oxaliplatin, irinotecan and cetuximab in advanced 
gastric cancer. Anticancer research 2011; 31(12), 4439–43.  
[29]  
Moehler, M, Mueller, A, Trarbach, T et al. Cetuximab with irinotecan, folinic acid and 5-
fluorouracil as first-line treatment in advanced gastroesophageal cancer: a prospective multi-
center biomarker-oriented phase II study. Annals of oncology 2011; 22(6), 1358–66.  
[30] 
Schønnemann, KR, Yilmaz, M, Bjerregaard, JK et al. Phase II study of biweekly 
cetuximab in combination with irinotecan as second-line treatment in patients with platinum-
resistant gastro-oesophageal cancer. European journal of cancer 2012; 48(4), 510–7. 


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[31] 
Wethington SL, Wright JD & Herzog TJ.  Key role of topoisomerase I inhibitors in the 
treatment of recurrent and refractory epithelial ovarian carcinoma. Expert Rev Anticancer Ther. 
2008; 8(5):819-31. 
[32] 
Perez, EA, Hillman, DW, Mailliard, JA et al. Randomized phase II study of two 
irinotecan schedules for patients with metastatic breast cancer refractory to an anthracycline, a 
taxane, or both. J. Clin. Oncol. 2004; 22(14): 2849–55.  
[33] 
Kümler, I, Brünner, N, Stenvang, J, et al. A systematic review on topoisomerase 1 
inhibition in the treatment of metastatic breast cancer. Breast Cancer Res. Treat. 2013; 138(2): 
347–58.  
[34] 
Andreopoulou, E., & Sparano, J. A. Chemotherapy in patients with anthracycline- and 
taxane-pretreated metastatic breast cancer: an overview. Curr. Breast Cancer Rep. 2013; 5(1): 
42–50.  
[35] 
Drummond, DC, Noble, CO, Guo, Z, et al. Development of a highly active 
nanoliposomal irinotecan using a novel intraliposomal stabilization strategy. Cancer Res. 2006; 
66(6): 3271–7.  
[36] 
Awada, A, Garcia, AA, Chan, S, et al. Two schedules of etirinotecan pegol (NKTR-102) 
in patients with previously treated metastatic breast cancer: a randomised phase 2 study. Lancet 
Oncol. 2013; 14(12): 1216–25.  
[37] 
Anders, C., Deal, A. M., Abramson, V., et al. TBCRC 018: phase II study of iniparib in 
combination with irinotecan to treat progressive triple negative breast cancer brain metastases. 
Breast Cancer Res Treat. 2014: 146(3), 557–66.  
[38] 
Kümler I, Brünner N, Stenvang J, Balslev E, Nielsen DL. A systematic review on 
topoisomerase 1 inhibition in the treatment of metastatic breast cancer. Breast Cancer Res Treat. 
2013 Apr;138(2): 347-58. 


 
 
 
 
Protocol Amendment Summary 
 
 
 
A Pilot Study in Patients Treated with MM-398 to Determine Tumor Drug Levels and to Evaluate 
the Feasibility of Ferumoxytol Magnetic Resonance Imaging to Measure Tumor Associated 
Macrophages  
 
 
     
Summary of changes from Protocol version 1.0 dated 26 Aug 2012 to version 2.0 dated 2 May 2013 
 
       Sponsor: 
 
 
  One Kendall Square 
  Suite B7201 
  Cambridge, MA  02139 
  Phone:  617-441-1000 
 
IND Number: 102799 
EudraCT Number: 2011-004687-30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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.  


MM-398-01-01-02 V2.0  
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Merrimack Pharmaceuticals 
CONFIDENTIAL 
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Overview 
The overall changes and rationale for the changes incorporated in this protocol are as follows:  
x 
Section 2. Background 
This section was updated to include details on the disease indications that were included for 
the protocol and to provide a background and rationale for these additional indications. 
  
x 
Section 2.1.4. Clinical Experience 
This section was updated to clarify the UGT1A1 allele that is analyzed. 
 
x 
Section 2.2.3. Interaction of ferumoxytol and MM-398 
The number of patients to be enrolled was clarified to provide a maximum number. Between 
12 and 20 patients will be enrolled in this study.  
This change has been made throughout the protocol, where applicable. 
 
x 
Section 3. Objectives 
Sections 3.1 Primary Objectives, 3.2 Secondary Objectives, and 3.3 Exploratory Objectives 
were updated per changes to the disease indications added. These changes have been made 
throughout the protocol, where applicable. 
  
x 
Section 4. Study Design 
This section was updated with the added disease indications, as above. Also, a cap to the 
number of patients with ER/PR positive breast cancer was introduced. The rationale for the 
selection of added disease indications was included. 
 
x 
Section 4.1. Enrollment and Treatment 
The number of patients to be enrolled was clarified to provide a maximum number, as above. 
 
x 
Section 5.1. Inclusion Criteria 
 
The inclusion criterion a) was updated with the added disease indications. 
 
The inclusion criterion b) was updated to provide clarification on the required size of 
the lesion(s) for the biopsies. 
 
x 
Section 6.1.6. Dose Reduction Due to Toxicity 
This section was updated to clarify the CTCAE version used in this study. 
 
x 
Section 7.1.6. Disease Evaluation 
This section was updated to remove the language regarding the extent of disease assessment. 
Per RECIST guidelines, no extent of disease assessment is required for disease evaluation.  
 


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x 
Section 7.2.2 Serum Chemistry 
Iron levels measurements were added at the 30 Day Follow-up visit. 
 
x 
Section 7.2.3. Serum Biomarkers 
This section was updated to correct the list of samples to be collected. Also, the section 
heading was updated to reflect these corrections. 
 
x 
Section 7.2.6. Urinalysis 
This section was updated to correct an error. Presence of blood rather than hemoglobin level 
will be analyzed in the urinalysis. 
 
x 
Section 7.2.8. Pharmacokinetic Assessments 
This section was updated to correct several errors.  
 
Plasma rather than serum samples will be collected for PK analyses.  
 
Table 12 was corrected to include a PK timepoint that had been missed in error, but 
was present in the schedule of assessments (section 8).  
 
Tables 11 and 12 were updated to add window periods for sample collection. 
 
x 
Section 7.3.1. Fresh Tumor Biopsies 
This section was updated to clarify the MRI images to be used for the selection of lesions to 
biopsy. 
 
x 
Section 7.4. Ferumoxytol Magnetic Resonance Imaging 
 
This section was updated to clarify the MRI collection schedule and process. 
 
x 
Section 8. Schedule of Assessments 
 
The cycle break-down in weeks was changed to days to clarify the due dates for all 
assessments. 
 
The screening procedures must be completed within 28 or 7 days of ferumoxytol 
dose, and not from the first dose of MM-398. 
 
The body weight for ferumoxytol dose on Day 1 can be collected within 7 days of 
dosing. 
 
Two independent ECG readings will be performed at the 30 Day Follow-up visit. 
 
The 2 independent ECG readings at screening and follow-up are to be completed at 
least 1 minute apart and no longer 5 minutes apart.  
 
The PK samples to collect were changed from serum to plasma to reflect the 
clarification made in section 7.2.8. 
 
The Fe-MRI collection schedule on ferumoxytol phase Day 1 was updated in the 
footnotes to reflect the clarification made in section 7.4. 
 
Iron levels will be measured at the 30 Day Follow-up visit. 


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 
Windows for all samples collection, disease assessment, 30 Day Follow-up visit were 
included. 
 
Footnotes were updated to provide clarifications regarding the assessments outlined 
in the table. 
 
x 
Section 9.2. Documenting Adverse Event 
This section was updated to clarify the starting time for treatment-emergent adverse event 
reporting. 
 
x 
Section 10.1. Case Report Forms 
This section was updated to include what information will be collected in the database for 
screen-failed patients. 
 
x 
Section 10.3. Sample Size 
The number of patients to be enrolled was clarified to provide a maximum number of patients 
to be enrolled, as above. 
 
x 
Section 12. References 
 
Errors in references were corrected. 
 
Included references for data added in section 2. 
 


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Revised Protocol Sections 
Note: All deletions have been identified by strikethroughs. 
          All additions have been identified by underlining. 
 
Administrative changes, changes to correct grammatical, spelling or formatting errors, and 
changes in numbering of the sections, tables or figures, are not included in this section. 
 
All changes in the protocol were added to the study synopsis (section 1). 
 
Section 2. Background 
…………... 
To maximize the information from this study, patients that are most likely to achieve the objectives of 
the study will be enrolled.  Although the first three patients enrolled in the study can have any solid 
tumor, subsequent patients will be limited to those with colorectal a subset of indications. Selection of 
these indications is based on the expected higher levels of tumor-associated macrophages, the 
potential sensitivity to irinotecan based on clinical experience and/or the presence of the pro-drug 
converting carboxyl esterase enzymes (CES) and the amenability to imaging and biopsy collection. 
These indications include colorectal cancer (CRC), non-small cell lung cancer (NSCLC) or, triple 
negative breast cancer (TNBC).  These three tumor types were selected based on:, ER/PR positive 
breast cancer, pancreatic cancer, ovarian cancer, gastric cancer, GEJ adenocarcinoma and head and 
neck cancer.  No more than three patients with ER/PR positive breast cancer can be enrolled in the 
study and similar restrictions may be placed on other tumor types to ensure a heterogeneous 
population at study end. 
 Probable high levels of macrophages 
 Potential sensitivity to irinotecan based on the presence of the converting carboxylesterase 
enzyme (CES) and/or clinical experience 
 Amenability to imaging and biopsy collection 
Merrimack Pharmaceuticals’ tumor microarray analysis of patient samples showed that both 
colorectal CRC and NSCLC have a significant subset with higher levels of the CD68 marker for 
tumor associated macrophages. In addition,This is in agreement with published findings reviewed by 
Heusinkveld and van der Burg (2011) [24]. This review also provides supportive information on the 
presence of tumor-associated macrophages in other indications, including ovarian, gastric and 
pancreatic cancers. Head and neck cancer has been shown to achieve high deposition of pegylated 
liposomes in an imaging study by Harrington et al. (2001) [25] and contains many immune cells, 
including phagocytic dendritic cells and macrophages (reviewed in [26, 27]). In-house profiling of 
human primary xenografts showed high CES enzyme activity (measured by tumors ability to convert 
irinotecan to SN38) in CRC and NSCLC patient tumor samples.   
…………... 
Similarly, Nogami et al (2012) reported that in a phase II study the combination of irinotecan and 
amrubicin was effective in patients with relapsed NSCLC [5]. Combinations of cetuximab with 
irinotecan have shown promising responses particularly in TNBC [6].    and more recently also in 


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gastro-oesophageal cancer [28, 29, 30]. Finally, topoisomerase I inhibitors such as topotecan and 
irinotecan provide very effective and tolerable treatment options for recurrent ovarian cancer [31]. 
 
Section 2.1.4. MM-398 Clinical Experience 
…………… 
TABLE 2: SUMMARY OF ONGOING STUDIES WITH MM-398 
 
 
Section 2.2.3. Interaction of ferumoxytol and MM-398 
…………… 
In this pilot study, we propose to use Fe-MRI imaging in 12up to 20 patients being treated with MM-
398 to both determine the imaging parameters that could be applied to future clinical trials and to 
better define the appropriate strategy for incorporating ferumoxytol in TAM imaging for MM-398 
studies. 
…………… 
Section 3. Study Objectives 
Section 3.1. Study Objectives 
In patients with CRC, NSCLC, TNBC or other solid tumorsNSCLC, CRC, TNBC, ER/PR positive 
breast cancer, pancreatic cancer, ovarian cancer, gastric cancer, GEJ adenocarcinoma or head and 
neck cancer, who are undergoing therapy with MM-398: 
x 
To evaluate the feasibility of delayed ferumoxytol MRI (Fe MRI) to identify tumor 
associated macrophages (TAMs) 
x 
To measure tumor levels of irinotecan and SN-38 
 


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Section 3.2. Secondary Objectives 
In patients with CRC, NSCLC, TNBC or other solid tumorsNSCLC, CRC, TNBC, ER/PR positive 
breast cancer, pancreatic cancer, ovarian cancer, gastric cancer, GEJ adenocarcinoma or head and 
neck cancer, who are undergoing therapy with MM-398: 
x 
To estimate the correlations between Fe-MRI, TAM levels, and tumor levels of irinotecan 
and SN38 with administration of MM-398 
x 
To determine the value of Fe-MRI in directing tissue biopsy 
x 
To characterize the safety profile of MM-398 in the presence of ferumoxytol  
x 
To assess tumor response 
x 
To characterize the PK of MM-398 
 
Section 3.3. Exploratory Objectives 
In patients with CRC, NSCLC, TNBC or other solid tumorsNSCLC, CRC, TNBC, ER/PR positive 
breast cancer, pancreatic cancer, ovarian cancer, gastric cancer, GEJ adenocarcinoma or head and 
neck cancer, who are undergoing therapy with MM-398: 
x 
To estimate the correlations between potential pharmacodynamic markers (Fe-MRI, TAM, 
tumor irinotecan, tumor SN38 levels) and safety 
x 
To estimate the correlations between potential pharmacodynamic markers (Fe-MRI, TAM, 
tumor irinotecan, tumor SN38 levels) and tumor response 
x 
To characterize each tumor biopsy to permit multivariate comparative analyses between 
tumor characteristics, Fe-MRI signal and drug metabolite levels 
 
Section 4. Study Design 
This study will enroll at least 12 patients with NSCLC, CRC, TNBC or other solid tumors.  After the 
first approximately 12 patients, up to 20 in total. The first three patients that are enrolled can have any 
solid tumor type; however subsequent patients must have NSCLC, CRC, TNBC, ER/PR positive 
breast cancer, pancreatic cancer, ovarian cancer, gastric cancer, gastro-oesophageal junction 
adenocarcinoma or head and neck cancer. No more than three patients, only patients with NSCLC, 
CRC or TNBC will be enrolled.   with ER/PR positive breast cancer can be enrolled in the study and 
similar restrictions may be placed on other tumor types to ensure a heterogeneous population at study 
end. 
These indications were selected based on data suggesting that these tumor types have high levels of 
CD68 (tumor associated macrophages) and carboxylesterase enzyme (CES) activity, or high levels of 
deposition, any of which may correlate to MM-398 response.  
There are four stages to this study: 
…………… 


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x 
MM-398 Treatment Phase (Day 5/C1D1 – progression of disease): patients receive an MM-
398 dose of 80 mg/m2 every 2 weeks and undergo biopsies and other required assessments 
…………… 
 
Section 4.1. Enrollment and Treatment 
At leastBetween 12 and 20 patients will be enrolled in this study.   
…………… 
 
Section 5.1. Inclusion Criteria 
In order for inclusion into the study, patients must have/be: 
a) For the first three patients enrolled, pathologically confirmed solid tumors that have recurred or 
progressed following standard therapy, or that have not responded to standard therapy, or for 
which there is no standard therapy, or who are not candidates for standard therapy.  For patients 
subsequently enrolled, pathologically confirmed NSCLC, CRC, NSCLC or TNBC, ER/PR 
positive breast cancer, pancreatic cancer, ovarian cancer, gastric cancer, GEJ adenocarcinoma or 
head and neck cancer that has recurred or progressed following standard therapy or that have not 
responded to standard therapy, or for which there is no standard therapy, or who are not 
candidates for standard therapy. 
b) Documented metastatic disease with 2 lesions measuring at least 2 cm in diameter, and amenable 
to multiple pass percutaneous biopsies. In rare circumstances, only a single metastatic lesion may 
be amenable to percutaneous biopsy. A subject may still be a candidate for this trial provided that 
the single target lesion is substantial enough in size to allow for multiple pass biopsies on 
multiple days and, in the opinion of the interventional radiologist, multiple passes from the Pre 
MM398 biopsy will not overlap or interfere with the planned Post MM 398 biopsy. 
…………… 
 
Section 6.1.6. Dose Reduction Due to Toxicity 
The toxicity of each cycle must be recorded prior to the administration of a subsequent cycle and 
graded according to the NCI CTCAE (Version 4.02).   
…………… 
 
Section 7.1.6. Disease Evaluation 
Tumor response will be evaluated according to the Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1, to establish disease progression by computed tomography 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 


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method of assessment must be used throughout the study.  Investigators should select target and non-
target lesions in accordance with RECIST v1.1 guidelines. Follow up measurements and overall 
response should also be in accordance with these guidelines.  
The extent of disease assessment should be completed until it has been determined the patient has 
progressive disease (in accordance with RECIST v1.1). In the event the patient discontinues study 
treatment for reasons other than disease progression, an extent of disease assessment should be 
completed as soon as possible relative to the date of study termination to ensure disease progression is 
not present and to assess overall disease status. In such patients, this assessment should occur no later 
than the date of the 30 day follow up visit. 
 
Section 7.2.2. Serum Chemistry 
…………… 
Iron levels (ferritin, iron and transferrin saturation) will be measured at the screening visit, and at the 
time of the first MM-398 dose of Cycle 2 (first additional cycle) only and at the 30 Day Follow-up 
visit. 
 
Section 7.2.3. Serum Biomarkers Biomarker Samples 
SerumWhole blood, plasma and urine will be collected to potentially identify factors that may 
correlate with tumor response and resistance to MM-398.   
…………… 
 
Section 7.2.6. Urinalysis 
A urinalysis will include descriptions of color and clarity; pH; specific gravity; and analyses of 
hemoglobinblood, glucose, ketones and total protein. 
…………… 
 
Section 7.2.8. Pharmacokinetic Assessments 
SerumPlasma samples will be collected to determine the levels of MM-398 and SN-38.   
…………… 
TABLE 11 SUMMARY OF PK TIMEPOINTS IN FERUMOXYTOL PHASE 
Sample 
Time-point 
Window 
1 
Immediately prior to ferumoxytol infusion 
---5 mins 
2 
At the end of the ferumoxytol infusion 
±+5 mins 
3 
+2 hours after the completion of the ferumoxytol infusion 
±30 mins 


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4 
+24 hours after the completion of the ferumoxytol infusion 
± 1 hour 
5 
Immediately prior to Day 4 biopsy 
---30 mins 
 
TABLE 12 SUMMARY OF PK TIMEPOINTS IN TREATMENT AND FOLLOW-UP 
PHASES 
Sample 
Time-point 
Window 
1 
Immediately prior to MM-398 infusion on Day 1 
---5 mins 
2 
At the end of the MM-398 infusion 
±+5 mins 
3 
+2 hours after the completion of the MM-398 infusion 
±30 mins 
4 
Immediately prior to the Day 34 post treatment biopsy 
---30 mins 
5 
+168 hours/7 days after the completion of the MM-398 
infusion 
±24 hours 
6 
Immediately prior to MM-398 infusion on C1D15 
-24 hours 
67 
30 day follow up visit 
--- 
 
 
Section 7.3.1. Fresh Tumor Biopsies 
…………… 
On Day 4 of the ferumoxytol phase, the lesion(s) selected for biopsy will be based on the results of 
the Fe-MRI obtained on Days 1, 2 and 4. 
…………… 
On Cycle 1 Day 34 of the MM-398 Treatment phase, the lesion(s) selected for biopsy will be based 
on the results of the Fe-MRI obtained on Days 1, 2 and 4 of the ferumoxytol phase. 
…………… 
 
Section 7.4. Ferumoxytol Magnetic Resonance Imaging 
…………… 
Two MRI images will be collected on Day 1 of the ferumoxytol phase. The first image will be 
acquired prior to the ferumoxytol infusion, and the second one, immediately after the end of 
ferumoxytol administration. The subjects will return on Day 2 and Day 4 for delayed Fe-MRIs using 
the same protocol and sequences as on Day 1.  
 
Section 8. Schedule of Assessments 


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Footnotes:  
1. Procedures to be completed within 28 days of firstferumoxytol dose of MM-398 
2. Procedures to be completed within 7 days of firstferumoxytol dose of MM-398 
3. Body weight to be collected within 7 days of ferumoxytol dose 
4. 3. Two independent readings at least 5 minutes1 minute apart prior to the start of MM-398 
infusion  
5. 4. One reading prior to the start of the MM-398 infusion and one reading post infusion of MM-
398 is required 
6. 5. Procedure completed every 2 cycles for each additional cycle 
7. 6. Samples collected at the following timepoints: immediately prior to ferumoxytol infusion (-5 
min); at the end of the ferumoxytol infusion (±5 mins) and +2 hours after the completion of the 
ferumoxytol infusion (±30 mins) 
8. 7. Sample collected +24 hours after the completion of the ferumoxytol infusion (±2 hours) 
9. 8. Sample collected immediately prior to ferumoxytol Day 4 biopsy (-30 mins) 
10. 9. Samples collected at the following timepoints inon C1D1 of the MM-398 Treatment Phase: 
just prior to the MM-398 infusion (±-5 mins); at the end of  the MM-398 infusion (±5 mins); +2 
hours after the completion of the MM-398 infusion (±30 mins);  
11. Sample collected immediately prior to the Day 34 post treatment biopsy and(-30 mins) 
12. Sample collected +168 hours/7 days after the completion of the MM-398 infusion (±24 hours) 
13. 10. Sample obtained just prior to dosing with MM-398 (±24 hours) 
14. 11. Biopsy collected +72 hours/3 days (± 3 hours) after the completion of the MM-398 infusion 
15. 12. MM-398 administration should occur ±2 days from scheduled date of administration 
16. 13. Two biopsies collected as outlined in Section 7.3  


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17. Two Fe-MRI collected as outlined in Section 7.4 
18. 14. In addition to normal labs, iron levels will be measured at screening visit and, at the time of 
the first MM-398 dose of Cycle 2 (first additional cycle) only and at the 30 Day Follow-up visit. 
19. 15. Result not required prior to enrollment in the study, but patients positive for UGT1A1*28 
may have future doses reduced as described in Section 6.1.6.3 
20. 16. Urine and blood will be collected for biomarker analyses 
21. 17. Unless completed in the prior 6 weeks 
18. Final PK draw from week 1 visit (i.e. +168 hours/7 days after the completion of the MM-398 
infusion) 
22. 19. Collection of archived tumor block or paraffin embedded slides is optional 
23. Disease evaluations should be done every 8 weeks (± 7 days) after 1st dose  
24. Samples should be obtained ± 2 days from scheduled date of collection 
25. The 30-Day Follow-Up visit should occur 30 days (± 7 days) after last dose  
 
 


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Section 9.2. Documenting Adverse Event 
…………… 
Treatment-emergent adverse event reporting will begin as of the first dose administration of 
ferumoxytol. 
…………… 
 
Section 10.1. Case Report Forms 
…………… 
The datafollowing information for the patients who screen-failed will not be entered into the 
database: screening visit date, informed consent form, demographics, eligibility, adverse events, 
concomitant medication and procedures, and overall study termination. 
…………… 
 
Section 10.3. Sample Size 
Approximately Between 12 and 20 patients will be enrolled in this study. 
…………… 
 
Section 12. References 
[1] 
Weinstein JS, Varallyay CG, Dosa E, et al. Superparamagnetic iron oxide nanoparticles: 
diagnostic magnetic resonance imaging and potential therapeutic applications in 
neurooncology and central nervous system inflammatory pathologies, a review. Journal of 
cerebral blood flow and metabolism official journal of the International Society of Cerebral 
Blood Flow and Metabolism. 2010;30(1):15–35. 
…………… 
[7] 
Innocenti F, Kroetz DL, Schuetz E, et al. Comprehensive pharmacogenetic analysis of 
irinotecan neutropenia and pharmacokinetics. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology. 2009;27(16):2604–14 
…………… 
[15] 
Daldrup-Link HE, Golovko D, Ruffell B, et al. MRI of tumor-associated macrophages with 
clinically applicable iron oxide nanoparticles. Clinical cancer research : an official journal of 
the American Association for Cancer ResearchClin Cancer Res. 2011;17(17):5695–704.  
…………… 


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[24] 
Heusinkveld, M, & Van der Burg, SH Identification and manipulation of tumor associated 
macrophages in human cancers. J Transl Med 2011; 9(1), 216-229. 
[25] 
Harrington, KJ, Mohammadtaghi, S, Uster, PS et al. Effective targeting of solid tumors in 
patients with locally advanced cancers by radiolabeled pegylated liposomes. Clin Cancer Res 
2001; 7(2), 243–54. 
[26] 
Duray, A, Demoulin, S, Hubert, P et al. Immune suppression in head and neck cancers: a 
review. Clin Dev Immunol 2010; 2010(i), 701657.  
[27] 
Kross, KW, Heimdal, JH, & Aarstad, HJ. Mononuclear phagocytes in head and neck 
squamous cell carcinoma. European archives of oto-rhino-laryngology 2010; 267(3), 335–44.  
[28]  
Wöll, E, Greil, R, Eisterer, W et al. Oxaliplatin, irinotecan and cetuximab in advanced gastric 
cancer. Anticancer research 2011; 31(12), 4439–43.  
[29]  
Moehler, M, Mueller, A, Trarbach, T et al. Cetuximab with irinotecan, folinic acid and 5-
fluorouracil as first-line treatment in advanced gastroesophageal cancer: a prospective multi-
center biomarker-oriented phase II study. Annals of oncology 2011; 22(6), 1358–66.  
[30] 
Schønnemann, KR, Yilmaz, M, Bjerregaard, JK et al. Phase II study of biweekly cetuximab 
in combination with irinotecan as second-line treatment in patients with platinum-resistant 
gastro-oesophageal cancer. European journal of cancer 2012; 48(4), 510–7. 
[31] 
Wethington SL, Wright JD & Herzog TJ.  Key role of topoisomerase I inhibitors in the 
treatment of recurrent and refractory epithelial ovarian carcinoma. Expert Rev Anticancer 
Ther. 2008; 8(5):819-31. 
 
 
 


Merrimack Pharmaceuticals 
 
 
          MM-398-01-01-02 
 
Table of Changes, Version 2.0 to Version 3.0 
Page 1 of 2 
Protocol Section 
Update 
Rationale 
Changes made throughout 
Administrative changes to correct 
typos and formatting 
N/A 
Changes made throughout 
Added language to distinguish 
between the Pilot Phase and 
Expansion Phase 
Addition of an Expansion Phase to the protocol to further investigate the 
use of ferumoxytol (FMX) as an imaging diagnostic 
Title 
Added text “and to Predict Patient 
Response to Treatment” 
To include an objective of the Expansion Phase, to evaluate the feasibility 
of ferumoxytol magnetic resonance imaging to predict patient response to 
treatment, in the protocol title 
1 Study Synopsis 
Updated to reflect amendment 
changes described in this document 
Updated to reflect amendment changes described in this document 
2 Background 
Added language regarding 
metastatic breast cancer 
To provide additional rationale for examining this patient population in the 
Expansion Phase of the study 
2.1.4 and 2.1.5  
Updated clinical trial information 
and safety information 
Provides additional information on completed and ongoing trials, as well as 
new safety data obtained from a recently completed trial 
2.2.3 Interaction of 
Ferumoxytol and MM-398 
Added language regarding the 
Expansion Phase 
Provides rationale for adding an Expansion Phase to the study 
3 Study Objectives 
Added objectives for the Expansion 
Phase 
To further investigate the feasibility of ferumoxytol MRI  
4 Study Design 
Added language regarding the 
Expansion Phase 
Provides information on the design of the Expansion Phase, and clarifies 
the Pilot Phase vs. the Expansion Phase 
4.1 Enrollment and 
Treatment 
Added language regarding the 
Expansion Phase 
Added specific requirements for a pharmacodynamic evaluable population 
within the Expansion Phase, in order to ensure all appropriate data are 
collected to perform the analysis related to the primary objectives 
5.1 Inclusion Criteria and 5.2 
Exclusion Criteria 
Revised and added criteria  
To clarify and add criteria specific to the patient populations that will be 
enrolled in the Expansion Phase 
5.3 Patient Discontinuation 
Added language 
Clarifies that patients may be discontinued from the study due to clinical 
and/or symptomatic deterioration 
5.4 Patient Replacement 
Added Section 
Added specific requirements for a pharmacodynamic evaluable population 
within the Expansion Phase, in order to ensure all appropriate data are 
collected to perform the analysis related to the primary objectives 
6.2.3 Administration of 
Ferumoxytol 
Added language 
To clarify that ferumoxytol will be provided by the hospital pharmacy or 
commercial supply 
6.4 Concomitant Therapy 
Added language 
To clarify permitted and prohibited medications for Cohort 3 of the 
Expansion Phase 


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Table of Changes, Version 2.0 to Version 3.0 
Page 2 of 2 
Protocol Section 
Update 
Rationale 
6.4.3 Therapy for Diarrhea 
Added language 
To clarify that institutions may opt to follow their own guidelines for the 
management of diarrhea 
7.1.6 Disease Evaluation; 
Section 7.1.6.1 Modified 
RECIST Criteria for Cohort 3 
Added language  
Language regarding the use of modified RECIST criteria was added to 
provide additional instructions for the evaluation of CNS disease for patients 
enrolled into Cohort 3 of the Expansion Phase; addition of a baseline 18F-
FDG PET/CT was also added in order to identify metabolically active 
lesions prior to treatment 
7.1.6.2 Criteria for Treatment 
Termination due to 
Progressive Disease 
Added Section 
To specify the reasons that patients may be discontinued from study 
treatment due to progressive disease per Cohort, and to allow for patients 
to remain on treatment under certain conditions, if the Investigator feels that 
the patient is deriving clinical benefit 
7.2.8 Pharmacokinetic 
Assessments 
Removed PK sampling during 
Ferumoxytol Phase, and edited PK 
timepoints during treatment and 
follow-up phases 
Data gathered during the Pilot Phase of the study was used to inform the 
adjustments made to the PK sample collection time points during the 
Expansion Phase. Collection of PK samples during the FMX Phase is no 
longer required, while additional PK sampling will be performed during 
Cycles 2-3 of the Expansion Phase.  
7.3.1.2 Expansion Phase 
Biopsies 
Added Section 
To highlight the changes made to the biopsy schedule from the Pilot Phase 
to the Expansion Phase; the biopsy requirement has been simplified for the 
Expansion Phase to require only one pre-treatment biopsy 
7.4 Ferumoxytol Magnetic 
Resonance Imaging 
Added language regarding the 
Expansion Phase; revised MRI time 
points 
Data gathered during the Pilot Phase of the study was used to inform the 
adjustments made to the MRI time points during the Expansion Phase of 
the study. Tables were added to summarize the various time points for the 
new scan groups to which patients will be assigned during the Expansion 
Phase. 
8.2 Expansion Phase  
Schedule of Assessments added  
To distinguish the different requirements in the Expansion Phase, a 
separate Schedule of Assessments for this phase of the study was added 
10.3 Statistical Analysis 
Section revised 
To provide additional details on the planned analysis for the study 
10.4 Study Populations 
Section Added 
To clarify the patient populations that will be analyzed 
10.5 Disposition and 
Baseline Characteristics, 
10.6 Efficacy Analysis, 10.7 
Safety Analysis, 10.8 
Biomarker Subgroup 
Analysis, 10.11 Sample Size 
Sections revised, Section 10.3 
Sample Size was moved to Section 
10.11 
To provide additional details, including information specific to the Expansion 
Phase of the study  
11 Extension Phase 
Section Added 
To allow for any ongoing patients to continue to receive study treatment 
after the study analyses have been completed 
 

































SAP_000.pdf: 
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 Page 1 of 34 
 
Statistical Analysis Plan 
 
A Phase 1 Study in Patients Treated with MM-398 (Nanoliposomal 
Irinotecan, nal-IRI,) to Determine Tumor Drug Levels and to 
Evaluate the Feasibility of Ferumoxytol Magnetic Resonance 
Imaging to Measure Tumor Associated Macrophages and to Predict 
Patient Response to Treatment 
 
 
 
PROTOCOL VERSION AND DATE: VERSION 6.0 – 03 APRIL 2017 
 
 
SAP Version 
Date 
Final Version 1.0 
30 October 2018 
Final Version 1.1 
28 February 2019 
 


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 Page 2 of 34 
 
 
STUDY NUMBER: 
MM-398-01-01-02  
EudraCT number: 
2014-003673-42 
PROTOCOL TITLE: 
A PHASE 1 STUDY IN PATIENTS TREATED 
WITH MM-398 (NANOLIPOSOMAL 
IRINOTECAN, NAL-IRI) TO DETERMINE 
TUMOR DRUG LEVELS AND TO EVALUATE 
THE FEASIBILITY OF FERUMOXYTOL 
MAGNETIC RESONANCE IMAGING TO 
MEASURE TUMOR ASSOCIATED 
MACROPHAGES AND TO PREDICT PATIENT 
RESPONSE TO TREATMENT 
(PROTOCOL V 6.0) 
 
SAP VERSION: 
Version 1.1 
SAP DATE: 
28 February 2019 
 
Further to your review and agreement to the Statistical and Analysis Plan version indicated 
above, please sign to indicate approval for your area of responsibility: 
 
RESPONSIBILITY NAME, TITLE & OFFICE 
SIGNATURE 
DATE 
Clinical Statistics 
Designee 
 
Adjoint 
 
Ipsen Innovation SAS 
 
 
Medical 
Development  
 
 
Oncology 
Ipsen Bioscience, Inc. 
 
 
 
RESPONSIBILITY NAME, TITLE & OFFICE 
SIGNATURE 
DATE 
Biostatistics Lead 
 
Associate Director, 
Ipsen Bioscience, Inc. 
650 East Kendall Street 
Cambridge, MA  02142 
 
 
PPD
PPD
PPD
PPD
PPD


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 Page 3 of 34 
 
Biostatistics 
Reviewer 
 
Senior Biostatistician 
Ipsen Bioscience, Inc. 
650 East Kendall Street 
Cambridge, MA  02142) 
 
 
 
 
 
 
 
 
PPD




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Table of Contents 
LIST OF ABBREVIATIONS ............................................................................................. 7 
1 OVERVIEW 
9 
2 STUDY OBJECTIVES AND ENDPOINTS ................................................................ 9 
2.1 Primary Objectives........................................................................................................ 9 
2.2 Secondary Objectives.................................................................................................. 10 
2.3 Exploratory Objectives ............................................................................................... 10 
3 STUDY DESIGN........................................................................................................ 11 
3.1 General Design and Plan ............................................................................................. 11 
3.2 Treatment Assignment ................................................................................................ 12 
3.3 Treatment Blinding ..................................................................................................... 12 
4 SAMPLE SIZE DETERMINATION ......................................................................... 13 
5 SEQUENCE OF PLANNED ANALYSES ................................................................ 13 
5.1 Interim Analyses ......................................................................................................... 13 
5.2 Final Analyses ............................................................................................................. 13 
6 ANALYSIS POPULATIONS .................................................................................... 13 
7 GENERAL STATISTICAL METHODS ................................................................... 14 
7.1 General Methodology ................................................................................................. 14 
7.2 Methods for Missing Data, Multiple Observations, and Outliers ............................... 15 
7.2.1 
General Considerations ..............................................................................15 
7.2.2 
Partial and Missing Dates ..........................................................................15 
7.3 Multicenter Studies ..................................................................................................... 16 
7.4 Multiple Comparisons and Multiplicity ...................................................................... 16 
7.5 Planned Subgroups, Interactions, and Covariates ....................................................... 16 
7.6 Definitions and General Terminology ........................................................................ 17 
7.6.1 
Baseline ......................................................................................................17 
7.6.2 
Protocol Deviations ....................................................................................17 
7.6.3 
Study Periods .............................................................................................17 
7.6.4 
Derived and Computed Variables ..............................................................17 
8 STUDY SUBJECTS ................................................................................................... 19 
8.1 Protocol Deviations ..................................................................................................... 19 
8.2 Inclusion and Exclusion Criteria ................................................................................. 19 


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9 DEMOGRAPHICS AND BASELINE CHARACTERISTICS ................................. 19 
9.1 Demographics ............................................................................................................. 20 
9.2 Baseline Characteristics .............................................................................................. 20 
9.3 Prior Anti-Cancer Therapy, Radiotherapy, and Surgery ............................................ 20 
9.4 Medical History and Pre-existing Conditions ............................................................. 20 
9.5 Prior and Concomitant Therapies ............................................................................... 20 
9.6 Concomitant Procedures ............................................................................................. 21 
10 TREATMENT COMPLIANCE AND EXPOSURE .................................................. 21 
11 EFFICACY ANALYSES ........................................................................................... 21 
11.1 
Primary Efficacy Endpoints: .............................................................................. 21 
11.2 
Primary Efficacy Analysis: ................................................................................ 22 
11.3 
Secondary Efficacy Analysis ............................................................................. 23 
11.3.1 
Tumor Response-related Variables ............................................................23 
11.3.2 
Secondary efficacy variables (All Phases) .................................................24 
12 SAFETY ANALYSES................................................................................................ 28 
12.1 
Adverse Events .................................................................................................. 28 
12.2 
Clinical Laboratory Evaluations ........................................................................ 30 
12.3 
Vital Signs .......................................................................................................... 31 
12.4 
Electrocardiograms ............................................................................................ 31 
12.5 
ECOG Performance Score ................................................................................. 31 
12.6 
Physical Examinations ....................................................................................... 31 
12.7 
Pregnancies ........................................................................................................ 31 
13 OTHER ANALYSES ................................................................................................. 31 
13.1 
Pharmacodynamic Marker Analysis .................................................................. 31 
14 Population Summary Conventions ............................................................................. 31 
15 REFERENCES 32 
16 APPENDIX A 33 
 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BC 
Breast cancer 
BUN 
Blood urea nitrogen 
CES 
Carboxylesterase  
CL 
Clearance 
Cmax 
Maximum concentration 
CNS 
Central nervous system 
CRC 
Colorectal cancer 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
DOR 
Duration of objective response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ER 
Estrogen Receptor 
FMX-MRI 
Ferumoxytol magnetic resonance imaging 
FMX 
Ferumoxytol 
GCP 
Good Clinical Practice 
HER2 
Human epidermal growth factor receptor 2 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
Kilogram 
L 
Liter 
mg 
Milligram 
MRI 
Magnetic resonance imaging 
ng 
Nanogram 
nm 
Nanometer 
NSCLC 
Non-small cell lung cancer 
PD 
Pharmacodynamic; or Progressive disease 
PET 
Positron emission tomography 
PK 
Pharmacokinetic 
PI 
Principal investigator 
PR 
Progesterone Receptor or Partial response 
RECIST 
Response evaluation criteria in solid tumors 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
t1/2 
Half-life 
TAM 
Tumor associated macrophages 
TNBC 
Triple negative breast cancer 
ULN 
Upper limit of normal 
WBC 
White blood count 


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1 OVERVIEW 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for protocol 
MM-398-01-01-02: A phase 1 study in patients treated with MM-398 (Nanoliposomal 
Irinotecan, nal-IRI) to determine tumor drug levels and to evaluate the feasibility of ferumoxytol 
magnetic resonance imaging to measure tumor associated macrophages (TAMs) and to predict 
patient response to treatment. 
 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the FDA and International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH E9): Guidance on 
Statistical Principles in Clinical Trials (US FDA, 1998). 
The following documents were reviewed in preparation of this SAP: 
 Clinical Research Protocol MM-398-01-01-02, Version 6.0 dated 03 APRIL 2017 
 Subject case report forms (CRFs) for Protocol MM-398-01-01-02 V6.0 
 ICH Guidance on Statistical Principles for Clinical Trials (US FDA, 1998) 
 FDA Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs 
and Biologics (US FDA, 2007). 
The reader of this SAP is also encouraged to read the clinical protocols for details on the conduct 
of this study, and the operational aspects of clinical assessments and timing for completing a 
patient in this study. 
The purpose of this SAP is to outline the planned analyses to be completed to support the 
completion of the Clinical Study Report (CSR) for protocol MM-398-01-01-02 V6.0. Additional 
post-hoc analyses may be performed to better understand the observed results. 
2 STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 Primary Objectives  
Pilot Phase (Completed) 
In patients with NSCLC, CRC, TNBC, ER/PR positive breast cancer, pancreatic cancer, ovarian 
cancer, gastric cancer, GEJ adenocarcinoma or head and neck cancer, who are undergoing 
therapy with MM-398: 
 To evaluate the feasibility of delayed ferumoxytol MRI (FMX-MRI) to identify tumor 
associated macrophages (TAMs) 
 To measure tumor levels of irinotecan and SN-38  
Expansion Phase: 
In patients with locally advanced or metastatic breast cancer: 
 To further investigate the feasibility of ferumoxytol (FMX) quantitation in tumor lesions   
 To characterize the relationship between ferumoxytol (FMX) tumor uptake and tumor 
response to MM-398  


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2.2 Secondary Objectives 
All Phases: 
 To characterize the safety profile of MM-398 in the presence of FMX  
 To assess tumor response to treatment 
 To characterize the pharmacokinetics (PK) of MM-398 
Pilot Phase (Completed): 
 To estimate the correlations between FMX-MRI, TAM levels, and tumor levels of 
irinotecan and SN-38 with administration of MM-398 
 To determine the value of FMX-MRI in directing tissue biopsy 
Expansion Phase: 
 To characterize the efficacy of MM-398 in patients with locally advanced or metastatic 
breast cancer using key efficacy indicators such as objective response rate and clinical 
benefit rate  
 To assess the association between deposition, as visualized by ferumoxytol imaging, and 
measures of efficacy 
 To further characterize the safety profile of MM-398, in the presence of FMX, in patients 
with metastatic breast cancer  
 To assess the analytical performance of FMX-MRI measurements and optimize FMX-
MRI parameterization 
 
2.3 Exploratory Objectives 
Pilot Phase (Completed): 
 To estimate the correlations between potential pharmacodynamic (PD) markers (FMX-
MRI, TAM, tumor irinotecan, tumor SN-38 levels) and safety 
 To estimate the correlations between potential PD markers (FMX-MRI, TAM, tumor 
irinotecan, tumor SN-38 levels) and tumor response 
 To characterize each tumor biopsy to permit multivariate comparative analyses between 
tumor characteristics, FMX-MRI signal and drug metabolite levels 
Expansion Phase: 
 To evaluate a set of potential biomarkers from tumor tissue and blood samples for their 
ability to predict PK and/or response to MM-398 treatment 
Exploratory analyses will be performed ad-hoc only. When applicable, detailed analyses 
and results will be documented separately. 
 


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3 STUDY DESIGN 
3.1 General Design and Plan 
This study comprises two phases: pilot phase and expansion phase.  
Pilot phase will enroll approximately 12 patients, up to 20 in total. The first three patients that 
are enrolled can have any solid tumor type; however subsequent patients must have NSCLC, 
CRC, TNBC, ER/PR positive breast cancer, pancreatic cancer, ovarian cancer, gastric cancer, 
gastro-oesophageal junction adenocarcinoma or head and neck cancer. No more than three 
patients with ER/PR positive breast cancer can be enrolled in the Pilot Phase and similar 
restrictions may be placed on other tumor types to ensure a heterogeneous population. 
These indications were selected based on data suggesting that these tumor types have high levels 
of CD68 (tumor associated macrophages) and carboxylesterase enzyme (CES) activity or high 
levels of deposition, any of which may correlate to MM-398 response.  
 
The Expansion Phase will enroll cohorts of single indications of patients with locally advanced 
or metastatic breast cancer in 3 cohorts of 10 patients each depending on sub-type of breast 
cancer: 
Cohort 1: ER and/or PR-positive breast cancer  
            Cohort 2: Triple negative breast cancer (TNBC) 
            Cohort 3: Breast Cancer (BC) with active brain metastasis 
There are four stages to each phase of this study: 
 Screening (-28d): patients undergo screening assessments to determine if they are eligible 
for the study  
 Ferumoxytol (FMX) (Day 1  Day 2): patients receive ferumoxytol infusion and undergo 
required FMX-MRI scans and pre-treatment biopsy (if applicable, see Cohort 
requirements) prior to receiving MM-398 
 MM-398 Treatment (C1D1  progression of disease): patients receive an MM-398 dose of 
60 mg/m2 every 2 weeks, which should be dose escalated to 80 mg/m2 every 2 weeks in 
subsequent doses depending on patient tolerance, other required assessments, and undergo 
a post-treatment (MM-398) multiple pass core biopsy  
 Follow up (+30d from last dose): patients return to clinic 30 days after their last dose of 
MM-398 for final safety assessments 
Ferumoxytol magnetic resonance imaging (FMX-MRI) will be done for both pilot phase and 
expansion phase.   The schedule for pilot phase FMX-MRI is:  pre-dose of ferumoxytol, 1-4 
hours post dose and 24 hours post dose of ferumoxytol. 
The schedule for expansion phase is outlined in Tables 1 and 2: 
 
Table 1 Summary of Expansion Phase MRI Scan Groups (Cohorts 1 and 2) 




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4 SAMPLE SIZE DETERMINATION 
No formal hypothesis testing is performed for this study. Therefore, the Pilot and Expansion 
Phases are not powered to detect statistical differences on any parameters. Results will be 
descriptive. 
The Pilot Phase will enroll 12 to 20 patients with various indications, while the Expansion Phase 
will enroll approximately 30 metastatic breast cancer patients across three cohorts.   
The Expansion Phase ORR is estimated to be around 29% with a 95% confidence interval (14.6- 
46.3) [Awada, 2013]. Other studies showed similar response rates ranges ranging from 5-32% 
[Kümler, 2013]. Hypothesizing a true ORR of 30%, the probability of at least 14 responses of 30 
evaluable patients would be 0.04. The probability of at least 13 responses would be 0.084. 
 
5 SEQUENCE OF PLANNED ANALYSES 
5.1 Interim Analyses 
No interim analysis will be performed. Data may be analyzed while study is ongoing for 
administrative purposes. 
5.2 Final Analyses 
No formal hypothesis testing will be performed in the Pilot or Expansion Phases of this study.  
Descriptive statistics will be calculated to summarize categorical and continuous parameters.  
Parameters will be reported by study phase (pilot and expansion phase) and expansion phase will 
be further summarized by each cohort and total.  When appropriate, the Pilot and Expansion 
study phases may be pooled. The final analysis will be conducted when the last patient enrolled 
in expansion phase discontinued study treatment for any reason or after the patient has been 
treated for six months, whichever comes first.  A single cut-off date will be applied wherein all 
data for all patients up to that date will be included in the analysis and all data reported after the 
cut-off date will be excluded from analysis. 
Exploratory analyses and/or post-hoc analyses completed to support planned study analyses, 
which were not identified in this SAP, will be documented and reported in appendices and/or 
addendum to the CSR. 
Subsequent analyses of the data may be generated as needed per regulatory obligation.  
 
6 ANALYSIS POPULATIONS 
 
 Screened population: This population includes all patients screened (i.e. who signed the 
informed consent). 
 Safety population: This population includes all patients receiving at least one dose of 
MM-398 or ferumoxytol. If ferumoxytol safety population is different from MM-398 
safety population, safety analysis will be performed separately on both populations. 


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Depending upon patients receiving MM-398 and not ferumoxytol and vice versa, the safety 
population may be expanded in order to not dilute any adverse event rate: 
o Ferumoxytol safety population:  any patient receiving ferumoxytol.  All analyses 
using this population will be based on the treatment actually received. 
o MM-398 safety population: all patient receiving at least one dose of MM-398.  All 
analysis using this population will be based on the treatment actually received. 
 Efficacy evaluable population: This population includes all patients receiving at least one 
dose of MM-398. All statistical analyses of data on non-imaging related efficacy analyses 
will be performed using efficacy evaluable population.  
 Pharmacodynamic (PD) evaluable population: This population includes all efficacy 
evaluable patients with the following: a) pre-treatment FMX-MRI scan(s) and b) 
radiological scans at 8 weeks. All statistical analyses of data on imaging related efficacy 
analyses will be performed using PD evaluable population.  
 Pharmacokinetic (PK) population: This population includes patients receiving at least 
one dose of MM-398, and blood samples at the predefined timepoints adequately collected 
(with no major protocol deviations affecting the PK variables & with sufficient number of 
plasma concentrations to estimate the main PK parameters (Cmax, AUC)). PK analysis 
will be documented in a separate SAP. 
The term ‘All Screened Patients’ will be used to describe the set of all patients who signed 
informed consent, including patients who failed screening and any others who initiated screening.  
7 GENERAL STATISTICAL METHODS 
7.1 General Methodology 
Categorical/qualitative data will be summarized using the number of non-missing observations, 
frequency counts and percentages. All percentages will be presented as one-decimal point, unless 
otherwise specified. Percentages equal to 100 will be presented as 100% and percentages will not 
be presented for zero frequencies. 
For continuous variables, descriptive statistics will include the number of non-missing 
observations (n), mean, standard deviation, median, minimum and maximum. Missing data will 
be counted but not included in percentage calculations. Where applicable, the same number of 
decimal places as in the raw data will be presented when reporting minimum and maximum, 1 
more decimal place than in the raw data will be presented when reporting mean and median, and 
standard deviation.  
Unless otherwise specified, patients will be counted only once in each tabular summary (e.g. 
each parameter & visit combination). Reported data that are excluded from tables, e.g. patients 
excluded from the corresponding analysis population or extraneous measurements (e.g. repeat 
assessments), will be included in the patient listings. 
The pre-treatment period is the time from informed consent to the date of first study drug 
administration of ferumoxytol or MM-398 respectively. On-treatment period for ferumoxytol is 
defined as time from ferumoxytol treatment administration to prior to MM-398 administration or 
within 30 days from date of ferumoxytol termination if patient didn’t receive MM-398.  The on-
treatment period for MM-398 is defined as time from the first administration of MM-398 to 30 


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days after date of MM-398 termination. Observations recorded on the same date of the first 
administration of study drug will be considered as on-treatment, unless otherwise indicated by 
collection time. The post-treatment period is the time following 30 days after the last 
administration of study drug.  
In general, the patient listings will be sorted by phase, patient number and assessment date (and 
time) if applicable.  
For patients who received study drug the reference start date (RFSTDT) is the date of MM-398 
administration. Study day is computed as: 
 (event/visit date  RFSTDT), if event/visit date < RFSTDT 
 (event/visit date  RFSTDT+1), if event/visit date ≥ RFSTDT. 
Tables, figures, and listings (TFLs) including intext TFLs as described in this document and in 
the mock shells, will be created using SAS version 9.4 or higher.  Mock table, listing, and figure 
shells will be developed for detailed information on the layout.  
7.2 Methods for Missing Data, Multiple Observations, and Outliers 
7.2.1 General Considerations 
In general, data will be analyzed as received from the clinical database. Hence, missing 
measurements including those caused by dropouts will not be imputed.    
7.2.2 Partial and Missing Dates 
Missing or partially missing date in the following situations will be imputed for purposes of 
analysis. 
Partial Dates for Death: It is anticipated that nearly all death dates will be completely captured. 
Any partially missing date of this type will be queried before statistical analyses are performed. 
In cases of partial dates, death date may be known to month and year. For the primary analysis, 
date recorded as month and year only will be imputed to the later date of: 1st of the 
corresponding month and last known alive date plus one day.   
Partial/Missing Dates for Study-Related Visits or Procedures: It is anticipated that all study-
related visit and procedure dates entered into the clinical study database will be complete (i.e. 
day, month, year are all recorded) and accurate. Any missing or partially missing date of this 
type will be queried before statistical analyses are performed. If the day, month, or year is still 
unknown, then the dates will be imputed as follows for purposes of analysis: 
  If the day of the visit or procedure date is missing, then take the previous visit and add 
the number of days to the next visit according to the visit schedule.  
  If the month of the visit or procedure date is missing, then take the previous visit and add 
the number of months to the next visit according to the visit schedule. 
  If the year of the visit or procedure date is missing, then the year will be queried. If the 
year is unknown, no imputation of year will take place.  
 


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Partial/Missing Start Date for Adverse Events or concomitant medications: Missing adverse 
event (AE) dates will be imputed for the purpose of classification as treatment emergent or not. 
For any adverse event or concomitant medication that has a missing or incomplete start date, a 
query will be issued to capture the full date. If only a partial date is reported for the start of an 
AE or medication, a complete date will be estimated using the following algorithm: 
 Completely missing (i.e., missing the year, month and day): the date of first study drug 
administration. Therefore, any such AE would be treatment emergent, and any such 
medication would be concomitant. 
 Only the year is reported (i.e., missing the month and day): earlier date of ‘1 January’ and 
the date of first study drug administration. 
 The year and month are reported (i.e., missing the day): earlier date of first day of the 
month and the date of first study drug administration. 
 
Partial/Missing End Date for Adverse Events or concomitant medications: If only a partial 
date is reported for the end of an AE or medication, a complete date will be estimated: 
 Completely missing: then the AE or medication will be considered ongoing at the end of 
the study.  
 Only the year is reported: ‘31 December’ will be used, unless this is after the date of final 
follow-up, in which case the AE or medication will be considered ongoing at the end of 
the study. 
 The year and month are reported: the last day of the month will be used, unless this is 
after the date of final follow-up, in which case the AE or medication will be considered 
ongoing at the end of the study. 
 
Partial/Missing start date of post study drug anticancer therapies:  If only a partial date is 
reported for the start date of post study drug anticancer therapies, a complete date will be 
estimated: 
 Completely missing (i.e., missing the year, month and day): the date of last study drug 
administration+1. 
 Only the year is reported: later date of ‘1 January’ and the date of last study drug 
administration+1. 
 The year and month are reported: later date of first day of the month and the date of last 
study drug administration +1. 
7.3 Multicenter Studies 
No by-center displays or adjustments for center are planned for this study. 
7.4 Multiple Comparisons and Multiplicity 
No testing will be performed in this study. 
7.5 Planned Subgroups, Interactions, and Covariates 
No subgroup analysis is planned. 


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7.6 Definitions and General Terminology 
7.6.1 Baseline 
 Baseline for Ferumoxytol Safety Period 
Baseline for the ferumoxytol period is the last observation before the administration of 
ferumoxytol.  
 Baseline for MM-398 Safety Period 
Baseline for the MM-398 safety period is the last observation before the first administration of 
MM-398.  
7.6.2 Protocol Deviations 
Important Protocol Deviations (IPDs) will be identified and documented for all patients in the 
safety population prior to database lock based on a review of patient data by sponsor. 
The potentially important protocol deviations to be reviewed include, but are not limited to 
patients who:  
1. Receipt of any prohibited therapies as defined in Section 6.5 of the protocol  
2. Inclusion/exclusion criteria deviations, unless a waiver was granted 
3. Significant deviations in study drug administration 
All IPDs will be listed by patient. The number and percentage of patients with IPDs will be 
summarized by type of deviation and by cohort. 
7.6.3 Study Periods 
For the evaluation of safety, assessments will be assigned to study periods. These will be: 
 Ferumoxytol safety period: from time of the first dose of ferumoxytol to the time of the 
first dose of MM-398. If an observation contains a date only, then the corresponding 
ferumoxytol safety period is the time from the date of the first dose of ferumoxytol to the 
day before the date of the first administration of MM-398. If the patient does not receive 
MM-398, the ferumoxytol safety period ends at 30 days after the date of the ferumoxytol 
dose.  
 MM-398 safety period: from time of the first dose of MM-398 to 30 days after the date of 
the last study drug administration of MM-398. If an observation contains a date only, 
then the corresponding MM-398 safety period begins on the date of the first 
administration of MM-398. 
 Events/observations will be assigned to study periods based on the start date or date and 
time if time is available. 
7.6.4 Derived and Computed Variables 
7.6.4.1 General 
When applicable, below derivation rules should be followed:  


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Time in months: the following will be used to compute time from date 1 to date 2 in months, 
which will be presented to one decimal place: 
time in months =(date2-date1+1)/(365.25/12); 
Age: the number of years since birth to date of informed consent. In SAS, this is computed as:  
          age = floor((intck('month',birthdate,ICdate)- (day(ICdate) < day(birthdate))) / 12); 
Body temperature in °C: body temperature will be presented in Celsius to one decimal place. 
Conversion from Fahrenheit is: 
temperature in °C = ([temperature in °F]-32)*(5/9); 
Weight in kg: weight will be presented in kilograms to one decimal place. Conversion from 
pounds is: 
weight in kg =0.4536*{weight in lb}; 
Height in cm: height will be presented in whole centimeters. Conversion from inches is: 
height in cm =2.54*{height in inches}; 
BMI: body mass index in kg/m2, presented to one decimal place: 
BMI ={weight in kg}/{height in cm/100}2; 
Time since cytological/histo-pathological diagnosis: time from date of first cytological or 
histo-pathological diagnosis to the date of informed consent in months. 
Time since last anticancer therapy: time from date of last dose of most recent prior anticancer 
therapy to the date of informed consent in months.  For example, if PAENDTC is the variable for 
prior anticancer last dose date: 
time since last treatment ={max(PAENDTC)-date of informed consent}; 
Time since metastatic diagnosis: time from date of first metastatic diagnosis to the date of 
informed consent in months. 
Time on treatment MM-398: number of days from first treatment to last treatment: 
{date of last MM-398 dose} - {date of first MM-398 dose}+1; 
Dose intensity (mg/m2/week): 
{cumulative actual dose in mg/m2}*7/ {days of exposure} 
where days of exposure for MM-398: (date of last study drug administration + 14  date of first 
study drug administration)  
 


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8 STUDY SUBJECTS 
Patient disposition for expansion Phase will be summarized by each cohort and total.  The total 
number of all screened patients will be used and presented in the column header and serves as 
the denominator for calculating percentage.   Following will be presented in the disposition table: 
 
The number and percentage of patients enrolled 
 
The number and percentage of patients screened failures 
 
Reasons for screen failures 
 
The number and percentage of patients dosed with ferumoxytol (Ferumoxytol Safety 
Population) 
 
The number and percentage of patients dosed with MM-398 (MM-398 Safety 
Populations) 
In addition, patient disposition will be summarized using safety population:  
 
The number and percentage of patients included in Efficacy Evaluable Population 
 
The number and percentage of patients included in PD population 
 
The number and percentage of patients discontinued from treatment early by reasons for 
discontinuation 
 
The number and percentage of patients discontinued from study (i.e. did not complete 
study to 30-day follow-up) early by reasons for discontinuation. 
8.1 Protocol Deviations 
Prior to database lock, Important Protocol Deviations (IPDs) will be identified through 
programmatic checks of study data, as well as through review of selected data listings. The 
potential IPDs to be reviewed include, but are not limited to, patients who: 
• 
Did not meet key inclusion/exclusion criteria  
• 
Received any disallowed concomitant medication during the treatment period 
• 
Other 
Individual IPDs will be presented in a data listing. The number and percentage of patients with 
IPDs will be summarized by study phases and overall. 
8.2 Inclusion and Exclusion Criteria 
Violations of key inclusion and exclusion criterion will be included in protocol violation 
tabulations.  Inclusion criteria will be listed for non-screen failures who did not meet criteria. 
Exclusion criteria will be listed for non-screen failures who met criteria. 
9 DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographics and baseline data will be presented by Pilot and Expansion Phases, where patients 
in expansion phases will be summarized by each cohort and total. No formal statistical analysis 
will be performed on these data. 


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Summaries will be created for the following patient characteristics: 
 Patient demographics (each analysis population) 
 Baseline disease characteristics (each analysis population) 
 Prior therapies (each analysis population) 
 Medical history and pre-existing conditions (MM-398 safety population) 
 Concomitant therapies (MM-398 safety population) 
 
9.1 Demographics 
A summary of the number and percentage of patients in each category for gender, race and 
ethnicity will be presented. Age (years), height (cm), weight (kg), body mass index (BMI) and 
body mass index group will be summarized using summary statistics for continuous variables. 
9.2 Baseline Characteristics 
The following baseline characteristics will be summarized, where applicable, by study phases 
and cohorts within expansion phase: 
 ECOG Status  
 UGT1A1*28 allele ( Homozygous 7/7, non-Homozygous) 
 Cancer site 
 Status of brain metastases 
 Time since histo-pathological diagnosis 
 Stage at diagnosis 
 Time since metastatic diagnosis 
9.3 Prior Anti-Cancer Therapy, Radiotherapy, and Surgery 
The following prior anticancer therapy (related to study indication) characteristics will be 
tabulated by study phases and cohorts within expansion phase: 
 Type of prior anti-cancer therapy 
 Administration setting 
 Number of prior anti-cancer regimens 
Time since last anti-cancer therapy prior to study enrollment will be summarized. 
Prior radiotherapies and prior surgeries related to study indication will be tabulated, with further 
tabulation by location and by reason for treatment/procedure. 
9.4 Medical History and Pre-existing Conditions 
Patient medical history will be coded by System Organ Class (SOC) and Preferred Term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA), version 17 or higher. Prior 
medical history will be tabulated.  
9.5 Prior and Concomitant Therapies  
Summaries of all medications taken during the course of the study will be recorded. Medications 
will be standardized based on the World Health Organization Drug Classification Dictionary 


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(WHODRUG, version 01DEC2017 WHODDE) Anatomic Therapeutic Class (ATC) Level II 
preferred term. 
All medications (excluding study drug) taken during the course of the study with a start date or 
an end date on or after the date of the first dose of MM-398, or marked as ongoing will be 
considered concomitant. Medications stopped prior to the date of the first dose of study drug will 
be considered as prior medication. Prior medications will be flagged on the concomitant 
medication listing. 
The number and percent of patients taking medications will be summarized by study period and 
WHODRUG ATC Level II and preferred term. In the tabular presentation, medications will be 
sorted by frequency and then alphabetically by preferred term.  If a patient has more than one 
qualifying record for a medication, the patient will be counted only once in the tabulation.  
9.6 Concomitant Procedures 
Concomitant procedures will be presented in a listing which will include the procedure term 
(verbatim), date, indication (reason for the procedure), yes/no indicator of relationship to an 
adverse event, and findings from the procedure. 
10 TREATMENT COMPLIANCE AND EXPOSURE 
Treatment exposure will be summarized separately for ferumoxytol and MM-398. Exposure to 
ferumoxytol will be summarized by the amount of drug administered, both as mg/kg and total 
mg.   
The following MM-398 exposure metrics will be summarized by cycle: 
 summary statistics for the amount of drug administered, in mg/m2 
 summary statistics for the amount of drug administered, in mg 
 number of patients with dose delay 
 number of patients with dose reduction. 
Overall exposure of MM-398 will be summarized by: 
 frequency table of the total number cycles of doses administered 
 summary statistics for treatment duration in weeks 
 cumulative dose received, in mg/m2 
 cumulative dose received, in mg 
 dose intensity, in mg/m2/wk 
11 EFFICACY ANALYSES 
11.1 Primary Efficacy Endpoints: 
The efficacy endpoints will be summarized for efficacy evaluable population and PD evaluable 
population by using descriptive statistics.  
Pilot Phase: 


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 Feasibility of FMX-MRI on identifying tumor associated macrophages (TAMs):  
FMX-MRI will be conducted on day 1 before and 1-4 h after intravenous ferumoxytol (FMX) 
administration, then after 24 h and/or 72 h.  For the quality scan of FMX-MRI, scanner type (i.e. 
1.5T), impact of scan quality on analysis (i.e. adequate for evaluation, suboptimal but completed 
for evaluation, or inadequate for evaluation), reasons for scan suboptimal/inadequate) and scan 
location (i.e. Body) will be assessed. 
 Tumor Levels of Irinotecan and SN-38:  
During pilot phase, two biopsies are collected on Day 4 of the ferumoxytol phase and two 
biopsies are collected three days after the first dose of MM-398.  Tumor levels of irinotecan and 
SN-38 in core biopsy will be measured after MM-398 dosing. 
 
Expansion Phase: 
 Feasibility of Ferumoxytol (FMX) Quantitation in Tumor Lesion 
Feasibility of ferumoxytol (FMX) quantitation in tumor lesion is also assessed through the 
acquisition of baseline and follow-up images of sufficient quality that enable quantitative 
analysis to be performed.  
Eligible patients should have serial FMX-MRI scans prior to and following FMX infusion as 
determined by their scan group.  After MRI acquisition, the R2* signal is used to calculate FMX 
levels in plasma, tumor lesions and reference tissue by comparison to a phantom-based standard 
curve.   
 The Relationship Between Ferumoxytol (FMX) tumor uptake and tumor response 
to MM-398 
FMX-MRI will be done for various tissues and at different timepoints.  Corrected FMX uptake 
(post-baseline value  baseline value) will be recorded by each time point and tissues.  
Ferumoxytol uptakes will be associated with change in tumor lesion size. 
 
11.2 Primary Efficacy Analysis:  
Pilot Phase  
In patients with NSCLC, CRC, TNBC, ER/PR positive breast cancer, pancreatic cancer, ovarian 
cancer, gastric cancer, GEJ adenocarcinoma or head and neck cancer, who are undergoing 
therapy with MM-398: 
 To evaluate the feasibility of delayed ferumoxytol MRI (FMX-MRI) to identify tumor 
associated macrophages (TAMs) 
The quality of FMX-MRI scan on impact of evaluation will be summarized descriptively 
by evaluation time points. For the quality scan of FMX-MRI, number of FMX-MRI scans 
obtained, number of scans accepted for evaluation, and scan location (i.e. Body) at each 
time point will be assessed. If there is more than one image data at the same timepoint for 
a patient, image data are averaged first before summarizing. 


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 To measure tumor levels of irinotecan and SN-38  
Tumor levels of irinotecan and SN-38 during Pilot phase were assessed through tumor 
tissue biopsy.  The data are summarized using descriptive statistics with n, min, max, 
mean 25th percentiles (Q1), 75th percentiles (Q3) and median per lesion. Tumor levels of 
irinotecan and SN-38 in core biopsy are reported in Merrimack Pharmaceuticals Synopsis 
Clinical Study Report MM-398-01-01-02, published on 18-Dec-2014 (Appendix X). No 
further analysis is required.  
Expansion Phase 
In patients with locally advanced or metastatic breast cancer: 
 To further investigate the feasibility of ferumoxytol (FMX) quantitation in tumor lesions   
Feasibility of ferumoxytol (FMX) quantitation in tumor lesion is assessed through the 
acquisition of baseline and follow-up images of sufficient quality that enable quantitative 
analysis to be performed. Sufficient quality is assessed by summarizing images that are 
adequate for evaluation, suboptimal but completed for evaluation, or inadequate for evaluation 
at each visit. 
 To characterize the relationship between ferumoxytol (FMX) tumor uptake and tumor 
response to MM-398  
Ferumoxytol uptakes will be associated with change in tumor lesion size. Corrected FMX 
results (ug/mL) from target lesion(s) at 24-hour scan is used to measure FMX tumor uptake. 
For the repeated scans performed at the same timepoint, the FMX tumor uptake will be 
averaged first before summarizing. For patient with multiple target lesions, average corrected 
FMX results should be used for analysis. FMX uptake will be classified as ‘low tumor uptake’ 
or ‘high tumor uptake’ using overall median as cutoff. Change in tumor size is used to assess 
tumor response to MM-398. For patient with multiple target lesions, the best change in tumor 
size achieved should be used.  The relationship between dichotomous FMX tumor uptake 
classification and tumor response to MM-398 will be assessed using Fisher’s exact test. 
 
11.3 Secondary Efficacy Analysis  
All Phases: 
 To assess tumor response to treatment 
11.3.1 Tumor Response-related Variables  
 Investigator determined tumor response assessment 
Investigator determined tumor assessments will be performed at baseline and at 8-week intervals 
following initiation of MM-398. Overall tumor response for post-baseline assessments will be 
classified as Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive 


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Disease (PD), Not Evaluable (NE) or Non-CR/Non-PD (no-target disease only) per RECIST 
version 1.1 criteria or modified RECIST criteria for cohort 3 CNS disease only.  
For each tumor assessment, investigators will evaluate and report on the CRF a classification of 
overall tumor response and its components (target lesions, non-target lesions, and new lesions). 
Main analyses of tumor response related variables will be based on the investigator assessment 
of tumor response. 
Derived efficacy evaluations including progression-free survival, best overall response, and 
objective response rate will be based on investigator determined tumor response data.  
 Radiological tumor response assessment 
In addition to investigator determined tumor response assessment, tumor that have FMX uptake 
measurement will also be measured radiologically in central facility. Response classifications 
will be algorithmically computed from the data on target lesions, non-target lesions and new 
lesions. The radiological tumor response will be reported separately for associating with 
ferumoxytol (FMX) uptake. 
11.3.2 Secondary efficacy variables (All Phases) 
Secondary efficacy analysis will be based on Investigator determined tumor response assessment 
following RECIST 1.1. Cohort 3 CNS disease will be analyzed according to RECIST and 
modified RECIST, separately. The worst case between RECIST and modified RECIST may be 
reported. 
11.3.2.1 
Progression-Free Survival (PFS)  
PFS is defined as the time in months from first dose of MM-398 to the date of radiologic disease 
progression by RECIST or mRECIST (cohort 3 CNS disease) per Investigator assessment or 
death due to any cause, whichever occurs first. 
Date of Progression: the earliest date that an overall tumor response of PD or death is recorded. 
Data handling conventions for determining the date of progression are outlined in Table 3.  
If progression is associated with a new lesion, the date of progression is the date when the new 
lesion was detected, where progression is associated with the sum of target lesions and different 
lesions are measured on different dates in a given visit, use the earliest date for visit as the date 
of progression.  
For patients who do not have qualifying progressive disease or death, the date of censoring for 
PFS is the date when the last valid tumor assessment determined a lack of progression. If the last 
valid tumor assessment involves measurements over multiple days in a visit, the date of the last 
measurement will be the censoring date. A tumor assessment is considered valid if data has been 
recorded for all target lesions and absence of new lesions is documented. Date of last non-
PD/non-NE assessment is the date of first dose date for patients without a valid post-baseline 
tumor assessment.  


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Table 3 Data handling rules for PFS analysis 
Condition 
Date of Progression or Censoring 
Event  
No baseline tumor assessments 
Date of first dose of MM-398 
Censored  
Progression documented within 12 
weeks* of baseline or the last non-
PD/non-NE tumor assessment 
Earliest of:  
 
date of radiographic assessment 
showing new lesion (if 
progression based on new 
lesion) or  
 
date of radiographic assessment 
of target/non-target lesions in 
which progression is 
documented 
Progression 
Death within 12 weeks* of last non-
PD tumor assessment without 
documented progression 
Date of death 
Progression 
Death or first documented 
progression after 12 weeks* from 
last non-PD tumor assessment  
Date of last non-PD assessment 
Censored 
None of the following: 
 
documented progression  
 
death 
 
treatment termination 
 
New anticancer therapy 
started 
 
cancer-related surgery 
Date of last non-PD assessment 
Censored 
Treatment termination for clinical 
deterioration without documented 
progression or death 
Date of last non-PD assessment or date of 
first dose of study drug MM-398  if no 
evaluable post-dose tumor assessment 
Censored 
Treatment termination for adverse 
event or other reason without 
documented progression or death 
Date of last non-PD assessment or date of 
first dose of study drug MM-398  if no 
evaluable post-dose tumor assessment 
Censored 
New anticancer therapy started prior 
to treatment termination without 
documented progression 
Date of last non-PD assessment prior to 
start of new anticancer therapy or date of 
first dose of study drug MM-398  if no 
evaluable post-dose tumor assessment 
Censored 
Cancer-related surgery prior to 
documented progression  
Date of last non-PD assessment prior to 
cancer related surgery or date of first dose 
of study drug MM-398  if no evaluable 
post-dose tumor assessment 
Censored 
*16 weeks will be used for PFS sensitivity analysis 
 


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As a sensitivity analysis, PFS will also be analyzed following the same censoring rule in table 3 
with 16 weeks of baseline or the last non-PD/non-NE tumor assessment time window being 
applied.  
Progression-Free Survival (PFS) will be presented for each cohort and overall for expansion 
phase.   
PFS assessed by investigator will be analysed using Kaplan-Meier method and descriptively 
summarized at 3 months interval for each dose level cohort. Median PFS time and corresponding 
95% confidence limits will be presented. 
11.3.2.2 
Best Overall Response (BOR) 
BOR is defined as the best response per RECIST recorded from first dose of MM-398 until 
progression or start of new anti-cancer therapy and/or surgery. Designation of SD requires at 
least one assessment of stable disease at least 4 weeks after starting treatment. Patients with 
insufficient data for response classification will be classified as Not Evaluable for best overall 
response in the efficacy evaluable population.  
 
The primary analysis for BOR will be based on the investigator-assessed response. BOR will be 
summarized by each cohort and overall for expansion phase. The analyses will be performed for 
efficacy evaluable population. 
11.3.2.3 
Objective Response Rate (ORR)  
ORR is defined as the proportion of patients with a BOR characterized as either a Complete 
Response (CR) or Partial Response (PR) relative to the total number of evaluable patients, 
expressed as a percentage. Evaluable patients are the treated patients with measurable disease at 
baseline. Patients with insufficient data for response classification will be classified as non-
responder for objective response in the efficacy evaluable population. 
The primary analysis for ORR will be based on the investigator-assessed response. ORR will be 
summarized by each cohort and overall for expansion phase and exact 95% confidence intervals 
based on the binomial distribution will be reported. The analyses will be performed for efficacy 
evaluable population. 
11.3.2.4 
Clinical Benefit Response (CBR) 
CBR24 is defined as the proportion of patients with a BOR characterized as a Complete Response 
(CR) at any time, Partial Response (PR) at any time, or Stable Disease (SD) ≥ 24 weeks relative 
to the total number of evaluable patients, expressed as a percentage. Evaluable patients are the 
treated patients with measurable disease at baseline. 
The primary analysis for CBR will be based on the investigator-assessed response. CBR will be 
summarized by each cohort and overall for expansion phase and exact 95% confidence intervals 
based on the binomial distribution will be reported. The analyses will be performed for efficacy 
evaluable population. 


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11.3.2.5 
Duration of Objective Response (DOR) 
DOR is defined as the time from first documentation of response (CR or PR whichever occurs 
first, by investigator assessment) to the date of disease progression or to death due to any cause, 
whichever occurs first. Duration of response will be computed only for patients who have CR or 
PR as best overall response. If progression or death does not occur for a patient with response, 
the patient’s duration of response will be censored in accordance with the rules used for PFS 
analysis.  Duration of objective response will be calculated for all patients that experience 
documented objective response during the study in weeks as follows: 
 
Duration of DOR (Months) = ((Date of Progression/Death/Censoring  Date of First Recorded CR 
or PR)+1) *12/365.25 
The primary analysis for DOR will be based on the investigator-assessed response. DOR will be 
summarized by each cohort and overall for expansion phase. The analyses will be performed for 
efficacy evaluable population. 
 
Imaging - Related: 
Pilot Phase: 
 To estimate the correlations between FMX-MRI, TAM levels, and tumor levels of 
irinotecan and SN-38 with administration of MM-398 
Scatter plot of FMX-MRI vs. tumor SN-38 level, TAM level and irinotecan level will be 
presented. For FMX-MRI, corrected FMX results across all scanned lesions at the same 
timepoint for a patient will be used. If there is more than one image data at the same 
timepoint for a patient, image data will be averaged first before summarizing. 
 
 To determine the value of FMX-MRI in directing tissue biopsy 
The value of FMX-MRI in directing tissue biopsy will be evaluated by summarizing the 
feasibility of ferumoxytol (FMX) quantitation in tumor lesions, feasibility of FMX-MRI 
to identify tumor associated macrophages (TAM), and the relationship assessment 
between ferumoxytol (FMX) tumor uptake and tumor response. 
 
Expansion Phase 
 To assess the association between deposition, as visualized by ferumoxytol imaging, 
and measures of efficacy 
The association will be performed on per lesion basis. The analysis will be combined into 
primary endpoint analysis “The Relationship Between Ferumoxytol (FMX) tumor uptake 
and tumor response to MM-398” in section 11.1 
 
 To assess the analytical performance of FMX-MRI measurements and optimize 
FMX-MRI parameterization 
The analytical performance of FMX-MRI measurements will be evaluated by 
summarizing phantom slopes and intercepts from all scans per instrument (site) and per 
instrument type (1.5 vs 3T). For each instrument or instrument type phantom slopes and 


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intercepts will be summarized per acquisition method (FSPGR vs MGRE) and per 
phantom type (body, head). The phantom slope over time will be summarized as rate of 
change (stability).  
Heterogeneity of lesion signal on baseline scan and 24h scan repeats will be summarized 
(interscan lesion signal  CV%; FSPGR and avg MGRE). Heterogeneity of signal 
between MGRE scan repeats will be summarized (intrascan lesion signal  CV%). 
Optimization of FMX-MRI parameterization will be evaluated by grouping FMX signals 
at 4 hour and 24 hours relative to the median value observed in the evaluable lesions and 
comparing these groups with the best change in lesion size seen by imaging (CT/MRI). 
Contrast to noise ratios of FMX lesion signals will be evaluated between responding and 
non-responding lesions (CR/PR) at all scan times. 
 
12 SAFETY ANALYSES 
Safety analyses will be based on safety population. 
The analysis of safety assessments in this study will include summaries following categories of 
safety and tolerability data collected for each patient: 
 Adverse Events 
o AEs and SAEs 
o AEs leading to discontinuation of study drug 
o TEAE 
o Deaths 
 Clinical Laboratory Investigations 
 Vital signs 
 ECG Investigations 
 Pregnancies (if any reported) 
 Physical exam 
Safety analyses will be presented for each safety population in accordance with the respective 
study periods (see Section 7.6.3). Safety analyses will be summarized by each cohort and overall 
for expansion phase. 
12.1 Adverse Events 
Adverse events will be coded using the MedDRA dictionary. Levels of classification will include 
primary system organ class and preferred term.  In addition, toxicity grading will be assigned 
according to NCI CTCAE. 
General Rules for summarizing AEs: 
(1) 
An AE will be considered as treatment-emergent (TE) if it begins on or after study drug 
dosing, starts prior to dosing and increases in grade/severity or seriousness after dosing, or 
starts prior to dosing but the causality changed to “related” after dosing. In case of missing 
dates, an AE will be considered as treatment-emergent. 


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(2) 
In the event of multiple adverse events being reported by the same patient, the most serious 
causality (related > not related) will be chosen. 
(3) 
In the event of multiple occurrences of the same adverse events being reported by the same 
patient, the maximum intensity (Grade 5 > Grade 4 > Grade 3 > Grade 2 > Grade 1 > 
missing > not applicable) and the most serious causality (related) will be chosen. 
(4) 
If a patient experiences the same AE (i.e. same preferred term) more than once, they are 
only counted once under the count for preferred term. 
(5) 
If a patient experiences more than one AE in a particular system organ class, they will only 
be included once in the count for the system organ class, but will appear in the count for 
each appropriate preferred term within the system organ class (unless it is the same preferred 
term).  
(6) 
AEs related to study drug tables include only those AEs with a relationship to study drug of 
‘related’ or if there is a missing relationship on the AE page of the CRF. 
(7) 
For AE severity the following rules will be applied in determining the counts of AEs: 
• 
An individual patient who experiences two AEs of the same preferred term of the 
same severity will be included once in the appropriate severity count for the particular 
AE. 
• 
An individual patient who experiences two AEs of the same preferred term but 
different severity will be included once in the severity count for the higher severity 
but not in the count for the lesser severity. 
• 
In the total counts for each severity classification, an individual patient who 
experiences two AEs of different preferred term of the same severity will be included 
once in the total for the appropriate severity. 
• 
In the total counts for each severity classification, an individual patient who 
experiences two AEs of different preferred term of different severities will be 
included once in the total for each of the appropriate severities. 
 
Tabular summaries will be presented for each cohort and overall for expansion phase. Summaries 
will include the number and percentage of patients and classified by primary system organ class 
and preferred term. The following summaries will be reported for AEs, TEAE regardless of drug 
relationship, TEAE related to study drug, TEAE grade 3 and above regardless of drug relationship, 
TEAE grade 3 and above related to study drug, serious AEs (SAEs), AE leading to study drug 
discontinuation, and AE leading to death: 
• 
Overall summary of adverse events will descriptively summarize all adverse events, 
treatment-emergent adverse events (TEAE), serious adverse events (SAEs), TEAE related 
to study drug, TEAE with CTCAE grade 3 and above, TEAE related to study drug with 
CTCAE grade 3 and above, TEAE leading to death, TEAE related to study drug leading to 
death, TEAE related to study drug leading to discontinuation, and TEAE related to study 
drug leading to dose adjustment (interruption or decrease). 
• 
Summary of TEAE by system organ class (SOC) and preferred term (PT) by decreasing 
frequency.  
• 
Summary of TEAE by CTCAE grade, SOC and PT, by decreasing frequency. 


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• 
Summary of TEAE related to study drug by SOC and PT, by decreasing frequency. 
• 
Summary of TEAE by CTCAE grade 3 and above, SOC and PT, by decreasing frequency. 
• 
Summary of TEAE related to study drug by CTCAE grade 3 and above, SOC and PT, by 
decreasing frequency. 
• 
Summary of TEAE related to study drug leading to dose adjustment (interruption or 
decreased), discontinuation and death by SOC and PT, by decreasing frequency. 
• 
Summary of TEAE related to study drug leading to discontinuation and death by SOC and 
PT, by decreasing frequency. 
• 
Summary of SAE by SOC and PT, by decreasing frequency. 
• 
Summary of SAE related to study drug by SOC and PT, by decreasing frequency. 
 
Listings of all AEs/TEAEs/SAEs will be presented by treatment group and sorted by patient id, 
start time, primary system organ class, preferred term and verbatim text for all adverse events 
recorded during the study, onset day relative to the first treatment date of AEs, date of Resolution, 
AEs, SAEs, related to study drug.  
 
Listing of AE leading to study drug discontinuation and death will be presented in each study 
period and treatment group.  
 
 
12.2 Clinical Laboratory Evaluations 
Scheduled clinical safety laboratory parameters will be summarized. Absolute laboratory values 
will be summarized by visit. Maximum and minimum change from baseline laboratory data will 
be summarized. Baseline will be the last measurement taken prior to the first study drug 
administration of MM-398. Frequency and percent of abnormal laboratory values will be 
assessed. Shift to most severe toxicity grade will be summarized. These include: 
 Hematology: hemoglobin, hematocrit, leukocytes, differential white blood cell count, 
absolute neutrophil count, platelets.  
 Chemistry: sodium, potassium, chloride, bicarbonate, alkaline phosphatase, ALT 
(SGPT), AST (SGOT), uric acid, blood area nitrogen, creatinine, LDH, glucose 
(random), calcium, magnesium, phosphate, total bilirubin, direct bilirubin, total protein, 
albumin.  
 Urinalysis: A urinalysis will include descriptions of color and clarity; pH; specific 
gravity; and analyses of blood, glucose, ketones and total protein. A microscopic 
examination of the urine, to include WBC, RBC, bacteria and casts will be performed if 
the urinalysis is abnormal.   
Abnormal lab values will be classified as low (lower than normal limit), normal (within normal 
range) and high (> upper normal limit). Laboratory values will also be assessed according to NCI 
CTCAE Version 4.0 or higher, where possible.  Abnormal lab values will be flagged (Low [L], 


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High, [H], abnormal clinically significant [C],) where applicable in the listing. Any unscheduled 
laboratory assessments will be flagged [U] in the listing. 
In addition, a separate listing will be created for all grade 3 and higher post-baseline laboratory 
observations and any out-of-range values that are identified by the investigator as being clinically 
significant. 
 
12.3 Vital Signs 
Vital signs data will be listed.  In the vital signs listings, all values outside the normal ranges will 
be flagged to indicate whether they are above the upper limit of reference range (H) or below the 
lower limit of the reference range (L). Vital signs will be tabulated for the change from baseline 
by timepoint. 
12.4 Electrocardiograms 
Listings will be presented for ECG data.  All ECG results of clinical significance, and those 
graded as CTCAE Grade 3 will be identified in the listing. 
12.5 ECOG Performance Score 
ECOG performance score will be summarized by study phase, study period, and study week. 
12.6 Physical Examinations 
Results of physical examinations will be listed by patient. 
12.7 Pregnancies 
Patients are to be discontinued from the study if they become pregnant.  Pregnancy data will be 
shown in a data listing if applicable. No special analysis will be performed on the pregnancy 
data.  
13 OTHER ANALYSES 
13.1 Pharmacodynamic Marker Analysis 
Post-hoc biomarker analysis may be performed. Details of analyses will be documented in a 
separate document. 
 
14 Population Summary Conventions 
 The population analyzed/displayed will be clearly and consistently identified on TLFs 
and will be identical in name to that identified in the protocol or SAP. 


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 Population sizes will be presented for each cohort as totals in the column header as 
(N=xxxx), where appropriate. 
 All population summaries for continuous variables will include: n, mean, SD, minimum, 
and maximum. Other summaries (e.g. median, quartiles, 5%, 95% intervals, CV or %CV) 
may be used as appropriate. 
 Summary statistic n values will denote the number of patients with non-missing values. 
 Population summaries for categorical variables will include only categories where at least 
one patient had a response.  
 In general, percentages will be rounded and reported to a single decimal point (xx.x%). 
Where percentages are reported as integers, percentages greater than 0% but <1% will be 
reported as <1% and percentages greater than 99% but <100% will be reported as >99%. 
A percentage of 100% will be reported as 100%, while 0% will be reported as a blank. 
 Population summaries that include p-values will report the p-value to three decimal 
places with a leading zero (0.001).  P-values <0.001 will be reported as <0.001. 
 
15 REFERENCES 
Awada, A, Garcia, AA, Chan, S, et al. (2013) Two schedules of etirinotecan pegol (NKTR-102) 
in patients with previously treated metastatic breast cancer: a randomised phase 2 study. 
Lancet Oncol., 14(12): 1216 25 
Eisehauer, EA et al. (2009). New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1). Eur. J Cancer, 45, 228 - 247. 
Kümler, I, Brünner, N, Stenvang, J, et al. (2013) A systematic review on topoisomerase 
1inhibition in the treatment of metastatic breast cancer. Breast Cancer Res. Treatm 
138(2): 347 58. 
ICH. (1995, November). E3: Structure and Content of Clinical Study Reports. Retrieved from 
http://www.ich.org 
ICH. (2005, November). The Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Retrieved from 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500002879.pdf 
US FDA. (2007, May). Guidance for Industry: Clinical Trial Endpoints for the Approval of 
Cancer Drugs and Biologics. Retrieved from 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/ucm0715900 
US FDA. (1998, September 16). International Conference on Harmonization; Guidance on on 
Statistical Principles fo Clinical Trials. Federal Register, 63(179), pp. 49583 - 49598. 
 
 


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16 APPENDIX A 
From http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
decreased 
6.2 mmol/L - 
4.9  mmol/L -  
<4.9 mmol/L 
  
< LLN  
<6.2 mmol/L 
Hemoglobin 
increase 
↑ in >0 – 2 g/dL 
above ULN  
↑ in >2 – 4 g/dL 
above ULN  
↑ in >4 g/dL 
above ULN  
  
or > BL if 
BL>ULN 
or > BL if 
BL>(ULN+2) 
or > BL if 
BL>(ULN+4) 
Lymphocyte 
decrease 
0.8x109/L – 
0.5x109/L  – 
0.2x109/L  – 
<0.2x109/L   
<LLN 
<0.8x109/L 
<0.5x109/L 
Neutrophils 
decrease 
1.5x109/L – 
1.0x109/L  – 
0.5x109/L  – 
<0.5x109/L   
<LLN 
<1.5x109/L 
<1.0x109/L 
Platelets decrease 
75.0x109/L – 
50.0x109/L – 
25.0x109/L – 
<25.0x109/L 
<LLN 
<75.0x109/L 
<50.0x109/L 
WBC decrease 
3.0x109/L – 
2.0x109/L – 
1.0x109/L – 
<1.0x109/L 
<LLN 
<3.0x109/L 
<2.0x109/L 
ALT 
>1 ULN –  
>3xULN – 
>5xULN – 
>20xULN 
increase 
3xULN 
5xULN 
20xULN 
Alkaline 
Phosphatase 
increase 
>1 ULN –  
>2.5xULN – 
>5xULN – 
>20xULN 
2.5xULN 
5xULN 
20xULN 
AST  
>1 ULN –  
>3xULN – 
>5xULN – 
>20xULN 
increase 
3xULN 
5xULN 
20xULN 
Total Bilirubin 
increase 
>1 ULN –  
1.5xULN 
>1.5xULN – 
3xULN 
>3xULN – 
10xULN 
>10xULN 
Creatinine 
increase 
>1xBL – 
>1.5xBL – 
>3xBL – 
>6xBL or 
1.5xBL or 
3xBL or 
6xBL or 
>6xULN  
>1xULN – 
>1.5xULN – 
>3xULN – 
  
1.5xULN 
3xULN 
6xULN 
  


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Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Calcium increase 
Corrected 
calcium*:  
> 2.9 mmol/L– 
> 3.1 mmol/L– 
>3.4 mmol/L 
>ULN – 
3.1 mmol/L 
3.4 mmol/L 
<2.9 mmol/L 
  
  
Calcium decrease 
Corrected 
calcium*: 
1.75 mmol/L –  
1.5 mmol/L – 
<1.5 mmol/L 
2.0 mmol/L – 
<2.0 mmol/L 
<1.75 mmol/L 
<LLN 
  
  
Albumin 
decrease 
3 g/dL - <LLN 
2 g/dL - < 3 g/dL 
< 2 g/dL 
  
Magnesium 
decrease 
0.5 mmol/L - 
<LLN 
0.4 mmol/L - 
<0.5 mmol/L 
0.3 mmol/L - 
<0.4 mmol/L 
<0.3 mmol/L 
Magnesium 
increase 
>ULN – 1.23 
mmol/L 
  
>1.23 mmol/L – 
3.30 mmol/L 
>3.30 mmol/L 
Potassium 
decrease 
3.0 mmol/L - 
<LLN 
  
2.5 mmol/L <3.0 
mmol/L 
<2.5 mmol/L 
Potassium 
increase 
>ULN – 5.5 
mmol/L 
>5.5 mmol/L – 
6.0 mmol/L 
>6.0 mmol/L – 
7.0 mmol/L 
>7.0 mmol/L 
Glucose decrease 
3.0 mmol/L - 
<LLN 
2.2 mmol/L – 3.0 
mmol/L 
1.7 mmol/L - 
<2.2 mmol/L 
<1.7 mmol/L 
Sodium decrease 
130 mmol/L - 
<LLN 
  
120 mmol/L - 
<130 mmol/L 
<120 mmol/L 
Sodium increase 
>ULN – 150 
mmol/L 
>150 mmol/L – 
155 mmol/L 
>155 mmol/L – 
160 mmol/L 
>160 mmol/L 
Phosphate 
decrease 
0.8 mmol/L - 
<LLN 
0.6 mmol/L - 
<0.8 mmol/L 
0.3 mmol/L - 
<0.6 mmol/L 
<0.3 mmol/L 
Uric Acid 
increase 
>ULN – 0.59 
mmol/L 
  
>0.59 mmol/L 
  
*Corrected calcium (mmol/L) = Ca(mmol/L) + 0.02[40(g/L)  albumin(g/L)]; refer to calcium 
(mmol/L) lab normal range for LLN and ULN values.