Conditions: Tumors
Keywords: FOLR-1 solid tumors
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 206
Healthy volunteers: no

Brief summary:
The purpose of this study is to test mirvetuximab soravtansine (IMGN853) in participants with ovarian cancer and other FOLR-1 positive tumors.

Detailed description:
The study consists of a dose-escalation phase that will evaluate 2 dosing schedules (Schedule A and Schedule B) of mirvetuximab soravtansine and up to 5 dose-expansion groups at the maximum tolerated dose (MTD). The first 4 escalation cohorts will be single participant cohorts. Subsequent escalation cohorts will use a standard 3+3 design, with each cohort consisting of 3 or 4 to 6 participants. Data were collected and analysed for the escalation and expansion groups by dose schedule and not by individual dose.

Arms:
arm 1: Participants will receive mirvetuximab soravtansine intravenous (IV) infusion on Day 1 of every 21-day (every 3 weeks \[Q3W\]) cycle. Dose escalation for this group schedule will start at 0.15 milligrams per kilogram (mg/kg) and proceed through 7.0 mg/kg. Doses calculated initially based on participant's total body weight (TBW); then from protocol amendment 5 onwards, calculated based on adjusted ideal body weight (AIBW). Participants will continue to receive mirvetuximab soravtansine (for clinical benefit) until unacceptable toxicity or withdrawal of consent, whichever comes first, or until the sponsor terminate the study. arm 2: Participants will receive mirvetuximab soravtansine IV infusion on Days 1, 8, and 15 of every 28-day cycle. Dose escalation for this group schedule will start at 1.1 mg/kg (calculated based on AIBW) and proceed through 2.5 mg/kg. Participants will continue to receive mirvetuximab soravtansine (for clinical benefit) until unacceptable toxicity or withdrawal of consent, whichever comes first, or until the sponsor terminate the study. arm 3: Participants with epithelial ovarian cancer (EOC) will receive mirvetuximab soravtansine 6.0 mg/kg (maximum tolerated dose \[MTD\]) IV infusion on Day 1 of every 21-day (Q3W) cycle (calculated based on AIBW). Participants will continue to receive mirvetuximab soravtansine (for clinical benefit) until unacceptable toxicity or withdrawal of consent, whichever comes first, or until the sponsor terminated the study. arm 4: Participants with endometrial cancer (EC) will receive mirvetuximab soravtansine 6.0 mg/kg (MTD) IV infusion on Day 1 of every 21-day (Q3W) cycle (calculated based on AIBW). Participants will continue to receive mirvetuximab soravtansine (for clinical benefit) until unacceptable toxicity or withdrawal of consent, whichever comes first, or until the sponsor terminate the study.

Interventions: intervention 1: Mirvetuximab soravtansine
Intervention descriptions: intervention 1: Mirvetuximab soravtansine IV infusion will be administered as per dose and schedule specified in the respective arms.

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 1, First-in-Human Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of 
IMGN853 in Adults with Ovarian Cancer and other FOLR1-
Positive Solid Tumors 
Study Number 
0401 
Study Phase: 
1 
Product Name: 
IMGN853 
IND Number: 
111,915 
Indication: 
Relapsed or Refractory FOLR1-Positive Solid Tumors 
Investigators: 
Multicenter 
Sponsor: 
ImmunoGen, Inc. 
830 Winter Street 
Waltham, MA 02451 USA 
Sponsor Contact: 
 
 
Phone: 
 
E-mail: 
Original Protocol Date: 
01 March 2012 
Amendment No. and Date: 
Amendment 1: 13 April 2012 
Amendment 2: 18 October 2012 
Amendment 3: 07 March 2013 
Amendment 4: 07 May 2013 
Amendment 5: 18 October 2013 
Amendment 6: 27 November 2013 
Amendment 7: 13 August 2014 
Amendment 8: 26 August 2014 
Amendment 9: 25 February 2015 
Amendment 10: 02 September 2015 
Confidential Statement 
This document is the proprietary and confidential property of ImmunoGen, Inc. 
NCT#: NCT01609556


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SPONSOR SIGNATURE PAGE  
 
 
 
 
 
830 Winter Street 
Waltham, MA 02451 
United States of America 
Tel: 
 
FAX: 
 
 
Date 
 
 
 


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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for IMGN853.  I have read the ImmunoGen 
Protocol #0401 and agree to conduct the study as outlined and in conformance with Good 
Clinical Practices (GCPs) and applicable regulatory requirements.  I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
_______________________________________________________ 
Printed Name of Investigator 
 
_______________________________________________________ 
Signature of Investigator 
 
______________ 
Date 
 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation or 
Specialist Term 
Explanation 
ADC 
Antibody drug conjugate 
ADCC 
Antibody-dependent cell mediated cytotoxicity 
AIBW 
Adjusted ideal body weight 
AE 
Adverse event 
ALT 
Alanine aminotransferase (SGPT) 
AMC 
Antibody maytansinoid conjugate 
ANC 
Absolute neutrophil count 
ALK-P 
Alkaline phosphatase 
aPTT 
Activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the time-concentration curve 
BAC 
Bronchioloalveolar carcinoma 
β-hCG 
beta-human chorionic gonadotropin  
BUN 
Blood urea nitrogen 
Cmax 
Maximum plasma drug concentration 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CL 
Clearance 
CR 
Complete response/remission 
CRF 
Case report form 
CRC 
Cohort Review Committee 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
DLT 
Dose limiting toxicity 
DM4 
N2’-[4-[(3-carboxypropyl)dithio]-4-methyl-1-oxo-2-sulfopentyl]-N2’-
deacetylmaytansine 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of Response 
EC 
Endometrial cancer 


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Abbreviation or 
Specialist Term 
Explanation 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
ELISA 
Enzyme-linked immunosorbent assay 
EOC 
Epithelial Ovarian Cancer 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed, paraffin embedded 
FIH 
First in Human 
FOLR1, FRα 
Folate receptor 1/Folate receptor α 
GCIG 
Gynecologic cancer intergroup  
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GPI 
Glycophosphatedylinositol 
HADA 
Human anti-drug antibody 
HAHA 
Human anti-human antibody 
Hct 
Hematocrit 
HED 
Human Equivalent Dose 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HNSTD 
Highest non-severely toxic dose 
IBW 
Ideal body weight 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IMGN 
ImmunoGen 
IND 
Investigational New Drug  
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
LBW 
Lean body weight 
LDH 
Lactic acid dehydrogenase 
LFT 
Liver function test 


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Abbreviation or 
Specialist Term 
Explanation 
Mab 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MRSD 
Maximum Recommended Starting Dose 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PCFT 
Proton-coupled folate transporter 
PD 
Progressive disease 
Pd 
Pharmacodynamic(s) 
PET 
Positron emission testing 
PFS 
Progression-free survival 
PGP 
p-glycoprotein 
PK 
Pharmacokinetics 
PO 
Per orem (by mouth) 
PR 
Partial response/remission 
PT 
Prothrombin time 
qPCR 
Quantitative real time polymerase chain reaction 
RBC 
Red blood cell (count) 
RNA 
Ribonucleic acid 
RP2D 
Recommended phase 2 dose 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
STD 
Standard  Deviation 
SGOT 
Serum glutamic oxaloacetic transaminase (AST) 
SGPT 
Serum glutamic pyruvic transaminase (ALT) 
SOC 
Standard of Care 
SOP 
Standard Operating Procedure 
SoD 
Sum of the longest diameters 


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Abbreviation or 
Specialist Term 
Explanation 
STD 
Severely Toxic Dose 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Half-life 
TBW 
Total body weight 
TTP 
Time to progression 
ULN 
Upper limit of normal 
US 
United States 
VHL 
Von Hippel Lindau 
VSS 
Volume of distribution at steady state 
WBC 
White blood cell (count) 
WCBP 
Woman of child bearing potential 
WHO 
World Health Organization 
WHO-DD 
World Health Organization –Drug Dictionary 
 


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PROTOCOL SYNOPSIS 
Title of Study:  A Phase 1, First-in-Human Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of IMGN853 in Adults with Ovarian Cancer and 
other FOLR1-positive Solid Tumors 
Study center(s): up to 10 in the United States and 1 site in Canada 
Studied period (months): Approximately 50 months 
(including follow up) 
First patient enrolled: June 28, 2012 
First patient dosed: July 9, 2012 
Phase of development: 1 
 
Purpose/rationale:  IMGN853 is a specific, targeted antibody maytansinoid conjugate (AMC) that binds 
with high affinity to folate receptor 1 (FOLR1), a GPI-linked protein, which is highly expressed on the 
surface of solid tumors, particularly epithelial ovarian cancer, endometrial cancer, NSCLC and renal cell 
cancer.  IMGN853 consists of a humanized anti-FOLR1 monoclonal antibody (M9346A) attached via a 
disulfide containing linker to the cytotoxic maytansinoid, DM4.  Once released within the target cell, 
DM4 acts as an anti-mitotic agent that inhibits tubulin polymerization and microtubule assembly, 
resulting in cell cycle arrest and apoptosis.  
In vitro, IMGN853 binds cell surface FOLR1 with high apparent affinity (≤ 0.1 nM) and shows potent 
(IC50 ≤ 1 nM) and selective cytotoxicity against tumor cells expressing FOLR1.  IMGN853 additionally 
demonstrates significant activity against FOLR1-positive xenografts, with partial and complete 
remissions observed in ovarian and NSCLC models.  Together with the selective upregulation of FOLR1 
in solid tumors, these results provide the rationale for exploring the clinical utility of IMGN853. 
This first-in-human (FIH) Phase 1 study is designed to establish the maximum tolerated dose (MTD) and 
determine the recommended Phase 2 dose (RP2D) of IMGN853 when administered intravenously as a 
single agent in adult patients with relapsed or refractory ovarian cancer and other FOLR1-positive solid 
tumors.  The safety, tolerability, pharmacokinetics (PK), pharmacodynamics (Pd), immunogenicity, and 
preliminary anti-tumor activity of IMGN853 will be characterized.  Two dosing schedules will be 
evaluated in this study: 
Schedule A: IMGN853 administered on Day 1, with cycles repeating every 21 days (Q3W) 
Schedule B: IMGN853 administered on Days 1, 8, and 15, with cycles repeating every 28 days (modified 
weekly) 
Amendment 10 Update: further evaluation of dosing Schedule B has been discontinued in this study. 
Objectives: The primary objectives of this study are to determine the MTD (dose escalation) 
and define the RP2D (MTD expansion) for the two dosing schedules.  The secondary objectives 
are to evaluate the safety and tolerability of IMGN853 and to characterize the PK, Pd, 
immunogenicity and preliminary efficacy of IMGN853.  The exploratory objectives are to 
determine any association between FOLR1 expression levels and clinical response and to 
evaluate potential biomarkers in blood and tumor tissue that might predict response to 
IMGN853.  
The study objectives are detailed in Sections 2.1, 2.3, and 2.5, and corresponding study 
endpoints are defined in Sections 2.2, 2.4, and 2.6. 
Number of patients (planned):  


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It is estimated that 209 patients* will be enrolled into the study. 
• Dose Escalation Phase: (1) Schedule A: 44 patients (2) Schedule B: 25 patients 
• Dose Expansion Cohort 1: Patients with epithelial ovarian cancer (EOC) which is 
resistant to platinum-based therapy: 40 patients  
• Dose Expansion Cohort 2: Advanced or recurrent uterine cancer : 20 patients  
• Dose Expansion Cohort 3 : Patients with relapsed EOC, which is amenable to biopsy: 20 
patients 
• Dose Expansion Cohort 4: Relapsed/refractory NSCLC adenocarcinoma or 
bronchioloalveolar carcinoma (BAC): 20 patients 
• Dose Expansion Cohort 5: Patients with EOC which has relapsed following platinum-
based therapy: 40 patients; this cohort of patients will receive prophylactic corticosteroid 
eye drops  
*NOTE: Every effort will be made to ensure the requisite number of patients are accrued in 
each cohort, and to this end, communications with the site will be monitored carefully. There 
are instances however, where, as a result of simultaneous screening activities, patients may 
qualify for the study at the same time, resulting in slight over-enrollment in individual cohorts 
The estimated study duration is approximately 50 months for patient accrual, dosing, and follow 
up. 
Study Design Overview and Schema: This is an open label, Phase 1, non-randomized, FIH 
study of IMGN853 in adult patients with FOLR1-positive solid tumors that have relapsed, or 
are refractory to standard therapies.  Two dosing schedules will be evaluated in this study:  
Schedule A: IMGN853 administered on Day 1, with cycles repeating every 21 days (Q3W) 
The dose escalation phase will initially enroll 1 patient each at the first four dose levels.  
Patients will be enrolled to subsequent cohorts using a standard 3+3 design, with each cohort 
consisting of 3 or 4 to 6 patients.  Amendment 10 Update: Dose escalation is complete and the 
MTD was determined to be 6 mg/kg (AIBW) and available data available to date indicate that 
the MTD is equal to the RP2D. Schedule A is currently being evaluated in the dose expansion 
cohorts.   
Schedule B: IMGN853 administered on Days 1, 8, and 15, with cycles repeating every 28 days 
(modified weekly) 


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The starting dose of IMGN853 was 1.1 mg/kg, which was 1/3 the 3.3 mg/kg dose level, which 
was deemed clinically safe in nine patients on a Q3W schedule.  All doses were calculated 
according to adjusted ideal body weight (AIBW).  Patients were enrolled in cohorts of 3 to 6 
patients and the MTD was determined to be 2.0 mg/kg (AIBW).  The CRC convened to review 
safety, PK and efficacy data from the dose escalation cohorts, as well as available data from 
patients treated on Schedule A.  These findings were presented at the ASCO annual meeting 
(Borghei 2015). 
The modified weekly schedule did not provide any apparent safety or efficacy advantage. Based 
on safety and overall response data collected through May 2015, the CRC determined that all 
new patients will receive IMGN853 treatment according to Schedule A (Q3W) only (Figure 2). 
All new patients enrolled in the trial will receive IMGN853 at the MTD of 6 mg/kg once every 
three weeks. Of note, safety data that are available to date indicate that the MTD is equal to 
the RP2D. 
The study design and methodology is outlined in detail in Section 4.1. 
 
 


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Main Criteria for Study Eligibility:  
Diagnosis, allowable prior therapy and disease measurability: 
• Dose Escalation Phase: 
All patients must have a pathologically documented, definitively diagnosed, advanced solid tumor 
that is refractory to standard treatment, for which no standard treatment is available, or the patient 
refuses standard therapy.  Patients may have measurable or non-measurable disease.  There is no 
upper limit on the number of prior treatment regimens the patient may have received, and prior 
treatment with folate receptor-targeting investigational agents is allowed. 
Enrollment (without prior documented FOLR1 expression) will be limited to the following 
histologic subtypes, which have a high incidence of FOLR1 positivity: 
• 
Serous or endometrioid EOC, primary peritoneal cancer, or fallopian tube cancer 
• 
Serous or endometrioid endometrial cancer 
• 
Adenocarcinoma or Bronchioloalveolar carcinoma (BAC) Non-small cell lung cancer (NSCLC) 
Patients with tumor types not listed above must have confirmation of ≥ 1% tumor cells with ≥ 1 FOLR1 
positivity by immunohistochemical staining (IHC) prior to enrollment (see the Laboratory Manual for IHC 
screening procedures).  The tumor samples will be analyzed for folate receptor alpha FRα expression in 
the Companion Diagnostics Pharma Services CAP-accredited and CLIA-certified laboratory and Pathology 
Services at Ventana Medical Systems, Inc. 
• Dose Expansion Phase: 
• Dose Expansion Cohort 1 – patients with platinum resistant EOC 
o Patients must have histologically-confirmed EOC, primary peritoneal cancer or 
fallopian tube cancer that is resistant to platinum therapy.  
o Patients must have platinum-resistant ovarian cancer, which is defined as disease 
that responded to primary platinum therapy and then progressed within six 
months or disease that progressed during or within six months of completing 
subsequent platinum therapy.  
o Patients must meet the minimum requirement of FOLR1 positivity by IHC (≥25% of 
tumor staining at ≥2+ intensity).  
o Patients with primary platinum refractory disease (those who have not responded to a 
platinum-based regimen or experienced disease recurrence within three months of 
completing their first platinum-based regimen) are excluded.   
o Patients with clear cell or low grade ovarian cancer are excluded. 
o Patients should not have received more than five prior systemic treatment regimens.  
o Patients must have at least one lesion that meets the definition of measurable according 
to RECIST 1.1 (Appendix E). 
 
• Dose Expansion Cohort 2– patients with advanced or recurrent uterine 
malignancies 


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o Patients must have histologically-confirmed diagnosis of advanced or recurrent 
uterine cancer  
o Patients must have confirmation of FOLR1 expression by IHC (enrollment cut-off H score 
≥100). 
o Patients must have received at least one platinum-based chemotherapy regimen and no 
more than five prior systemic treatment regimens (including cytotoxic chemotherapy, 
hormonal therapy, and targeted therapy, or any other investigational treatment in the 
adjuvant or the metastatic setting) for EC. 
o The subject must have at least one lesion that is measurable on CT or MRI scan 
determined by investigator per RECIST Version 1.1 
• Dose Expansion Cohort 3, relapsed ovarian cancer, which is amenable to biopsy: 
o Patients must have relapsed EOC, primary peritoneal cancer or fallopian tube cancer; 
patients with primary refractory disease (those who have not responded to a platinum-
based regimen or experienced disease recurrence within three months of completing 
their first platinum-based regimen) are excluded. 
o Patients with clear cell or low grade ovarian cancer are excluded. 
o Patients must be willing to undergo tumor biopsy prior to the first dose of IMGN853 and 
on Cycle 2, Day 8±3 days. 
o Patients must meet the minimum requirement of FOLR1 positivity by IHC (≥25% of 
tumor staining at ≥2+ intensity).  
o There is no upper limit on the number of prior treatment regimens (cytotoxic and/or 
targeted therapies) the patient may have received. 
o Patients may have measurable or non-measurable disease (such as large abdominal 
masses that cannot be accurately measured) as defined by RECIST 1.1 (Appendix E). 
• Dose Expansion Cohort 4, relapsed/refractory NSCLC adenocarcinoma or BAC 
o Patients must have histologically or cytologically-confirmed NSCLC adenocarcinoma or 
BAC, and must be refractory to or cannot tolerate standard of care (SOC). 
o Patients must meet the minimum requirement of FOLR1 positivity by IHC (≥25% of 
tumor staining at ≥1+ intensity).  
o There is no upper limit on the number of prior treatment regimens (cytotoxic and/or 
targeted therapies) the patient may have received. 
o Patients may have measurable or non-measurable disease (such as large masses 
that cannot be accurately measured) as defined by RECIST 1.1 (Appendix E). 
 
 
 
 
• 
Dose Expansion Cohort 5 - Patients enrolled in this cohort will receive corticosteroid eye 
drops as primary prophylaxis to assess whether they reduce the risk or severity of blurred 
vision and/or keratopathy observed following treatment with IMGN853. 


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o Patients must have one of the following pathologically documented, definitively 
diagnosed tumor types: 
- 
Advanced EOC  
- 
Primary peritoneal cancer  
- 
Fallopian tube cancer  
o Patients must have received at least 3 but not more than 4 prior systemic treatment 
regimens 
o Patients must have confirmation of ≥ 2 FOLR1 positivity by IHC (≥25% of tumor staining 
at ≥2+ intensity).  
o Patients with primary platinum refractory disease (those who have not responded to a 
platinum-based regimen or experienced disease recurrence within three months of 
completing their first platinum-based regimen) are excluded.   
o Patients with clear cell or low grade ovarian cancer are excluded. 
o Patients must be willing and able to self-administer corticosteroid eye drops four times 
a day, for the first 10 days of each cycle, during active study treatment.  
o Patients must have measurable or non-measurable disease (such as large abdominal 
masses that cannot be accurately measured) per RECIST 1.1 (Appendix E). 
Main Eligibility Criteria for All Patients: 
• Patients with CNS metastases are eligible if they meet the requirements outlined in 
the Inclusion Criteria (Section 3.1.1).  Other standard inclusion criteria will be 
employed and are detailed in Section 3.1.1. 
• Patients will be excluded if they have > Grade 1 peripheral neuropathy, or an active 
or chronic corneal disorder. 
• Patients who have received prior allogeneic or autologous bone marrow transplants 
will not be enrolled.  
Additional exclusion criteria are detailed in Section 3.1.2.   
Investigational product, dosage, and mode of administration: Two IMGN853 administration 
schedules will be investigated: 
Schedule A: IMGN853 administered IV on Day 1, with cycles repeating every 21 days (Q3W) 
• The starting dose was 0.15 mg/kg based on total body weight. 
• With amendment 5, the starting dose using adjusted ideal body weight (AIBW) was 
5.0 mg/kg. 
Schedule B: IMGN853 administered IV on Days 1, 8, and 15, with cycles repeating every 28 days 
(modified weekly schedule) 
• 
The starting dose was 1.1 mg/kg, calculated using AIBW. 
• 
The MTD was 2.0 mg/kg (AIBW). This schedule of administration will not be further 
evaluated in this study. 
The dose of IMGN853, used in both Schedule A and Schedule B dose escalation schedules and 
in all expansion cohorts, will be calculated using adjusted ideal body weight (AIBW).  Treatment 
guidelines and dose modification guidelines are detailed in Section 5.9. 


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Duration of treatment: The period of observation extends from the time the patient receives the first 
dose of IMGN853 until the final follow-up study visit.  Patients will continue to receive IMGN853 until 
they develop progressive disease (PD), unacceptable toxicity, withdraw consent, or until the Sponsor 
terminates the study. Patients who discontinue study drug for reasons other than PD will be followed 
until PD or start of new anti-cancer therapy, or death, whichever occurs first.   
Statistical methods: There will be no formal hypothesis testing.  All descriptive statistical analyses will 
be performed using the most recently released and available SAS statistical software, unless otherwise 
noted.  For categorical variables, the number and percent of each category within a parameter will be 
calculated.  For continuous variables, the sample size (n), mean, median, and standard deviation, as well 
as the minimum and maximum values, will be presented.  Missing data will not be imputed unless 
otherwise stated.  There will be a detailed description of patient disposition; patient demographics and 
baseline characteristics will be summarized.  PK data will be presented descriptively and graphically. 
No formal interim analysis is planned for this study.  However, a review of safety data and available 
preliminary PK data will be conducted by the Cohort Review Committee (CRC, Section 4.1.2) upon 
completion of each dose escalation cohort, and every 2 or 4 weeks during MTD Dose Expansion. A 
statistical analysis plan (SAP) will fully describe the planned analyses for this study.  
Sample Size:  Ascending doses of IMGN853 will be evaluated to identify the MTD for both 
dosing schedules.  The actual number of patients accrued during this phase will be determined 
largely by the findings observed during the course of their treatment.   
Following identification of the MTD for Schedule A (Q3W), there will be an expansion phase 
which will accrue two cohorts each at the MTD:  
(1) Dose Expansion Cohort 1:  40 patients with platinum resistant EOC. The sample size of 
Schedule A Cohort 1 was increased from 20 to 40 to better define the frequency of ocular 
adverse events and assess the impact of the proposed toxicity management guidelines. 
Given a sample size of 40 patients, the power to detect a difference of 20% (rate of Blurry vision 
drop from 50% to 30%) is 68% using one-sided alpha of 20% and Chi-Square test statistics.(2) 
Dose Expansion Cohort 2: 20 patients with advanced or recurrent uterine cancer. 
Amendment 10 Update: The CRC committee met and reviewed the available safety and response data. 
The decision was made to proceed with Schedule A only. All new patients enrolled in the trial will 
receive IMGN853 at the MTD of 6 mg/kg once every three weeks. Safety data available to date indicate 
that the MTD is equal to the RP2D. 
(3) Dose Expansion Cohort 3: 20 patients with relapsed ovarian cancer, which is amenable to 
biopsy.  
(4) Dose Expansion Cohort 4:  20 patients with relapsed/refractory NSCLC adenocarcinoma or 
BAC. 
(5) Dose Expansion Cohort 5:  40 patients with relapsed EOC. In this cohort of patients, the use 
of corticosteroid eye drops as part of the management plan for treatment-emergent ocular 
adverse events will be evaluated. Given a sample size of 40 patients, the power to detect a 
difference of 20% (rate of Blurry vision decrease from 50% to 30%) is 68% using one-sided alpha 
of 20% and Chi-Square test statistics. 


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Cohorts evaluated under two dosing schedules, will be referenced in clinical study documents by 
both cohort number and schedule (e.g. Cohort 1A).  
If the true DLT rate at the MTD is 10-20%, there is a 98.5-99.9% probability of observing at 
least 1 dose limiting toxicity (DLT) in the 40 patient cohorts.  If the true response rate at the 
MTD is 20%, there is a 99.9% probability of observing at least 1 response in the 40 patient 
cohorts.   
Approximately 209 patients will be enrolled allowing for dropouts and expansion of dose 
escalation cohorts as needed.   


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................4 
PROTOCOL SYNOPSIS ................................................................................................................8 
TABLE OF CONTENTS ...............................................................................................................16 
1. 
INTRODUCTION ......................................................................................................25 
1.1. 
Target Background .....................................................................................................25 
1.2. 
IMGN853 ....................................................................................................................28 
1.3. 
Epithelial Ovarian Cancer (EOC), Endometrial Cancer (EC) and NSCLC ...............29 
1.3.1. 
EOC ............................................................................................................................29 
1.3.2. 
NSCLC .......................................................................................................................30 
1.3.3. 
Endometrial Carcinoma ..............................................................................................30 
1.4. 
Non-Clinical Studies of IMGN 853 ............................................................................30 
1.4.1. 
Pharmacology .............................................................................................................30 
1.4.2. 
Pharmacokinetics ........................................................................................................31 
1.4.2.1. 
Single Dose Non-GLP Studies in CD-1 Mice ............................................................31 
1.4.2.2. 
Single Dose Toxicokinetics of IMGN853 in Cynomolgus Monkeys .........................31 
1.4.2.3. 
PK of Free DM4 in Cynomolgus Monkeys ................................................................32 
1.4.3. 
Toxicology ..................................................................................................................32 
1.4.3.1. 
Single-Dose GLP Cynomolgus Monkey Toxicology Study ......................................32 
1.4.3.2. 
Single-Dose IV Toxicity Studies with DM4 in Mice and Monkeys ..........................33 
1.4.3.3. 
Acute Toxicity Profile of IMGN853 (M9346A-sulfo-SPDB-DM4) and 
M9346A-SPDB-DM4 in Female CD-1 Mice .............................................................34 
1.5. 
Rationale for the starting dose ....................................................................................34 
1.6. 
Clinical Hypothesis .....................................................................................................34 
1.7. 
Rationale for the Study Plan .......................................................................................34 
1.8. 
History of Amendments ..............................................................................................37 
1.8.1. 
Amendment 1 Summary of Key Changes ..................................................................37 
1.8.2. 
Amendment 2 Summary of Key Changes ..................................................................37 
1.8.3. 
Amendment 3 Summary of Key Changes ..................................................................38 
1.8.4. 
Amendment 4 Summary of Key Changes ..................................................................38 
1.8.5. 
Amendment 5 Summary of Key Changes ..................................................................39 
1.8.6. 
Amendment 6 Summary of Key Changes ..................................................................39 


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1.8.7. 
Amendment 7 Summary of Key Changes ..................................................................40 
1.8.8. 
Amendment 8 Summary of Key Changes ..................................................................40 
1.8.9. 
Amendment 9 Summary of Key Changes ..................................................................40 
1.8.10. 
Amendment 10 Summary of Key Changes ................................................................42 
1.9. 
Early Clinical Safety Findings ....................................................................................44 
1.10. 
Clinical Pharmacology ................................................................................................44 
1.10.1. 
Rationale for Dosing Based on Adjusted Ideal Body Weight ....................................44 
1.10.2. 
Rationale to Explore a Modified Weekly Dosing Schedule .......................................45 
2. 
TRIAL OBJECTIVES AND ENDPOINTS ...............................................................47 
2.1. 
Primary Objectives .....................................................................................................47 
2.2. 
Primary Endpoints ......................................................................................................47 
2.3. 
Secondary Objectives .................................................................................................47 
2.4. 
Secondary Endpoints ..................................................................................................47 
2.5. 
Exploratory Objectives ...............................................................................................47 
2.6. 
Exploratory Endpoints ................................................................................................48 
3. 
STUDY POPULATION .............................................................................................50 
3.1. 
Criteria for Selection of Patient Population ................................................................50 
3.1.1. 
Inclusion Criteria (All Patients) ..................................................................................52 
3.1.2. 
Exclusion Criteria (All Patients) .................................................................................53 
4. 
INVESTIGATIONAL PLAN .....................................................................................55 
4.1. 
Study Design ...............................................................................................................55 
4.1.1. 
Overview and Schema ................................................................................................55 
4.1.2. 
Cohort Review Committee .........................................................................................56 
4.1.3. 
Dose Escalation Guidelines ........................................................................................57 
4.1.3.1. 
Schedule A ..................................................................................................................57 
4.1.3.2. 
Schedule B ..................................................................................................................58 
4.1.3.3. 
Dose Escalation Rules (3+3 Design) ..........................................................................59 
4.1.4. 
Definition of Dose-Limiting Toxicity (DLT) .............................................................59 
4.1.5. 
Dose Expansion Cohorts .............................................................................................61 
5. 
STUDY TREATMENT ..............................................................................................63 
5.1. 
Description of Study Treatment ..................................................................................63 
5.2. 
IMGN853 Packaging ..................................................................................................63 
5.3. 
Storage, Handling and Compatibility .........................................................................63 


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5.4. 
Study Treatment Compliance .....................................................................................63 
5.5. 
Assignment of Patient Number ...................................................................................64 
5.5.1. 
Enrolled Patient Definition .........................................................................................64 
5.5.2. 
Patient Assignment to Dosing Schedules ...................................................................64 
5.6. 
Blinding ......................................................................................................................64 
5.7. 
Study Treatment Administration ................................................................................64 
5.7.1. 
Study Treatment Overview and Schedule ..................................................................64 
5.7.1.1. 
Every 3-Week Schedule (Q3W) .................................................................................64 
5.7.1.2. 
Modified Weekly  Schedule (Days 1, 8 and 15, Every 28 Days) ...............................64 
5.8. 
IMGN853 Preparation and Administration ................................................................65 
5.8.1. 
Premedication to Prevent Infusion Reaction ..............................................................65 
5.8.1.1. 
Schedule A ..................................................................................................................65 
5.8.1.2. 
Schedule B ..................................................................................................................65 
5.8.2. 
Premedication with Corticosteroid Eye Drops (Dose Expansion Cohort#5 
ONLY) ........................................................................................................................65 
5.8.3. 
Lubricating Eye Drops ................................................................................................65 
5.8.4. 
Calculation for Adjusted Ideal Body Weight .............................................................66 
5.8.5. 
IMGN853 Administration ..........................................................................................66 
5.8.6. 
Management of Potential IMGN853 Infusion-related Reactions ...............................67 
5.8.7. 
Monitoring and Management of Infusion-Associated Headaches ..............................69 
5.8.8. 
Monitoring and Management of Treatment-emergent Eye Disorders ........................69 
5.8.8.1. 
Monitoring - Potential Ocular Disorders ....................................................................69 
5.8.8.2. 
Management Guidelines for Eye Disorders ................................................................70 
5.8.9. 
Management of Non-Infectious Pneumonitis .............................................................71 
5.8.10. 
Monitoring and Management of Diarrhea ..................................................................73 
5.8.11. 
Monitoring and Management of Nausea and Vomiting .............................................73 
5.9. 
Treatment Guidelines ..................................................................................................74 
5.9.1. 
Re-treatment Criteria ..................................................................................................74 
5.9.1.1. 
To Begin a New Cycle of Treatment ..........................................................................74 
5.9.1.2. 
To Continue Treatment within a Cycle- Schedule B (modified weekly) ...................75 
5.9.2. 
Follow-up for DLTs and AEs Leading to Discontinuation ........................................75 
5.9.3. 
Criteria for Re-Initiation of Study Treatment Following Occurrence of a 
DLT .............................................................................................................................75 


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5.9.4. 
Dose Modification Guidelines ....................................................................................76 
5.9.4.1. 
Dose Reduction Following DLT ................................................................................76 
5.9.4.2. 
Criteria for Re-initiation of Study Treatment Following Occurrence of a 
DLT .............................................................................................................................76 
5.9.5. 
Discontinuation of Study Treatment Due to Toxicity ................................................76 
5.10. 
Removal of the Patients from the Trial or Study Drug ...............................................77 
5.10.1. 
Replacement of Patients who are Withdrawn Prior to the End of Cycle 1 .................77 
5.11. 
Period of Observation .................................................................................................77 
5.12. 
Concomitant Medications and Procedures .................................................................77 
5.12.1. 
Lubricating Artificial Tears ........................................................................................78 
5.12.2. 
Corticosteroid Eye Drops ...........................................................................................78 
5.12.3. 
Antiemetic and antidiarrheal medications ..................................................................78 
5.12.4. 
Acetaminophen ...........................................................................................................78 
5.12.5. 
Folate-Containing Vitamins........................................................................................78 
5.12.6. 
Antineoplastic Therapy ...............................................................................................78 
5.12.7. 
Hematopoietic Growth Factors ...................................................................................78 
5.12.8. 
Anticoagulants ............................................................................................................78 
5.12.9. 
Other Concomitant Medications .................................................................................79 
5.13. 
Overdose and Medication Error ..................................................................................79 
6. 
PHARMACOKINETIC (PK ASSESSMENTS) ........................................................80 
6.1. 
Overview .....................................................................................................................80 
6.2. 
PK Schedule ................................................................................................................80 
6.2.1. 
Schedule A ..................................................................................................................80 
6.2.2. 
Schedule B ..................................................................................................................80 
6.2.3. 
Additional PK Samples...............................................................................................81 
6.3. 
Immunogenicity Assessments ....................................................................................81 
7. 
TRANSLATIONAL RESEARCH STUDIES ............................................................82 
7.1. 
Correlation between FOLR1 Expression and IMGN853 anti-tumor activity ............82 
7.1.1. 
Evaluation of FOLR1 Expression in Tumor Tissue During Dose-Escalation 
and Dose Expansion ...................................................................................................82 
7.2. 
Exploratory Biomarker Studies ..................................................................................83 
7.2.1. 
Potential Markers of Drug Sensitivity ........................................................................83 
7.2.2. 
Potential Markers of Drug Resistance ........................................................................83 


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7.2.3. 
Folate Pathway Markers .............................................................................................83 
7.3. 
Pharmacodynamic (Pd) and Proof of Mechanism (POM) Analyses ..........................83 
7.3.1. 
Pd and PoM studies in Tumor Biopsies (EOC Expansion Cohort #3 Only) ..............83 
8. 
STUDY PROCEDURES ............................................................................................85 
8.1. 
Informed Consent .......................................................................................................85 
8.2. 
Inclusion and Exclusion Criteria ................................................................................85 
8.3. 
Confirmation of Disease Diagnosis ............................................................................85 
8.4. 
Demographic/Medical History ...................................................................................85 
8.5. 
Physical Examination, Weight and Height .................................................................85 
8.6. 
Vital Signs ..................................................................................................................86 
8.7. 
Electrocardiogram (ECG) ...........................................................................................86 
8.8. 
Pulse Oximetry ...........................................................................................................87 
8.10. 
Laboratory Assessments .............................................................................................87 
8.10.1. 
Clinical Laboratory Panels .........................................................................................87 
8.11. 
Pregnancy Screen ........................................................................................................88 
8.12. 
Eastern Cooperative Oncology Group Performance Status ........................................88 
8.13. 
Radiologic Imaging ....................................................................................................88 
8.14. 
Tumor Response Assessment .....................................................................................88 
8.15. 
Eligibility based on FOLR1 Expression .....................................................................89 
8.15.1. 
Dose Escalation Cohorts .............................................................................................89 
8.15.2. 
Dose Expansion Cohort #1, Platinum Resistant Ovarian Cancer ...............................89 
8.15.3. 
Dose Expansion Cohort #2, Advanced/Recurrent Uterine Cancer .............................89 
8.15.4. 
Dose Expansion Cohort #3, Relapsed Ovarian Cancer ..............................................89 
8.15.5. 
Dose Expansion Cohort #4, Relapsed/Refractory NSCLC Adenocarcinoma ............90 
8.15.6. 
Dose Expansion Cohort #5, Relapsed Ovarian Cancer ..............................................90 
9. 
ASSESSMENT OF SAFETY .....................................................................................91 
9.1. 
Adverse and Serious Adverse Events .........................................................................91 
9.1.1. 
Definition of Adverse Events .....................................................................................91 
9.1.1.1. 
Adverse Event (AE) ....................................................................................................91 
9.1.1.2. 
Serious Adverse Event (SAE) ....................................................................................92 
9.2. 
Recording Adverse Events .........................................................................................93 
9.2.1. 
Reporting Serious Adverse Events .............................................................................93 
9.2.2. 
Reporting a Pregnancy ................................................................................................94 


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10. 
STUDY ACTIVITIES ................................................................................................95 
10.1. 
Screening Visit (Days -28 to -1) .................................................................................95 
10.1.1. 
Standard of Care Assessments ....................................................................................96 
10.2. 
Cycle 1 Assessments ...................................................................................................96 
10.2.1. 
Cycle 1, Day 1 ............................................................................................................96 
10.2.2. 
Cycle 1, Day 2 ............................................................................................................98 
10.2.3. 
Cycle 1, Day 3 and Day 4, or 5 ...................................................................................98 
10.2.4. 
Cycle 1, Day 8 and 15 .................................................................................................98 
10.2.5. 
Cycle 1, Day 16 (Schedule B only) ............................................................................98 
10.2.6. 
Cycle 1, Day 22 (Schedule B only) ............................................................................98 
10.3. 
Cycle 2 Assessments ...................................................................................................98 
10.3.1. 
Cycle 2, Day 1 ............................................................................................................98 
10.3.2. 
Cycle 2, Day 8±3 Days ...............................................................................................99 
10.3.3. 
Cycle 2, Day 8 and 15 .................................................................................................99 
10.4. 
Cycle 3 Assessments .................................................................................................100 
10.4.1. 
Cycle 3, Day 1 ..........................................................................................................100 
10.4.2. 
Cycle 3, Day 2 ..........................................................................................................100 
10.4.3. 
Cycle 3, Day 3 and Day 4 or 5 (Schedule A Only) ..................................................101 
10.4.4. 
Cycle 3, Day 8 and 15 ...............................................................................................101 
10.4.5. 
Cycle 3, Day 16 (Schedule B only) ..........................................................................101 
10.4.6. 
Cycle 3, Day 22 (Schedule B only) ..........................................................................101 
10.5. 
Even-Numbered Cycles (2, 4, 6, etc.), End of Cycle ................................................101 
10.6. 
Cycles ≥ 4 Assessments ............................................................................................102 
10.6.1. 
Cycles ≥4, Day 1 .......................................................................................................102 
10.6.2. 
Cycles > 4, Day 8 and 15 (Schedule B) ....................................................................103 
10.7. 
End of Treatment Visit .............................................................................................103 
10.8. 
Follow-up Assessments ............................................................................................104 
11. 
STATISTICAL METHODS .....................................................................................106 
11.1. 
Sample Size ..............................................................................................................106 
11.2. 
Pharmacokinetic Analyses ........................................................................................107 
11.3. 
Safety Analyses ........................................................................................................107 
11.4. 
Efficacy .....................................................................................................................108 
12. 
QUALITY CONTROL AND ASSURANCE ..........................................................109 


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13. 
ADMINISTRATIVE CONSIDERATIONS, STUDY MONITORING AND 
DATA MANAGEMENT .........................................................................................110 
13.1. 
Investigators and Study Administrative Structure ....................................................110 
13.2. 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ...................................................................................................................110 
13.3. 
Ethical Conduct of the Study ....................................................................................110 
13.4. 
Patient Information and Consent ..............................................................................110 
13.5. 
Patient Confidentiality ..............................................................................................111 
13.6. 
Study Monitoring ......................................................................................................111 
13.7. 
Case Report Forms and Study Reports .....................................................................112 
13.8. 
Critical Documents ...................................................................................................112 
13.9. 
Protocol Violations/Deviations .................................................................................112 
13.10. 
End of Study .............................................................................................................113 
13.11. 
Study termination ......................................................................................................113 
13.11.1. 
Study Termination ....................................................................................................113 
13.11.2. 
Site Termination .......................................................................................................113 
13.12. 
Access to Source Documentation .............................................................................114 
13.13. 
Data Generation and Analysis ..................................................................................114 
13.14. 
Retention of Data ......................................................................................................114 
13.15. 
Financial Disclosure .................................................................................................114 
13.16. 
Publication and Disclosure Policy ............................................................................114 
14. 
LIST OF REFERENCES ..........................................................................................116 
APPENDIX A. SCHEDULE OF CLINICAL ASSESSMENTS –SCHEDULE A 
(Q3W) .......................................................................................................................120 
APPENDIX B. SCHEDULE OF CLINICAL ASSESSMENTS – SCHEDULE B 
(MODIFIED WEEKLY) ..........................................................................................124 
APPENDIX C. PHARMACODYNAMIC, PHARMACOKINETIC AND 
IMMUNOGENICITY ASSESSMENTS..................................................................127 
APPENDIX D. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS SCALE .......................................................................129 
APPENDIX E. RESPONSE DEFINITION (RECIST 1.1).......................................................130 
APPENDIX F. GYNECOLOGIC CANCER INTERGROUP (GCIG CRITERIA FOR 
EVALUATION OF CA-125 ....................................................................................137 
APPENDIX G. FACT/GOG-NEUROTOXICITY QUESTIONNAIRE, VERSION 4.0 .........138 
 


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LIST OF TABLES 
Table 1: 
FOLR1 expression by IHC in epithelial ovarian cancer, endometrial cancer, 
NSCLC and RCC1,2 ....................................................................................................26 
Table 2: 
PK Simulation to Evaluate Fractionated Dosing Regimens .......................................46 
Table 3: 
Planned Dose Levels (Schedule A) ............................................................................57 
Table 4: 
Planned Dose Levels (Schedule B; Dosed by AIBW)................................................59 
Table 5: 
DLT Definitions ..........................................................................................................61 
Table 6: 
Management Guidelines for Potential Infusion Reactions .........................................67 
Table 7: 
Schedule for Ophthalmologic Assessments ................................................................69 
Table 8: 
Management of Ocular Disorders ...............................................................................71 
Table 9: 
Management of Non-Infectious Pneumonitis .............................................................72 
Table 10: Management of Nausea and Vomiting .......................................................................74 
Table 11: Dose Modification Guidelines ....................................................................................76 
Table 12: Vital Sign Measurements ............................................................................................86 
Table 13: Clinical Laboratory Tests ...........................................................................................87 
Table 14: Adverse Event Severity ..............................................................................................93 
Table 15: Adverse Event Relatedness .........................................................................................93 
Table 16: Probability of Observing ≥ x Events (Response or DLT) For a 40 patient 
Cohort .......................................................................................................................107 
 


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LIST OF FIGURES 
Figure 1: 
IMGN853 Structure ....................................................................................................29 
Figure 2: 
Correlation Between Cmax and Total Body Weight (TBW), Ideal Body 
Weight (IBW), Lean Body Weight (LBW), and Adjusted Ideal Body Weight 
(AIBW) .......................................................................................................................45 
Figure 3: 
Study Design Schema .................................................................................................56 
Figure 4: 
Co-Administration of Steroid Eye Drops and Lubricating Eye Drops 
(Schema) .....................................................................................................................65 
 
  
 


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1. 
INTRODUCTION 
1.1. 
Target Background 
Folate receptor 1 (FOLR1; aka folate receptor α, FRα) is a glycosyl phosphatidylinositol (GPI)-
anchored cell surface protein that binds and internalizes folates, which are essential co-factors for 
one carbon transfer reactions that are required for DNA and RNA synthesis, cell growth and 
proliferation.  Marked upregulation of FOLR1 occurs during neonatal development and in 
cancer, suggesting that the receptor functions primarily under conditions of high folate demand.  
In contrast, normal adult tissues generally lack FOLR1 expression and employ alternative 
transporters such as folate receptor β (FRβ), reduced folate carrier (RFC) and proton-coupled 
folate transporter (PCFT) for folate uptake (Weitman 1992, Mantovani 1994, Elnakat 2004, 
Kelemen 2006, and IMGN853 Investigator’s Brochure).  
Published studies have demonstrated FOLR1 over expression by IHC in various epithelial 
tumors, particularly serous and endometrioid ovarian cancers, serous and endometrioid 
endometrial cancers, NSCLC (adenenocarcinoma or BAC histology) and clear cell renal 
carcinomas (Scorer 2010, Garin-Chesa 1993, Kalli 2008, Crane 2012, Franklin 1994, Dainty 
2007, Jones 2008, Akram 2004, and Allard 2007).  IHC results obtained at ImmunoGen are 
generally consistent with the literature (Table 1). 
 


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Table 1: 
FOLR1 expression by IHC in epithelial ovarian cancer, endometrial cancer, NSCLC and RCC1,2 
Indication 
Source 
N positive/N tested (% positive) 
 
IMGN2 
Literature Review1 
 
≥3 hetero3 
Any Positivity4 
Scorer 
Garin-Chesa 
Kalli 
Crane 
Epithelial Ovarian 
Cancer 
     Serous 
     Endometrioid 
     Mucinous 
     Clear Cell 
     Transitional Cell 
 
 
44/129 (34%) 
15/35 (43%) 
2/29 (7%) 
1/5 (20%) 
0/3  
 
 
100/129 (78%) 
26/35 (74%) 
5/29 (17%) 
3/5 (60%) 
2/3 (67%) 
 
 
33/52 (63%) 
ND 
2/12 (17%) 
1/7 (14%) 
2/5 (40%) 
 
 
27/27 (100%) 
15/20 (75%) 
3/5 (60%) 
3/4 (75%) 
ND 
 
 
85/104 (82%) 
26/39 (67%) 
2/9 (22%) 
19/30 (63%) 
ND 
 
 
135/165 (82%) 
7/32 (22%) 
6/11 (55%) 
4/5 (80%) 
ND 
 
 
Indication 
Source 
N positive/N tested (% positive) 
IMGN2 
Literature Review1 
 
≥2 hetero5 
Any Positivity4 
Scorer 
Franklin 
-- 
-- 
NSCLC 
     Adenocarcinoma 
     Large Cell 
     Squamous 
     Bronchoalveolar 
 
39/67 (58%) 
1/7 (14%) 
4/74 (5%) 
5/7 (71%) 
 
47/67 (70%) 
3/7 (43%) 
12/74 (16%) 
5/7 (71%) 
 
32/69 (46%) 
0/5 (0) 
5/55 (9%) 
2/4 (50%) 
 
9/10 (90%) 
3/5 (60%) 
4/22 (18%) 
5/5 (100%) 
 
 
 
 
 


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Indication 
Source 
N positive/N tested (% positive) 
IMGN2 
Literature Review1 
 
≥2 hetero5 
Any Positivity4 
Scorer 
Dainty 
Jones 
Allard 
Endometrial Cancer 
     Endometrioid adenocarcinoma 
     Adenosquamous 
     Undifferentiated carcinoma 
     Squamous cell carcinoma 
     Serous/non-endometrioid 
 
23/58 (40%) 
1/4 (25%) 
3/4 (75%) 
0/2 
ND 
 
40/58 (69%) 
3/4 (75%) 
3/4 (75%) 
0/2 
ND 
 
27/68 (40%) 
 
 
 
ND 
 
5/13 (38%) 
 
 
 
11/16 (69%) 
 
46/166 (28%) 
 
 
 
81/141 (64%) 
 
28/237 (12%) 
 
 
 
16/32 (50%) 
 
Indication 
Source 
N positive/N tested (% positive) 
IMGN2 
Literature Review1 
 
≥2 hetero6 
Any Positivity4 
Scorer 
-- 
-- 
-- 
Clear Cell Renal Cancer 
9/34 (26%) 
29/34 (85%) 
16/67 (24%) 
-- 
-- 
-- 
 
1 Literature data reflect any positivity. 
2 IMGN data are based on an in house developed and validated IHC assay, the scoring of which is different from the CLIA validated clinical study assay.  (see 
Investigator’s Brochure) 
3 Equivalent to ≥ 25% tumor staining at ≥ 2+ by clinical study assay 
4 any positivity for IMGN data represents ≥ 1 focal IHC staining  
5 Equivalent to ≥ 25% tumor staining at ≥ 1+ by clinical study assay 
6 Equivalency to clinical study assay not yet established


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Other cancers including small cell lung cancer (SCLC; 0/13 positive), colorectal cancer (0/92 
positive), pancreatic cancer (1/4 positive) and head and neck cancer (1/17 positive) tested at 
IMGN were largely negative for FOLR1 expression by IHC analyses (refer to Investigator’s 
Brochure). 
Several additional studies have further validated FOLR1 as a target in serous ovarian cancer.  
First, quantitative polymerase chain reaction (qPCR) studies show ubiquitous FOLR1 mRNA 
expression in serous ovarian cancer (Hough 2001) and high levels of FOLR1 mRNA correlate 
with poor response to chemotherapy and decreased disease free survival (Chen 2012).  Second, 
both Kalli et al and Crane et al have demonstrated that recurrent tumors retain FOLR1 
expression comparably to primary tumors as shown by serial biopsy sampling and IHC (Kalli 
2008, Crane 2012).  Third, studies with FOLR1-specific imaging agents have demonstrated real-
time FOLR1 expression at primary and metastatic tumor sites (Fisher 2008, Ghamande 2011, 
and van Dam 2011).  Finally, a truncated form of FOLR1 has been detected in ascites and blood 
of ovarian cancer patients (Basal 2009, Mantovani 1994), further confirming expression in this 
disease and suggesting that the receptor may serve as a circulating biomarker.  Collectively, 
these data suggest that FOLR1 is a promising target in solid tumors, particularly ovarian cancer. 
1.2. 
IMGN853 
Because of its tumor specific expression and capacity to internalize small and large molecule 
ligands, FOLR1 has emerged as a promising target for antibody maytansinoid conjugate (AMC) 
therapy.  AMCs combine the specificity of monoclonal antibodies to tumor antigens with the 
extraordinary cytotoxicity of maytansine derivatives, which are potent anti-microtubule agents 
that target proliferating cells.  IMGN853 is an AMC designed to target FOLR1.  It consists of the 
humanized anti-FOLR1 monoclonal antibody M9346A attached via a cleavable disulfide linker 
to the cytotoxic maytansinoid, DM4 (Figure 1). 
 
 


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Figure 1: 
IMGN853 Structure 
 
DM4 is ~2% by weight relative to Mab 
Due to the nature of the conjugation process, the number of DM4 molecules attached to the 
monoclonal antibody ranges from 1 to 7 molecules per antibody, with an average of 3 or 4 DM4 
molecules per antibody.  Conjugation of the maytansinoid to the tumor targeting antibody 
ensures that the cytotoxic component remains inactive in the circulation.  Release of the 
cytotoxic payload requires binding, internalization, and degradation of the antibody.  The 
released payload then kills the cell by inducing G2-M arrest and cell death.  Cellular processing 
of maytansinoid conjugates can also generate lipophilic catabolites that cross cell membranes 
and kill neighboring cells (Erickson 2006).   
1.3. 
Epithelial Ovarian Cancer (EOC), Endometrial Cancer (EC) and 
NSCLC 
The dose expansion phase of the study focuses on EOC, EC and NSCLC because they frequently 
express high levels of FOLR1and constitute significant unmet medical need.   
1.3.1. 
EOC 
EOC is a lethal disease with 21,990 new cases and 15,460 deaths expected in 2011.  The high-
grade serous subtype comprises 60 to 80% of all epithelial ovarian cancers and demonstrates the 
most aggressive disease course, with less than 25% of cases diagnosed in the early stages (tages I 
and II).  This characteristic is further reflected in the poor survival statistics (Cannistra 2004).  
Treatment for advanced disease involves surgical de-bulking, followed by platinum/taxane-based 
chemotherapy.  Although most patients initially respond to platinum-based chemotherapy, nearly 
all relapse and eventually develop drug resistant disease.  Disease recurring within six months of 
platinum-based chemotherapy is classified as platinum resistant, whereas, disease recurring 
greater than six months after therapy is termed platinum sensitive.  Patients with platinum 
resistant disease typically receive single agent chemotherapy (e.g. liposomal doxorubicin, 
topotecan, gemcitabine, paclitaxel, or other) at relapse.  Unfortunately, response rates associated 
S
NH
O
S
O
O
OH
MeO
Cl
N
O
O
O
NH
O
O
MeO HO
N
O
O
S
Ab
3-4


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with these treatments range from ~10 to 20 percent, and duration of response is typically 4-8 
months (Cannistra 2010, Matsuo 2010).  Similarly, overall survival rates are poor with a median 
overall survival rate of ~11 months.  Because platinum resistant ovarian cancer remains a 
significant unmet medical need, the NCCN guidelines recommend that platinum resistant 
patients participate in clinical trials (Morgan 2011). 
1.3.2. 
NSCLC 
Lung cancer is the leading cause of cancer death in the United States.  Approximately 220,000 
new cases of lung cancer are diagnosed in the US per year.  Of these, NSCLC comprises about 
75% of all lung cancers, with adenocarcinoma being the most common histology subtype.  
Although several chemotherapeutic agents and targeted therapies are approved for treatment of 
advanced lung cancer, no agents are curative and approximately 150,000 patients die each year 
of progressive disease.  Patients with advanced disease and good performance status may benefit 
from platinum-based chemotherapy doublets; however, objective response rates are low and one-
year survival rates remain at about 30-40% (Kelly 2001, Schiller 2002).  Thus, NSCLC remains 
a prevalent, unmet medical need that requires new therapeutic approaches. 
1.3.3. 
Endometrial Carcinoma 
In the US an estimated 49,560 news cases will be diagnosed, and 8,190 deaths from endometrial 
cancer (EC) will occur in 2013 (American Cancer Society 2013).  The 1- and 5-year relative 
survival rates for uterine corpus cancer are 92% and 82%, respectively.  The 5-year survival rate 
is 95%, 67%, or 16%, if the cancer is diagnosed at a local, regional, or distant stage, respectively.  
Despite the generally favorable prognosis for patients with local disease, for patients with 
recurrent or advanced disease, there remains unmet medical need for more effective treatments.  
To date, there is no approved treatment for adjuvant treatment of advanced or recurrent EC.  
Platinum agents, paclitaxel, and doxorubicin have been investigated as single agents and in 
combination for primary advanced and recurrent disease.  Not surprisingly, higher response 
rates, and greater toxicity, were observed with the combination regimens (Akram 2004, Humber 
2007).  The combination of paclitaxel and carboplatin is gaining favor as the preferred regimen 
for treating advanced and refractory EC; however, toxicity remains problematic; therefore, new 
treatment modalities are needed.  
1.4. 
Non-Clinical Studies of IMGN 853 
1.4.1. 
Pharmacology 
Results of nonclinical pharmacology studies demonstrate the following: 
• Marked expression of FOLR1 occurs in epithelial tumors, particularly serous and 
endometrioid ovarian cancers, serous and endometrioid endometrial cancers, clear cell 
RCC and NSCLC adenocarcinoma and BAC as assessed by IHC (Table 1 and 
Investigator’s Brochure). 
• IMGN853 shows potent (IC50 ≤ 1 nM) and selective cytotoxicity towards FOLR1-
positive tumor cells in vitro via a mechanism that involves binding to target antigen 
followed by IMGN853 internalization and degradation of M9346A, the antibody moiety 


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of IMGN853.  IMGN853 processing releases the cytotoxic payload, which then kills the 
cell via induction of G2-M arrest and consequent apoptosis. 
•  In vitro cytotoxicity studies suggest that cells sensitive to IMGN853 express higher 
levels of FOLR1 and release 10- to 100-fold more cytotoxic maytansinoid than cells 
resistant to IMGN853. 
• IMGN853 retains the inherent activities of its antibody moiety, M9346A, including 
binding affinity (apparent affinity ≤ 0.1 nM) and selectivity for FOLR1, capacity for 
uptake, internalization, and degradation by FOLR1-postive target cells, and ability to 
induce ADCC in vitro. 
• IMGN853 shows significant in vivo efficacy against ovarian (IGROV-1, OVCAR-3, and 
OV-90 models) and NSCLC (NCI-H2110 model) tumor xenografts. 
1.4.2. 
Pharmacokinetics 
Nonclinical studies with IMGN853-cross reactive (monkey) and non-cross reactive (mouse) 
species were conducted to define PK parameters and to determine the stability of the linker and 
impact of conjugation on antibody clearance.  An additional PK study with free DM4 was 
conducted in monkey.  These studies are summarized here and further detailed in the IMGN853 
Investigator’s Brochure.   
1.4.2.1. 
Single Dose Non-GLP Studies in CD-1 Mice 
IMGN853 shows biphasic pharmacokinetics upon single intravenous administration in CD-1 
mice with a distribution phase that lasts about 24 hours and a terminal elimination phase that 
follows first-order kinetics.  The elimination phase half-life of IMGN853 is about 5 days for 
conjugate and 10 days for the M9346A antibody component, indicating that DM4 is slowly 
released from IMGN853 during circulation in the mouse. 
To assess the impact of conjugation on the clearance of the parental M9346A antibody 
component of IMGN853, PK studies were performed with radiolabeled antibody species: 
unconjugated M9346A[3H] and IMGN853 (M9346A[3H]-sulfo-SPDB-DM4).  Unconjugated 
M9346A[3H]  and IMGN853 (M9346A[3H]-sulfo-SPDB-DM4)  show biphasic 
pharmacokinetics upon intravenous administration in CD-1 mice, with a distribution phase that 
lasts about 24 hours and a terminal elimination phase that follows first-order kinetics.  The 
clearance-dependent pharmacokinetic parameters, t1/2, CL, and AUC0-∞, were similar for both 
unconjugated M9346A[3H] and IMGN853 (M9346A[3H]-sulfo-SPDB-DM4), indicating that 
conjugation of DM4 has minimal impact on the plasma pharmacokinetic properties of M9346A 
antibody in CD-1 mice. 
1.4.2.2. 
Single Dose Toxicokinetics of IMGN853 in Cynomolgus Monkeys 
The pharmacokinetic profiles of IMGN853 and its M9346A antibody component were 
determined as part of a study to evaluate the toxicity of IMGN853 in cynomolgus monkeys 
administered as a single intravenous (slow bolus) injection.  The plasma clearance of IMGN853 
was measured using sandwich ELISA techniques, and showed an initial distribution phase of 
about 24 hours followed by a slower terminal elimination phase, with half-life of about 4 days 
for the conjugate.  At all dose levels of IMGN853 (1, 3, 5 and 10 mg/kg), the conjugate clearance 


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profiles and distribution volumes were similar, and both Cmax and AUC0-∞ increased with 
increasing conjugate dose, suggesting linear pharmacokinetics.  The volume of distribution at 
steady state (VSS) estimated from plasma concentrations of IMGN853 assessed over time, was in 
the range of the expected plasma volume of the animal. 
1.4.2.3. 
PK of Free DM4 in Cynomolgus Monkeys 
The plasma concentration of the maytansinoid in IMGN853, DM4, was evaluated in the 
cynomolgus monkey following administration of an IV dose of 0.1 mg/kg.  Free maytansinoid 
levels were measured using a sensitive ELISA method (LLQ = 3.6 ng/mL) that utilized a murine 
monoclonal anti-maytansinoid antibody.  The free maytansinoid concentration in plasma was 
about 0.56 µg/mL at 30 minutes post-infusion, falling below the limit of detection by 7 hours 
post infusion.  The observed rapid reduction in plasma concentration for free DM4 in the 
monkey is consistent with the pharmacokinetic parameters reported for maytansine in mice, 
which are characterized by a rapid initial distribution phase, a large volume of distribution (9.8 
L/kg), and a rapid terminal elimination phase (t½ about 2h). 
1.4.3. 
Toxicology 
A comprehensive nonclinical toxicology program has been conducted in mice and monkeys to 
support the use of IMGN853 in clinical trials in humans.  These studies are summarized here and 
further detailed in the IMGN853 Investigator’s Brochure.  Cynomolgus monkey was considered 
the most appropriate species for GLP toxicology based on preclinical work, which included 
sequence comparisons of FOLR1 orthologs, IHC studies of human and monkey (rhesus and 
cynomolgus) and binding affinity studies with rhesus monkey cell lines.  
1.4.3.1. 
Single-Dose GLP Cynomolgus Monkey Toxicology Study 
A single dose GLP toxicology study was performed in cynomolgus monkeys with doses of, 1, 3, 
5, or 10 mg/kg IMGN853 administered intravenously.  Vehicle and IMGN853-treated animals 
were evaluated after a 5- or 29-day recovery period to assess the reversibility of any observed 
toxic effects.  Test article-related effects were observed at 3, 5, and 10 mg/kg.  IMGN853-related 
alterations were typically dose-dependent and had returned to control levels or demonstrated a 
significant restoration towards normal by day 29. 
The principal findings included: 
• Bone marrow and lymphoid toxicity (5 and 10 mg/kg groups) characterized by decreased 
leukocyte counts (mean WBC and lymphocyte counts), red cell mass (i.e. Red blood cell 
count, hemoglobin, and hematocrit), and reticulocyte counts.  Bone marrow findings 
were characterized by generalized depletion of marrow, with decreased density of 
myeloid and erythroid elements.  Lymphoid findings included lymphocyte depletion, 
germinal center loss and decreased cortical follicle size in lymph nodes and depletion of 
white pulp in spleen.  All alterations in hematology parameters had resolved by day 7.  
Except for the observation of minimal bone marrow depletion in a single 10 mg/kg group 
male, no bone marrow and lymph node histopathology alterations were noted at the day 
29 recovery necropsy. 


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• Transient increases in mean neutrophil count (3, 5, and 10 mg/kg groups) and fibrinogen 
level (10 mg/kg group) observed on study day 2 and study days 2 and 5, respectively.  
Both alterations resolved by study day 7.    
• Injection site histopathology changes observed at the day 5 interim necropsy.  These 
changes included superficial and perivascular inflammation, ulceration, and edema of the 
dermis and subcutis.  Except for the observation of minimal superficial and perivascular 
injection site inflammation in a single 10 mg/kg group male, no injection site 
histopathology alterations were noted at the day 29 recovery necropsy.  
• Non-adverse test article-related serum chemistry findings included lower phosphorous 
and potassium levels in the 3, 5, and/or 10 mg/kg group females.  The lower serum levels 
of potassium and phosphorus did not correlate with other serum chemistry, 
histopathology, or clinical findings, and were considered changes of minimal 
toxicological or biological importance. 
Although a formal in vivo safety pharmacology study has not been conducted with IMGN853, no 
treatment-related cardiovascular, respiratory, or central nervous system alterations were noted in 
cage-side clinical observations or veterinary physical examinations. 
All laboratory abnormalities and histopathology alterations were considered non-adverse and 
reversible as they had returned to control levels or demonstrated a significant restoration towards 
normal by day 29.  Based on these findings, the highest non-severely toxic dose (HNSTD) was 
considered 10 mg/kg.   
1.4.3.2. 
Single-Dose IV Toxicity Studies with DM4 in Mice and Monkeys 
Single dose toxicity studies were performed in mice and monkeys to assess the toxicity of DM4, 
the cytotoxic payload of IMGN853 and to compare its toxicity with the parent maytansinoid 
molecule, maytansine, and the closely related chemical analogue, DM1. 
In the mouse study, a single dose of DM4 (1.2-4.1 mg/kg), DM1 (1.0-3.5 mg/kg), maytansine 
(1.2-3.2 mg/kg) or vehicle was administered intravenously and the mice were assessed clinically 
daily for 15 days.  Necropsy was performed at day 15 or earlier for severe morbidity.  The LD50 
was about 2.2 mg/kg (6.6 mg/m2) for DM4 and DM1 and 1.8 mg/kg (5.4 mg/m2) for 
maytansine.  DM1 and DM4 showed a similar toxicity profile at all 4 tested doses.  All mice 
survived the 1.0 mg/kg DM1 dose and only 1/8 mice died in the group treated with 1.2 mg/kg 
DM4, a DM4 dose equivalent to the amount of DM4 present in a ~59 mg/kg dose of IMGN853.  
Drug-related changes were observed in the gastrointestinal tract and bone marrow in mice 
terminated early due to morbidity.  The incidence and severity of the tissue lesions generally 
increased with increasing dose.  The gastrointestinal lesions were characterized by mucosal 
attenuation, glandular cell loss, and necrosis.  Bone marrow depletion roughly paralleled the 
incidence of changes in the alimentary tract, and was characterized by loss of cellularity across 
all myeloid components.  The observed changes in the alimentary tract and bone marrow were 
generally resolved by 15 days post-administration in the surviving animals.  No compound-
related histopathologic abnormalities were observed in the liver, heart, lung, or kidney at any 
dose level of maytansinoid tested.    
In the cynomolgus monkey study, DM4 was administered at 0.1 mg/kg via intravenous infusion.  
Animals were assessed clinically daily and necropsies were performed on Days 5 or 29.   


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There were no clear DM4-related effects noted on physical examination, body temperature, 
electrocardiogram, indirect blood pressure, heart rate, urinalysis, or organ weight assessments.   
DM4-related clinical pathology alterations included mild leucopenia primarily due to 
neutropenia, which corresponded microscopically to bone marrow depletion.  Transient 
elevations in alkaline phosphatase values were noted in DM4-treated animals.  Decreases in red 
blood cells and increases in platelets were seen in both control and treated animals.  
Morphologic changes associated with administration of 0.1 mg/kg DM4 were limited to 
depletion of bone marrow cellular elements only at Day 5.  No morphologic changes were noted 
at Day 29.   
1.4.3.3. 
Acute Toxicity Profile of IMGN853 (M9346A-sulfo-SPDB-DM4) and M9346A-
SPDB-DM4 in Female CD-1 Mice 
A study was conducted in CD-1 mice to determine the acute toxicity profile of IMGN853 which 
contains the novel sulfo-SPDB linker in comparison to an SPDB-DM4 conjugate for which 
extensive preclinical toxicity data exists.  The M9346A antibody does not cross-react with the 
murine FOLR1 antigen, and these results represent the non-targeted tolerability profile for these 
conjugates.  The tolerability profile and MTD (1.4 – 1.6 mg/kg based on DM4 concentration) of 
IMGN853 (M9346A-sulfo-SPDB-DM4) and M9346A-SPDB-DM4 were similar in CD-1 mice.  
The MTD of 1.4 – 1.6 mg/kg based on DM4 concentration is approximately 72-91 mg/kg based 
on antibody weight.  A second study with additional animals (N=24/group) confirmed the results 
of this study (see Investigator’s Brochure). 
1.5. 
Rationale for the starting dose 
The selection of the maximum recommended starting dose (MRSD) for this clinical trial was performed 
according to ICH S9 guidance.  The highest non-severely toxic dose (HNSTD) observed in the GLP 
toxicology studies conducted in cynomolgus monkeys HNSTD was 10 mg/kg.  Based on allometric 
scaling, the MRSD is 0.5 mg/kg, which represents 1/6 the HNSTD observed in the cynomolgus monkey 
toxicology study.  Specifically, the value represents 1/6 of 10 mg/kg, scaled to mg/m2, then calculated as 
a flat dose for a human with body surface area = 1.74 m2 and 70 kg.  
1/6 x 10 mg/kg (cyno HNSTD) x 12 (cyno conversion factor to mg/m2) = 20 mg/m2 
20 mg/m2 x 1.74 m2 x 1/70 kg = 0.497 mg/kg ≈ 0.5 mg/kg  
To allow an additional margin of safety, the starting clinical dose chosen was 0.15 mg/kg, which 
represents approximately 1/20 the HNSTD observed in the GLP toxicology study. 
1.6. 
Clinical Hypothesis 
A formal hypothesis will not be tested in this study.  Analysis of safety, tolerability, PK, Pd, and 
preliminary anti-tumor activity data will help guide future development of IMGN853. 
1.7. 
Rationale for the Study Plan 
This is a two part Phase 1, FIH study consisting of a dose escalation phase evaluating two dosing 
schedules of IMGN853 administration and up to 6 dose expansion groups at the MTD.  The 
primary aims of the dose-escalation are to evaluate the safety and tolerability of IMGN853, to 


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identify the MTD, and to characterize the PK profile of IMGN853 when administered IV for two 
dosing schedules: 
Schedule A: IMGN853 administered on Day 1, with cycles repeating every 21 days   
Schedule B: IMGN853 administered on Days 1, 8, and 15, with cycles repeating every 28 days  
The patient population for the dose escalation will include patients with tumors known to express 
FOLR1 at high incidence (e.g. serous and endometrioid ovarian cancer, serous and endometrioid 
endometrial cancer, NSCLC adenocarcinoma and BAC, clear cell carcinoma) and patients with 
other solid tumors with detectable FOLR1 (≥1% of tumor staining at ≥1+ intensity) by IHC.  
Based on the favorable safety margins suggested by the non-clinical cynomolgus monkey 
toxicology study and to minimize patient exposure to biologically-inactive doses of IMGN853, 
an accelerated dose escalation will be used for the first four cohorts as detailed in Section 4.1. 
Schedule A (Q3W): Once the MTD has been identified, enrollment to MTD dose-expansion 
Cohorts 1 and 2 will begin.  Patients enrolled to Cohort 1 must meet the minimum requirement 
of FOLR1 positivity by IHC (≥25% of tumor staining at ≥2+ intensity) and patients enrolled to 
Cohort 2 will have tumors with an H score ≥ 100 for FOLR1 by IHC.  The use of Schedule A in 
Cohort 3, 4, and 5 will be determined following review of the data for both dosing regimens, by 
the CRC. 
Schedule B (modified weekly): Patients will be enrolled in cohorts of 3 to 6 patients until the 
MTD is defined.  
Amendment 10 Update - The Schedule B MTD was established at 2.0 mg/kg (AIBW). The 
CRC to review safety, PK and efficacy results from both schedules.  The modified weekly 
schedule did not provide any apparent safety or efficacy advantage; moreover, while the Q3W 
schedule PK profile analysis indicated no accumulation of IMGN853, accumulation of 
IMGN853 was observed using the modified weekly schedule. Based on safety and tumor 
response data collected and reviewed through May 2015, the CRC determined that Schedule B 
will not be evaluated further in the current study (Borghei 2015). 
All new patients enrolled in the trial will receive IMGN853 at the MTD of 6 mg/kg once every three 
weeks (Figure 3). Safety data available to date indicate that the MTD is equal to the RP2D. Patients 
currently receiving IMGN853 study treatment according to Schedule B will continue to do so. 
Safety and tolerability will be further defined for the patient populations evaluated in the Dose 
Expansion phase of the study.  The dose expansion cohorts will additionally investigate 
IMGN853 Pd (MTD Expansion Cohort3), preliminary anti-tumor efficacy (MTD Expansion 
Cohorts 1, 2 and 4), and will assess the effectiveness of primary, prophylactic steroid eye drops 
in preventing or lessening ocular toxicity (Cohort 5). 
a. Expansion Cohort #1 - Patients with EOC, primary peritoneal cancer or fallopian tube 
cancer, which is resistant to their last platinum-based therapy, excluding those patients 
with primary platinum refractory disease. 
b. Expansion Cohort #2 – Patients with FOLR1-positive uterine cancer that is advanced or 
recurrent and has received at least one platinum-based regimen, and no more than five 
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c. Expansion Cohort #3 – Patients with biopsy-accessible relapsed or refractory ovarian 
cancer, primary peritoneal cancer or fallopian tube cancer 
d. Expansion Cohort #4 – patients with relapsed and refractory NSCLC adenocarcinoma 
or BAC 
e. Expansion Cohort #5 - Patients with EOC, primary peritoneal cancer or fallopian tube 
cancer, which has relapsed following platinum-based therapy, excluding those patients 
with primary platinum refractory disease or low grade or clear cell ovarian cancer.  
Patients enrolled in this cohort will be pre-treated with corticosteroid eye drops to assess 
whether prophylaxis with topical steroids prevents or lessens severity of keratopathy and 
blurred vision.   
Translational research studies described above and outlined in Section 7 should provide data that 
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1.8. 
History of Amendments 
1.8.1. 
Amendment 1 Summary of Key Changes 
 
The following changes were made to the original protocol following FDA review according to the 
agency’s recommendations.  The key changes are noted below: 
 
1. The starting dose was lowered to 0.15 mg/kg (1/20 HNSTD) in order to provide an extra margin of 
safety to study subjects. 
2. The rationale for the starting dose was revised and references to the NOAEL were removed as a 
consequent revision as a result of the lowering of the starting dose. 
3. Guidelines were added to the protocol for the management of potential IMGN853 infusion 
reactions. 
4. AE recovery criteria for starting a new cycle of treatment have been revised. 
5. Pulse Oximetry assessments were added. 
6. Several corrections were made throughout the protocol to correct a number of inconsistencies 
noted by the FDA during protocol review. 
7. Several administrative changes were made throughout the document for internal consistency and to 
improve readability and clarity.  
1.8.2. 
Amendment 2 Summary of Key Changes 
The primary reasons for amending the protocol are summarized below: 
1. The conflicting instructions regarding dose escalation were removed in the Dose Escalation 
Guidelines section of the protocol. 
2. The text describing the level of toxicity that would trigger dose expansion and reversion to 3+3 study 
design contained errors in the previous version.  These errors were corrected. 
3. Endometrioid endometrial cancer was added to the list of tumors that could be enrolled without 
prior documentation of FOLR1 positivity.  
4. Additional guidance was provided on the reporting of SAEs including the addition of a list of events 
that do not meet the criteria for ‘hospitalizations’, defining when death is reported as an SAE vs. as 
an outcome, outlining what constitutes the primary event term and specifying that sites should 
report CIOMS/safety letters to their local IRB/IEC in accordance with their requirements. 
5. Clarification was provided in the Sample Size section of the protocol, clearly stating that safety will 
be evaluated continuously, separately, and in aggregate in the expansion.  
6. The inclusion criteria were revised to clearly state that the use of low MW heparin and low dose 
aspirin is permitted. 
7. Guidance was added regarding those laboratory abnormalities that constitute adverse events. 


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8. Additional changes were made to correct typographical errors, provide minor updates (dates and 
contact information), correct footnote errors, and administrative corrections to improve consistency 
and clarity. 
1.8.3. 
Amendment 3 Summary of Key Changes 
The primary reasons for amending the protocol are summarized below 
1. The study design was revised to allow dose escalation beyond 9.0 mg/kg; the study schema 
was revised accordingly. 
2. The description of the patient population to be enrolled to Expansion Cohort 1 has been 
restricted to exclude patients with platinum-refractory disease and only focus on platinum 
resistant disease. 
3. The enrollment estimate for the dose-escalation cohort has been increased to 30 patients; 
therefore, the overall enrollment estimate has been increased to 72 patients. 
4. A section was added to the protocol describing clinical and PK findings to date. 
5. The efficacy objectives and endpoints duration of response (DoR), progression-free survival 
(PFS) and time to progression (TTP) have been added.  The statistics section has been 
updated accordingly. 
6. The section of the protocol describing dosage size and vial size has been revised, as a new 
(larger) vial size is being made available. 
7. The section of the protocol describing assignment of patient number has been updated. 
8. Treatment windows have been added to allow delay in a new cycle of up to 3 days to allow 
patients to adjust their visit schedules in Cycles > 3. 
9. A premedication regimen to prevent infusion reaction is now required for patients treated at 
dose levels > 5 mg/kg.  A suggested regimen is described in the protocol. 
10. For patients with elevated CA125 at baseline, the schedule for obtaining samples and 
confirming response have been clarified. 
11. Administrative changes were made for clarification purposes. 
1.8.4. 
Amendment 4 Summary of Key Changes 
The primary reasons for amending the protocol are summarized below 
1. Guidelines have been provided in the protocol for monitoring and managing ocular toxicity.  
Additionally, a requirement has been added for a complete ophthalmologic examination to be 
performed at baseline and end of study. 
2. Blood samples will be collected from patients with EOC, endometrial cancer and NSCLC to 
measure changes in the numbers of CTCs, and characterize FOLR1 expression on CTCs at 
baseline and at various time points during study participation.  The protocol has been 
amended to add these procedures and the Exploratory Objectives section was revised 
accordingly (Section 1.8.7) 


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3. The ability to deliver the IMGN853 cytotoxic payload to tumor will be assessed by 
measurement of anti-maytansine in tumor specimens, using IHC methods.  The protocol has 
been amended to add these procedures and the Exploratory Objectives section was revised 
accordingly. 
4. The section of the protocol describing clinical experience has been updated, including the 
statement regarding PK findings observed to date. 
5. The FOLR1 expression requirement for patients enrolled to the MTD Expansion Cohort Nos. 
1 and 2 has been increased from > 2 hetero to >3 hetero. 
6. Additional Pd procedures have been added to be included for analysis of pre- and post- dose 
biopsy specimens (Expansion Cohort 2).  
7. Cleaved caspase was removed from the Pd activity assessments. 
8. A new section was added to the protocol to define “End of Study.” 
1.8.5. 
Amendment 5 Summary of Key Changes 
1. FLT-PET procedures have been removed from the protocol. 
2. The dosing regimen has been revised; an adjusted ideal body weight calculation will be 
employed.   
3. CTCs will be collected from ovarian and endometrial cancer and NSCLC patients during 
dose escalation (Section 1.8.7).  
4. An additional MTD expansion cohort has been added, comprised of patients with advanced 
or recurrent endometrial cancer. 
5. Assessments of soluble FOLR1 and IMGN853 concentrations in ascites have been removed. 
6. The procedures for reporting of adverse events (AEs) due to study-related procedures 
occurring during the screening period were clarified.  The revised amendment ensures that 
AEs related to study procedures are captured during the screening period prior to first study 
drug. 
1.8.6. 
Amendment 6 Summary of Key Changes 
1. The study period and estimated number of patients have been updated. 
2. The protocol is being amended to evaluate an additional dosing schedule: IMGN853 
administered IV on days 1, 8, and 15 of each 28-day cycle. 
3. The results of a PK simulation study, evaluating various multiple-dosing schedules have been 
added. 
4. Sections of the protocol describing Pd studies have been revised for clarification and to align 
with objectives and endpoints. 
5. The visit window for the baseline ophthalmologic examination has been increased to 7 days. 


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1.8.7. 
Amendment 7 Summary of Key Changes 
1. The size of the MTD expansion cohorts has been increased to 20 patients each and the 
statistics sections of the protocol have been revised accordingly. 
2. The inclusion criteria for patients enrolled to the MTD Dose Expansion#1 (Platinum-resistant 
ovarian cancer) have been revised. 
3. The restriction excluding patients having received prior treatments with folate receptor-
targeting compounds has been removed. 
4. Analyses of circulating tumor cells (CTCs) have been removed. 
5. Patients with RCC will be required to be pre-screened for FOLR1 positivity before being 
enrolled to the study. 
6. The test and laboratory for the FOLR1IHC assay has been changed and threshold criteria for 
FOLR1 positivity have been revised.  [Note: this minor change was implemented via 
administrative letter dated June 13, 2014.] 
7. The guidelines for management of treatment-emergent eye disorders have been revised. 
8. Guidelines for management of diarrhea have been added. 
9. Retreatment criteria for non-hematologic criteria have been revised. 
10. Lubricating, preservative-free artificial tears have been added as a daily concomitant 
medication for all patients. 
11. The 6-hour PK time point has been removed for the Q3W PK assessments. 
12. The requirement for Day 8 and Day 15 physical exams for patients treated using Schedule B, 
has been removed in cycles > Cycle 4. 
13. The section of the protocol describing “expectedness” of treatment-emergent adverse events 
has been deleted. 
14. The symptom-directed physical examination has been removed from Schedule B assessments 
in Cycles ≥ 4. 
15. The clinical findings section of the protocol has been updated. 
1.8.8. 
Amendment 8 Summary of Key Changes 
1. Update the Criteria for Selection of Patient Population for Expansion Cohort #2 to clarify 
that patients must have measurable disease. 
2. Update the Inclusion Criteria for Selection of Patient Population for Expansion Cohorts #3 
and #4 to allow study participation for those patients who have received prior treatment with 
folate receptor-targeting compounds. 
3. Clarify advised use of preservative-free, lubricating artificial tears. 
4. Administrative changes were made for clarification purposes.  
1.8.9. 
Amendment 9 Summary of Key Changes 
1. Updated Exploratory Objectives and Endpoints. 


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2. The size of the MTD expansion cohort 1 has been increased to 40 patients, and the statistics sections 
of the protocol, the total numbers patients, and the Study Design Schema have been revised 
accordingly.    
3. The immunohistochemistry scoring threshold that determines patient eligibility for the MTD 
expansion Cohort 2 (advanced endometrial cancer) was increased to an H-score of > 100 to select 
the patients most likely to derive benefit from an anti-FOLR1 directed therapy.  
4. An exclusion criterion was added to exclude patients with a previous clinical diagnosis of treatment-
related pneumonitis.  
5. An exclusion criterion referencing patients who are receiving therapeutic doses of warfarin or other 
anticoagulant therapy was removed.  
6. The Early Clinical Safety Findings section has been replaced with a reference to the Investigator’s 
Brochure. 
7. The time for collection of the post-dose biopsy from patients enrolled in Cohort 3 has been changed 
to Cycle 2, Day 8±3.  In addition, patients who relapsed after showing clinical benefit will be asked to 
provide an optional biopsy to help understand the mechanism of resistance to IMGN853. 
8. A section describing the duration of the participation of the patients in the study has been added to 
the protocol for clarification purposes.  In addition, patients who meet the RECIST criteria for PD 
may now be allowed to remain on study if it is determined that they receive clinical benefit as 
agreed upon by the Investigator and the medical monitor. 
9. Sections describing the monitoring and management of infusion-related headaches, nausea and 
vomiting have been added to the protocol.  Monitoring guidelines for pneumonitis have been 
added.  A requirement for all patients enrolled in Schedule B to receive pretreatment with 
acetaminophen has been added to the protocol to align with the IB. 
10. A table outlining the management and dose-modification guidelines for ocular disorders has been 
added for clarification purposes. 
11. Update the Inclusion Criteria for Selection of Patient Population for Expansion Cohorts #2 to allow 
study participation for those patients who have received up to five prior systemic regimens. 
12. A table outlining the IMGN853 dose modification guidelines for both Schedule A and Schedule B has 
been added. 
13. A requirement for the use of lubricating artificial tears have been added to the Monitoring and 
Management of Treatment Emergent Eye Disorders and the Concomitant Medications and 
Procedures sections. 
14. A requirement for all patients, irrespective of whether or not they display ocular treatment-
emergent adverse events, to receive a complete ophthalmologic exam and ocular symptom 
assessment at End of Study or Follow-Up has been added.  In addition, patients who experience 
blurred vision, but had normal eye exams are now required to have complete exams prior to Day 1 
every other cycle.  Appendixes A and B as well as the Study Activities section have been modified 
accordingly.  
15. The requirement for treatment discontinuation of patients who showed clinical benefit but suffered 
a DLT has been removed.  


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16. Antiemetic and antidiarrhea medications have been added to the list of allowed concomitant 
medications.  
17. The window for the post-dose ECG has been changed from within 10 minutes to 1 hour for logistic 
reasons. 
18. The procedures for reporting of Serious Adverse Events have been updated. 
19. Requirement for confirmation of response has been removed to align with RECIST 1.1 requirements.  
Administrative changes were made for clarification purposes.  
1.8.10. 
Amendment 10 Summary of Key Changes 
1. The CRC decision, regarding selection of dosing schedule has been added to the protocol. As a 
result, Schedule B has been discontinued and all new patients enrolled in the study after 
implementation of this amendment will receive IMGN853 at the MTD of 6 mg/kg under Schedule A 
(once every three weeks). Additionally, provisional text that described actions to be taken if either 
Schedule A or Schedule B had been chosen has been updated for clarification purposes. Available 
clinical data indicates that the MTD defined for the Q3W schedule is equal to the RP2D; therefore, 
that statement has been added for clarification. 
2. A separate cohort of patients with relapsed ovarian cancer has been added. Patients enrolled into 
this cohort (Cohort 5) will self-administer corticosteroid eye drops for the first 10 days of each cycle 
while on active study treatment. The statistics sections of the protocol, the total numbers patients, 
and the Study Design Schema have been revised accordingly.    
3. Evaluation of effectiveness of primary, prophylactic steroid eye drops in preventing or lessening 
keratopathy and/or blurred vision has been added as a secondary objective, as has the 
corresponding endpoint. 
4. The eligibility criteria for expansion cohort 2 have been broadened to include any patient with 
FOLR1-positive uterine cancer. 
5. The wording to describe the IHC threshold positivity for the ovarian cohorts has been revised to 
remove the “hetero” descriptor, as it is irrelevant. 
6. The eligibility criteria for expansion cohort 3 (biopsy cohort) have been revised; patients with 
relapsed EOC are eligible and those with primary refractory EOC are excluded. 
7. An exploratory endpoint has been added. A bioinformatics approach will be used to infer the 
germline/somatic status of BRCA1 and BRCA2 mutations.  
8. The procedure for administration of corticosteroid eye drops has been added to the protocol. 
9. The procedure for administration of lubricating drops has been co-located to the section of the 
protocol that describes the procedure for administration of corticosteroids. 
10. A table outlining the management of non-infectious pneumonitis has been added. 
11. Pulmonary function tests have been added to the list of procedures that are required to be 
performed before Cycle 1 Day 1. The schedule of events and sections describing visits and 
assessments have been modified accordingly. 
12. The management guidelines for nausea and vomiting have been revised to remove the requirement 


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for administration of dexamethasone for grade 1 nausea and/or vomiting. 
13. A requirement was added to obtain a blood sample for measurement of homocysteine and 
methylmalonate during Cycle 2 and at the End of Treatment visit. 
14. Administrative changes were made for clarification purposes. 
 
 


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1.9. 
Early Clinical Safety Findings 
For detailed information regarding clinical safety of IMGN853, please refer to the Investigator’s 
Brochure.  
1.10. 
Clinical Pharmacology 
Pharmacokinetic (PK) parameters were determined for Cycle 1 dosing in each patient.  The clearance of 
IMGN853 is shown to be rapid at low doses (CL= 1.1 mL/hr/kg) with a half-life of approximately 1.5 days.  
While the clearance of IMGN853 is rapid (CL= 1.1 mL/hr/kg) at the lowest dose level (0.15 mg/kg), the 
clearance decreases with increasing dose with a half-life of about 5 days at doses ≥ 2.0 mg/kg.  The 
exposure (AUC) and the Cmax are shown to increase in a generally linear fashion with increasing dose of 
IMGN853.  These data are summarized in detail in Section 5.3.1 of the Investigator’s Brochure. 
1.10.1. 
Rationale for Dosing Based on Adjusted Ideal Body Weight 
Initial PK parameter analysis demonstrated that mean Cmax increased proportionally with the dose of 
IMGN853, however there was significant variability in inter-patient Cmax levels.  The variability in Cmax 
was particularly striking in the 5 mg/kg cohort, where PK was analyzed in 10 patients with a wide range 
of body weights (48.2 kg – 135.8 kg).  Further analysis identified a correlation between Cmax levels and 
the occurrence of TEAEs of ocular disorders, with higher Cmax values correlating with the occurrence of 
TEAEs of eye disorders.  Results from these analyses are detailed in Section 5.3.3 of the Investigator’s 
Brochure. 
A number of dosing strategies were investigated in an effort to maximize IMGN853 exposure, while 
maintaining Cmax and AUC0-24 levels within a range that was not associated with TEAEs of eye disorders 
for the great majority of patients (less than 150 µg/ml and 2785 hr*mg.ml, respectively) and with the 
least possible inter-patient variability in Cmax.  To this end, Cmax values were estimated using alternative 
dosing calculations for all patients treated in the 3.3 (n=3), 5.0 (n=10) and 7.0 mg/kg (n=5) dose groups.  
Calculated Cmax values were normalized to a 5 mg/kg dose level and compared to Cmax values observed 
from total body weight (TBW) dosing.  Three alternate formulas were evaluated: (1) Ideal body weight 
(IBW), Lean Body Weight (LBW) and Adjusted Ideal Body Weight (AIBW).  Of the three methods, dosing 
by AIBW body weight had the least total body weight dependence (Figure 2).  Based on the current data, 
dosing by AIBW weight is expected to reduce variance in Cmax compared to dosing according to TBW for 
patients across a spectrum of weights.  Refer to Section 5.3.3 of the Investigator’s Brochure  for details. 
 
 


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Figure 2: 
Correlation Between Cmax and Total Body Weight (TBW), Ideal Body 
Weight (IBW), Lean Body Weight (LBW), and Adjusted Ideal Body Weight 
(AIBW) 
 
 
The results of the PK modeling, suggest that dosing according to adjusted ideal body weight may 
reduce the variation in exposure within dosing cohorts.  Therefore, the adjusted ideal body 
weight calculation will be used to dose IMGN853 (see Section 5.8.4).  For Schedule A (Q3W) a 
new cohort of patients will be enrolled and treated at a starting dose level of 5 mg/kg based on 
AIBW.  In the ten patients previously treated at 5 mg/kg based on total body weight (TBW), 
ocular toxicity was observed in some patients, but the MTD was not exceeded and none of the 
ocular changes met the threshold for a DLT.  Modification of the dosing method to calculate 
dose based on adjusted ideal body weight is predicted to reduce ocular toxicity, by minimizing 
peak exposure levels (Cmax and AUC 0-24hrs).  The adjusted ideal body weight calculation will 
also be used to dose patients treated on Schedule B (modified weekly).  The starting dose will be 
1.1 mg/kg. 
1.10.2. 
Rationale to Explore a Modified Weekly Dosing Schedule 
As described in Section 1.10.1 a significant correlation between high Cmax values (≥ ~150 µg/ml) and 
incidence of ocular toxicity was observed across the 5 and 7 mg/kg dose levels when IMGN853 was 


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administered on day 1 of a 21-day cycle dosed by total body weight.  Alternate dosing schedules were 
explored via simulation to identify the dose levels that would achieve maximal exposure with limited 
accumulation and a Cmax below 150 µg/ml in order to minimize ocular toxicity risk.   
A population PK model based on rich and sparse (peak and trough) concentration-time profiles of 
IMGN853 following Q3W dosing (escalating dose) was developed.  Plasma concentrations of IMGN853 
were best modeled by a 3-compartment model and this model was used to simulate steady-state 
exposure to IMGN853 for various dosing schedules, including weekly (QW), every 2 weeks (Q2W), and 
weekly for 3 weeks in a 4 week cycle (modified weekly schedule).  
The modified weekly dosing regimen had minimal accumulation between cycles (accumulation index of 
1.06), while the QW dosing regimen resulted in the highest accumulation (accumulation index of 1.97).  
Comparing doses that gave equivalent Cmax levels, the modified weekly schedule allowed overall 
exposure increases of almost  ~2-fold while limiting Cmax to levels below that observed with ocular 
toxicity (Table 2). 
Table 2: 
PK Simulation to Evaluate Fractionated Dosing Regimens 
Schedule 
Dose  
(mg/kg) 
Cmax 
(µg/ml) 
Cmin 
(µg/ml) 
Cavg 
(µg/ml) 
AUC12W 
(h*mg/ml) 
Q3W 
4.2 
112 
7.8 
30 
61 
Q2W 
4.1 
119 
18 
44 
89 
QWx3 in 4W 
3.3 
119 
20 
52 
107 
 
The population PK model was also used to simulate a hypothetical population of 500 patients via Monte 
Carlo resampling.  Descriptive statistics were derived in order to determine a dosing regimen with the 
percentage of subjects with Cmax < 150 µg/ml to optimize the safety profile of IMGN853.  Using total 
body weight dosing, for the Q3W regimen, dose levels of 2.0, 3.3, and 3.8 mg/kg resulted in 99%, 95% 
and 90% of the population with a Cmax < ~150 µg/ml, respectively.  For the modified weekly regimen, 
dose levels of 1.5, 2.0 and 2.5 mg/kg per dose (or 4.5, 6, and 7.5 mg/kg per cycle) resulted in 99%, 95% 
and 90% of the population with a Cmax < 150 µg/ml, respectively.   
Results from the simulation studies suggest fractionated dosing may increase overall exposure while 
maintaining a lower Cmax and thus improve the toxicity profile.  The schedule on which IMGN853 is 
administered on Days 1, 8, and 15, with cycles repeating every 28 days (modified weekly), appears to 
minimize accumulation while simultaneously maximizing total exposure, and maintaining Cmax levels 
below 150 µg/ml. 


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2. 
TRIAL OBJECTIVES AND ENDPOINTS 
All objectives apply to both dosing schedules and all cohorts unless otherwise 
noted. 
2.1. 
Primary Objectives  
• Determine MTD and RP2D of IMGN853 when administered intravenously  
2.2. 
Primary Endpoints  
• MTD 
• RP2D 
2.3. 
Secondary Objectives 
• Evaluate the safety and tolerability of IMGN853 
• Evaluate the effectiveness of primary, prophylactic steroid eye drops in preventing or 
lessening keratopathy and/or blurred vision  
• Characterize the PK of IMGN853 when administered intravenously  
• Describe any preliminary evidence of IMGN853 antitumor activity  
• Characterize the immunogenicity of IMGN853 
2.4. 
Secondary Endpoints 
• Treatment-emergent adverse events and clinically significant ≥ Grade 3 changes in 
laboratory test results, physical examination, ECGs or vital signs 
• Treatment-emergent ocular adverse events 
• PK parameters: Cmax, AUC, terminal half-life (t½), clearance (Cl), volume of 
distribution at steady state (Vss), Tmax, AUC   
• Number of patients with RECIST 1.1 criteria (Appendix E) clinical responses and/or 
number of patients with GCIG CA-125 criteria clinical responses (Appendix F) 
− Objective response rate (ORR; MTD Expansion Cohorts # 1 and 2) 
− Duration of response (DOR) 
− Progression-free survival (PFS) 
− Time to progression (TTP) 
• Human-Anti-Human Antibody (HAHA) and Human-Anti-Drug Antibody (HADA) 
levels 
2.5. 
Exploratory Objectives 
• Determine the predictive value of FOLR1 expression on tumor cells as a biomarker 
for IMGN853 anti-tumor activity 


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• Explore the association of molecular alterations in oncogenic genes and pathways, 
and  established molecular tumor subtypes (e.g. the four molecular subtypes of high 
grade serous ovarian cancer) with FOLR1 expression and IMGN853 antitumor 
activity 
• Evaluate any additional tumor or blood based biomarkers that may be associated with 
sensitivity or resistance to IMGN853 (e.g., MDR1 expression, polymorphism) 
• MTD Expansion Cohort #3 only: Characterization of post-dose biopsy samples to 
evaluate: 
o Presence of IMGN853 in tumor 
o Pd activity measured as changes in Ki67 from baseline, and/or other biomarkers 
based on emerging data 
o Changes in FOLR1 expression post-treatment and at disease progression 
o Changes in the numbers of tumor infiltrating immune cells after treatment with 
IMGN853 
o Mechanism of relapse or treatment emerging resistance to IMGN853 
2.6. 
Exploratory Endpoints 
• Evaluate FOLR1 expression by IHC (protein), qRT-PCR (mRNA) or other 
quantitative methods 
• Establish mutational status, copy number alterations, and gene structure 
rearrangements in known oncogenic genes and pathways (e.g. mutations in p53, 
BRCA1/2 in ovarian cancer, PTEN/PIK3CA in endometrial cancer, EGFR, KRAS in 
NSCLC) 
• Infer somatic/germline status of BRCA1/2 mutations using data generated from tumor 
tissue 
• Analyze mRNA and/or protein expression of genes known to be over expressed or 
silenced in cancer, as well as genes associated with molecular cancer subtypes 
• Evaluate expression and polymorphism of drug transporters such as MDR1 (i.e. PgP) 
• Evaluate additional biomarkers identified in preclinical studies that  may be 
associated with IMGN853 sensitivity or resistance 
• MTD Expansion Cohort#3 Only: 
o Measure binding of IMGN853 to tumor cells in post treatment biopsy by anti-
Maytansine IHC 
o Compare the number of Ki-67 positive cells in baseline biopsies with that of post-
treatment biopsies using IHC 
o Compare FOLR1 expression in archival samples, baseline, and post-treatment 
(Cycle 2 Day8) biopsies by IHC 
o Compare the number of different types of immune cells in baseline biopsies with 
that of post-treatment biopsies using IHC for cell-type specific markers 


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o Compare FOLR1 expression and mutation status at baseline with those of 
biopsies taken after relapse 
 
 


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3. 
STUDY POPULATION 
3.1. 
Criteria for Selection of Patient Population 
1. Diagnosis, allowable prior therapy, and disease measurability requirements: 
A. Dose Escalation Phase: All patients must have a pathologically documented, definitively 
diagnosed, advanced solid tumor that is refractory to standard treatment, for which no standard 
treatment is available, or the patient refuses standard therapy.  Enrollment without prior 
documentation of tumor FOLR1 expression will be limited to the following histologic subtypes, 
which have a high incidence of FOLR1 positivity: 
a. Serous or endometrioid epithelial ovarian cancer, primary peritoneal cancer, or fallopian 
tube cancer 
b. Serous or endometrioid endometrial cancer 
c. Adenocarcinoma or BAC NSCLC 
d. Additional tumor types may be eligible, but require documented expression of FOLR1 
(≥1% of tumor staining at ≥1+ intensity) by IHC (see Laboratory Manual for IHC screening 
procedures) 
e. There is no upper limit on the number of prior cytotoxic or targeted therapies the 
patient may have received.  Patients may have received prior treatment with 
investigational compounds targeting folate receptor. 
f. Patients must have measurable or non-measurable disease (such as large abdominal 
masses that cannot be accurately measured) according to RECIST 1.1 (Appendix E). 
B. Dose Expansion Cohort 1: Patients must have EOC, which is resistant to platinum-based 
chemotherapy:  
a. Patients must have received prior platinum-based therapy for management of disease.  
b. Patients must have histologically-confirmed EOC, primary peritoneal cancer or fallopian 
tube cancer.  
c. Patients must have platinum-resistant ovarian cancer, which is defined as disease that 
responded to primary platinum therapy and then progressed within six months or 
disease that progressed during or within six months of completing subsequent platinum 
therapy. 
d. Patients must meet the minimum requirement of FOLR1 positivity by IHC (≥25% of 
tumor staining at ≥2+ intensity).  
e. Patients with primary platinum refractory disease (those who have not responded to a 
platinum-based regimen or experienced disease recurrence within three months of 
completing their first platinum-based regimen) are excluded. 
f. Patients with clear cell or low grade ovarian cancer are excluded.   
g. Patients must not have received more than five prior systemic treatment regimens.   


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h. Patients must have at least one lesion that meets the definition of measurable according 
to RECIST 1.1 (Appendix E). 
C. Dose Expansion Cohort 2: Patients must have histologically-confirmed diagnosis of advanced or 
recurrent uterine cancer. 
a. Patients must have received at least one platinum-based chemotherapy regimen and no 
more than five prior systemic treatment regimens (including cytotoxic chemotherapy, 
hormonal therapy, and targeted therapy, or any other investigational treatment in the 
adjuvant or the metastatic setting) for EC. 
b. Patients must have confirmation of an H score ≥100 for FOLR1 expression by IHC. 
c. Patients must have at least one lesion that is measurable on CT or MRI scan determined 
by investigator per RECIST Version 1.1 (Appendix E). 
D. Dose Expansion Cohort 3:  Patients must have relapsed EOC, which is amenable to biopsy. 
a. Patients must have histologically-confirmed EOC, primary peritoneal cancer or fallopian 
tube cancer who have progressed following completion of standard therapy. 
b. Patients with primary refractory disease (those who have not responded to a platinum-
based regimen or experienced disease recurrence within three months of completing 
their first platinum-based regimen) are excluded. 
c. Patients with clear cell or low grade ovarian cancer are excluded. 
d. Patients must be willing to undergo tumor biopsy prior to the first dose of IMGN853 and 
on Cycle 2, Day 8±3 days. 
e. Patients must meet the minimum requirement of FOLR1 positivity by IHC (≥25% of 
tumor staining at ≥2+ intensity).  
f. There is no upper limit on the number of prior treatment regimens (cytotoxic and/or 
targeted therapies) the patient may have received. 
g. Patients must have measurable or non-measurable disease (such as large abdominal 
masses that cannot be accurately measured) that can be safely biopsied. (Appendix E). 
E. Dose Expansion Cohort 4: Patients must have a histologically or cytologically-confirmed 
diagnosis of NSCLC adenocarcinoma or BAC, and must be refractory to or intolerant of standard 
therapy. 
a. Patients must meet the minimum requirement of FOLR1-positivity by IHC (≥25% of 
tumor staining at ≥1+ intensity). 
b. There is no upper limit on the number or prior treatment regimens the patient may 
have received (cytotoxic and/or targeted therapies).  
c. Patients must have measurable or non-measurable disease (such as large masses that 
cannot be accurately measured) per RECIST Version 1.1. (Appendix E). 


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F. Dose Expansion Cohort 5: Patients enrolled in this cohort will receive corticosteroid eye drops 
as primary prophylaxis to assess whether this treatment reduces the risk or severity of blurred 
vision and/or keratopathy observed in patients treated with IMGN853. 
a. Patients must have one of the following pathologically documented, definitively 
diagnosed tumor types: 
i. 
Advanced EOC  
ii. 
Primary peritoneal cancer  
iii. 
Fallopian tube cancer  
b. Patients must have received at least 3 but not more than 4 prior systemic treatment 
regimens. 
c.  Patients must meet the minimum requirement of FOLR1 positivity by IHC (≥25% of 
tumor staining at ≥2+ intensity). 
d. Patients with primary platinum refractory disease (those who have not responded to a 
platinum-based regimen or experienced disease recurrence within three months of 
completing their first platinum-based regimen) are excluded. 
e. Patients with clear cell or low grade ovarian cancer are excluded.   
f. Patients must be willing and able to self-administer low-dose corticosteroid eye drops 
four times daily, for the first 10 days of each cycle, during active study treatment. 
g. Patients must have measurable or non-measurable disease (such as large abdominal 
masses that cannot be accurately measured) per RECIST 1.1 (Appendix E). 
3.1.1. 
Inclusion Criteria (All Patients) 
1. Patients must be willing to provide an archival tumor tissue block or slides for biomarker 
analysis. 
2. > 18 years old at the time of informed consent. 
3. ECOG Performance Status 0 or 1    
4. Time from Prior Therapy:  
• 
Systemic Anti-Neoplastic Therapy: five half-lives or four weeks, whichever is shorter (6 
weeks for prior nitrosoureas or mitomycin C) 
• 
Radiotherapy: wide-field radiotherapy (e.g. > 30% of marrow-bearing bones) completed 
at least four weeks, or focal radiation completed at least two weeks, prior to starting 
study drug 
5. Patients must have recovered or stabilized from all therapy-related toxicities. 
6. Major surgery (not including placement of vascular access device or tumor biopsies) must be 
completed four weeks prior to Day 1.  Patients must have recovered or stabilized from the side 
effects prior to study treatment.  
7. Patients must have adequate hematologic, liver and kidney function as defined by the following 
parameters: 
a. Absolute neutrophil count (ANC) ≥  1.5 x 109/L (1,500 /µL) 


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b. Platelet count ≥ 100.0 x 109/L (100,000/µL; must not have been transfused within 
previous 10 days) 
c. Hemoglobin ≥ 9.0 g/dL, 
d. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or 24-hour creatinine clearance of 
≥ 60 mL/minute, 
e. AST ≤ 2.5 x ULN; ALT ≤ 2.5 x ULN (AST, ALT < 5 x ULN if liver metastases), and  
f. Serum bilirubin ≤ 1.5 x UNL 
8. Patients with CNS disease involvement are eligible if they have had brain metastases resected or 
have received radiation therapy ending at least 4 weeks prior to study day 1 and they meet all of 
the following criteria: (1) residual neurological symptoms ≤ Grade 1 (2) No dexamethasone 
requirement, and (3) Follow-up MRI shows no progression of treated lesions and no new lesions 
appearing. 
9. Patients must be willing and able to sign the informed consent form, and to adhere to the study 
visit schedule and other protocol requirements. 
10. Women of child bearing potential (WCBP), defined as a sexually mature woman who has not 
undergone surgical sterilization or who has not been naturally postmenopausal for at least 12 
consecutive months (i.e., who has had menses any time in the preceding 12 consecutive 
months) must agree to use effective contraceptive methods; examples include oral, parenteral, 
or implantable hormonal contraceptive, intra-uterine device, barrier contraceptive with 
spermicide, partner’s latex condom or vasectomy) while on study treatment and for at least 
twelve weeks after the last dose of study drug.   
11. WCBP must have a negative pregnancy test prior to the first dose of study treatment. 
12. Male patients must agree to use a latex condom even if he has had a successful vasectomy and 
continue to follow these requirements for at least twelve weeks following the last dose of study 
drug. 
3.1.2. 
Exclusion Criteria (All Patients) 
1. Grade >1 neuropathy 
2. Any active or chronic corneal disorder, including, but not limited to the following: Sjogren’s 
syndrome, Fuchs corneal dystrophy (requiring treatment), history of corneal 
transplantation,  active herpetic keratitis, and also active ocular conditions requiring on-going 
treatment/monitoring such as wet age-related macular degeneration requiring intravitreal 
injections, active diabetic retinopathy with macular edema,  presence of papilledema, acquired 
monocular vision  Serious concurrent illness, including, but not limited to the following: 
a. Clinically relevant active infection including known active hepatitis B or C, Human 
Immunodeficiency Virus (HIV) infection, varicella-zoster virus (shingles) or 
cytomegalovirus infection or any other known concurrent infectious disease, requiring 
IV antibiotics within 2 weeks of study enrollment. 
b. Significant cardiac disease such as recent myocardial infarction (≤ 6 months prior to Day 
1), unstable angina pectoris, uncontrolled congestive heart failure (New York Heart 


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Association > class II), uncontrolled hypertension (≥ CTCAE v4.03 Grade 3), uncontrolled 
cardiac arrhythmias, severe aortic stenosis, or ≥ Grade 3 cardiac toxicity following prior 
chemotherapy. 
c. History of multiple sclerosis or other demyelinating disease, Eaton-Lambert syndrome 
(para-neoplastic syndrome), history of hemorrhagic or ischemic stroke within the last six 
months, or alcoholic liver disease. 
d. Previous clinical diagnosis of treatment-related pneumonitis. 
3. Any other concomitant anti-cancer treatment such as immunotherapy, biotherapy, 
radiotherapy, chemotherapy, investigative therapy, or high-dose steroids; however, low-
dose steroids and Luteinizing Hormone Releasing Hormone (LHRH) at doses that have been 
stable for ≥ 14 days are permitted for patients with prostate cancer 
4. Known hypersensitivity to previous monoclonal antibody therapy or maytansinoids  
5. Prior history of solid tumor malignancy within the last 3 years except for adequately treated 
basal cell or squamous cell skin cancer, in situ cervical cancer, in situ breast cancer, in situ 
prostate cancer (patients must have shown no evidence of active disease for 2 years prior to 
enrollment) 
6. Concomitant administration of folate-containing vitamins 
8. Patients who have received prior allogeneic or autologous bone marrow transplants 
9. WCBP who are pregnant or breast feeding 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Study Design 
4.1.1. 
Overview and Schema 
This is an open label, Phase 1, non-randomized, safety, PK, and Pd study of IMGN853 in adult 
patients with solid tumors that have relapsed, and are refractory to standard therapies.  The 
estimated study duration is approximately 50 months for patient accrual, dosing, and follow up.  
The study will be conducted in 2 stages: dose escalation and dose expansion.  Two dosing 
schedules will be evaluated in this study: 
   Schedule A: IMGN853 administered on Day 1, with cycles repeating every 21 days (Q3W) 
   Schedule B: IMGN853 administered on Days 1, 8, and 15, with cycles repeating every 28 days 
(modified weekly schedule) 
• Approximately 209 patients* will be enrolled in the study.  
• Dose Escalation Phase: (1) Schedule A: 44 patients (2) Schedule B: 25 patients 
• Dose Expansion Cohort 1: Patients with Epithelial Ovarian Cancer (EOC) which is 
resistant to platinum-based therapy – 40 patients  
• Dose Expansion Cohort 2: Advanced or recurrent uterine cancer – 20 patients  
• Dose Expansion Cohort 3: Patients with relapsed EOC - 20 patients 
• Dose Expansion Cohort 4: Relapsed/refractory NSCLC adenocarcinoma or 
bronchioloalveolar carcinoma (BAC) 20 patients      
• Dose Expansion Cohort 5: Patients with Epithelial Ovarian Cancer (EOC) which 
has relapsed following platinum-based therapy – 40 patients; patients enrolled into 
this cohort will self-administer daily corticosteroid eye drops to assess whether 
prophylaxis with topical steroids prevents or lessens severity of  keratopathy and/or 
blurred vision.*NOTE: Every effort will be made to ensure the requisite number of 
patients are accrued in each cohort, and to this end, communications with the site 
will be monitored carefully. There are instances however, where, as a result of 
simultaneous screening activities, patients may qualify for the study at the same time, 
resulting in slight over-enrollment in individual cohorts 
The primary aim of the dose-escalation phase is to evaluate the safety and tolerability of 
IMGN853, to identify the MTD, and to characterize the PK profile of IMGN853.   
Schedule A - once the MTD has been identified, enrollment to MTD Expansion Cohorts 1 and 2 
will begin.  
Schedule B, the starting dose of IMGN853 was 1.1 mg/kg, which was 1/3 the 3.3 mg/kg dose 
level, which was deemed clinically safe in nine patients on a Q3W schedule. All doses were 
calculated according to adjusted ideal body weight (AIBW).  Patients were enrolled in cohorts of 
3 to 6 patients and the MTD was determined to be 2.0 mg/kg (AIBW).  The CRC to review 
safety, PK and efficacy data from the dose escalation cohorts, as well as available data from 
patients treated on Schedule A.  The modified weekly schedule did not provide any apparent 


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safety or efficacy advantage. These results were presented at the annual ASCO meeting (Borghei 
2015).  
Based on safety and overall response data collected through May 2015, the CRC determined 
that all  new patients enrolled in the trial will receive IMGN853 at the MTD of 6 mg/kg once 
every three weeks. Safety data available to date indicate that the MTD is equal to the RP2D. 
Moving forward, Schedule B will not be evaluated any further in this study; however, patients 
enrolled to Schedule B prior to the CRC decision, will continue on this schedule.   
The period of observation extends from the time the patient receives the first dose of IMGN853 
until the final follow-up study visit.  Patients will continue to receive IMGN853 until 
unacceptable toxicity or withdrawal of consent, whichever comes first, or until the Sponsor 
terminates the study.  Patients who meet the RECIST criteria for PD while on study may remain 
on study, provided there is evidence of clinical benefit and no unacceptable toxicity, as agreed 
upon by the Investigator and the medical monitor.  Patients who discontinue study drug for 
reasons other than PD will be followed until PD, start of new anti-cancer therapy, or death, 
whichever occurs first.   
The primary aims of the Dose Expansion phase are to further evaluate safety and tolerability and 
to assess IMGN853 Pd and preliminary efficacy. 
CTCAE version 4.03 will be used to grade adverse events. 
Figure 3: 
Study Design Schema 
 
4.1.2. 
Cohort Review Committee 
The CRC is comprised of the ImmunoGen Medical Monitor and Investigators from participating 
sites.  Once the last patient in a given cohort has completed a cycle of study treatment, a CRC 
meeting will be convened to review all safety data and decide whether to continue or halt dose 
escalation, further expand individual dose levels to gain additional safety data, or explore lower 
or intermediate dose levels.  


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Amendment 10 Update: The CRC convened to review safety, PK and efficacy data from the 
dose escalation cohorts, as well as available data from patients treated on Schedule A. The 
modified weekly schedule did not provide an apparent safety or efficacy advantage; moreover, 
while the Q3W schedule PK profile analysis indicated no accumulation of IMGN853, 
accumulation of IMGN853 was observed using the modified weekly schedule (Borghaei, 2015). 
Based on safety, PK and overall response data collected through May 2015, the CRC 
determined that the study will proceed with IMGN853 administered under Schedule A (Q3W) 
only (Figure 2). All new patients enrolled in the trial will receive IMGN853 at the MTD of 6 
mg/kg once every three weeks. Safety data available to date indicate that the MTD is equal to 
the RP2D. Patients currently being treated using Schedule B will continue to be dosed 
according to this schedule. 
4.1.3. 
Dose Escalation Guidelines 
Schedule A dose escalation is complete and the MTD is 6 mg/kg (AIBW); data available to 
date indicate that the MTD is equal to the RP2D. 
4.1.3.1. 
Schedule A 
The starting dose (Dose Level 1) for IMGN853 is 0.15 mg/kg, which is equivalent to 1/20 the HNSTD 
observed in the GLP cynomolgus monkey toxicology study.  The planned dose levels are outlined in 
Table 3.  IMGN853 will be given intravenously on Day 1 of every 21-day cycle.  Based on the favorable 
safety margins suggested by the non-clinical cynomolgus monkey toxicology study and to minimize 
patient exposure to biologically-inactive doses of IMGN853, the dose escalation phase will initially follow 
an accelerated titration design.  Each of the first 4 cohorts will consist of 1 patient.  From cohort 5 
onward, the dose escalation will proceed in a standard 3+3 design, with each cohort enrolling 3 or 4 to 6 
patients.   
Table 3: 
Planned Dose Levels (Schedule A) 
Dose Level 
Dose (mg/kg) 
Percent Increase 
From Previous Dose 
Level 
Number of Patients 
(Planned) 
1 
0.15 
N/A 1/20 HNSTD 
1 
2 
0.5 
233% 
1 
3 
1.0 
100% 
1 
4 
2.0 
100% 
1 
5 
3.3 
65% 
3 or 4-6 
6 
5.0 
52% 
3 or 4-6 
7 
7.0 
40% 
3 or 4-6 
8 
9.0 
28% 
3 or 4-6 
NOTE: If additional dose exploration is required to define the MTD then dose escalation may proceed 
at increments ≤ 40%.  The CRC will determine the magnitude of the dose escalation increments 
following review of available clinical and PK data from patients treated in the current cohort. 
 


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For Cohort 1, the first patient enrolled into the study will be observed for a 28 day period in Cycle 1 
before the patient is retreated and before a dose escalation decision will be made.  This 4 week period 
of observation will only apply to the first cycle for the first patient enrolled into the trial.  All subsequent 
cycles of treatment for this patient and all other patients will be of 3 weeks duration.  This additional 
week of observation is employed to provide an additional margin of safety to address skin findings that 
were improved but not completely resolved in all animals by day 28 in the GLP toxicology study.  During 
this time period, if there are no observations of CTCAE v4.03 ≥ Grade 2 dose limiting toxicities then dose 
escalation to 0.5 mg/kg will proceed and will follow the rules outlined below.  If a patient develops a ≥ 
Grade 2 toxicity for which a causal relationship to IMGN853 cannot be excluded, then 2 additional 
patients must be added to this dose level.  If no ≥ Grade 2 TEAEs are observed, dose escalation will 
revert to single patient cohorts through the 2 mg/kg dose level (inclusive). 
For Cohort 2 and beyond, decisions regarding dose escalation will be based on the occurrence of 
Cycle 1 dose limiting toxicity.  
In the absence of any > CTCAE Grade 2 or greater AEs observed at dose level 1 through 4, dose 
escalation will proceed according to the accelerated titration schema outlined in Table 3.  If the 
patient develops a ≥ Grade 2 toxicity for which a causal relationship to IMGN853 cannot be 
excluded, then 2 additional patients must be added to this dose level.  If no ≥ Grade 2 TEAEs are 
observed, dose escalation will revert to single patient cohorts through the 2 mg/kg dose level 
(inclusive). 
The occurrence of DLT for which a causal relationship to IMGN853 cannot be excluded, will 
trigger a transition to the standard 3+3 dose escalation schema. 
For patients enrolled to Cohorts 5 and above, dose escalation decisions will be made in 
accordance with a standard 3+3 design (Section 4.1.3.3). 
4.1.3.2. 
Schedule B 
Schedule B dose escalation is complete and the MTD is 2 mg/kg (AIBW). The modified weekly 
schedule will not be evaluated further in this study. In Schedule B, the starting dose of 
IMGN853 will be 1.1 mg/kg, which is 1/3 the 3.3 mg/kg Q3W dose level, which was deemed 
clinically safe in nine patients. 
Patients will be enrolled in cohorts of 3 to 6 patients until the MTD is defined (Section 4.1.3.3).  
Planned dose levels are listed below in Table 4 and will be administered based on AIBW body 
weight.  Based on emerging data, the CRC will decide the magnitude of the dose escalation and 
may determine that exploration of lower or intermediate dose levels is warranted.  If at any time, 
the administration of IMGN853 on a weekly basis is deemed to be suboptimal or PK/ 
Pharmacodynamics data supports a less frequent dosing regimen, the decision may be made by 
the CRC to select the less frequent dosing schedule. 
A patient will be deemed non-evaluable for dose escalation decisions and will not be counted 
toward the total cohort size if the patient did not receive a full course of treatment (i.e., all 
planned doses of IMGN853 for the first treatment cycle) and did not experience a DLT; or 
discontinued from the study prior to completing necessary safety evaluations through the end of 
the first cycle of treatment and did not experience a DLT.  Non-evaluable patients will be 
replaced unless accrual to the cohort has stopped due to the occurrence of at least two patients 
with DLT.  


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 Table 4: 
Planned Dose Levels (Schedule B; Dosed by AIBW) 
Dose Level 
Dose (mg/kg) 
Percent Increase From 
Previous Dose Level 
Number of Patients 
(Planned) 
1 
1.1 
N/A  
3 or 4-6 
2 
1.8 
65% 
3 or 4-6 
3 
2.5 
40% 
3 or 4-6 
4 
3.3 
32% 
3 or 4-6 
NOTE: If additional dose exploration is required to define the MTD then dose escalation may proceed at 
increments ≤ 25%.  The CRC will determine the magnitude of the dose escalation increments following 
review of available clinical and PK data from patients treated in the current cohort. 
4.1.3.3. 
Dose Escalation Rules (3+3 Design) 
• If none of the 3 or 4 patients experience a DLT, then dose escalation to the next dose 
level will occur. 
• If 1 of the initial 3 or 4 patients experiences a DLT, the cohort will be expanded to up to 
6 patients.  If no further DLT is seen, dose escalation to the next dose level may proceed. 
• If at least 2 out of 2 to 6 patients or more than 33% of patients in any given cohort 
experience a DLT, the maximum administered dose (MAD) is reached, and no further 
dose escalation will occur.  Enrollment into a cohort at lower dose level will be 
considered. 
• Each dose level will be evaluated in a similar fashion.  
The MTD is defined as the highest dose at which 1 or fewer among 6 patients or ≤ 33% 
experiences a DLT. 
Once the MTD has been exceeded, the CRC will decide whether lower dose levels should be 
explored further or whether an intermediate dose level should be evaluated.  If additional dose 
exploration beyond the highest dose shown in Table 3 is required to define the MTD then dose 
escalation may proceed at increments specified in Table 3 and Table 4.  The CRC will determine 
the magnitude of the dose escalation increments following review of available clinical and PK 
data from patients treated in the current cohort. 
If there is evidence of late-occurring or cumulative DLT(s), an ad hoc CRC may be scheduled 
with participating Investigators to discuss dose level or MTD reduction.  If agreed, the 
Investigators and Sponsor may increase the number of patients treated at a given dose level, or to 
enroll additional patients at the previously-completed dose level if doing so is necessary to better 
define the study drug’s safety.  Additionally, upon review of the safety data from the current 
cohort, the Sponsor, together with the Investigators may decide to evaluate an intermediate dose 
level. 
4.1.4. 
Definition of Dose-Limiting Toxicity (DLT) 
Dose limiting toxicity (DLT) will be defined as a TEAE or abnormal laboratory value related to 
study treatment (i.e., assessed as unrelated to disease, intercurrent illness, or concomitant 
medications), including those TEAEs and abnormal laboratory values that result in a failure to 


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meet the criteria for re-treatment.  DLTs will be considered related to the investigational agent 
unless there is clear evidence of an alternative explanation and this attribution is agreed to by the 
CRC.  
For the purposes of dose escalation and determination of the MTD, only DLTs that occur during 
the first cycle will be necessarily considered for decisions regarding dose escalation.  Clinically 
significant toxicities or treatment-emergent adverse events that meet the definition of dose 
limiting but occurring after Cycle 1 (dose modifying events) may be considered when 
determining the RP2D.   
If a patient experiences a DLT as outlined in Table 5, the study treatment must be stopped and 
the toxicity (ies) in question must be followed until resolution or stabilization.  If treatment is to 
be resumed then retreatment criteria must be met (Section 5.9.3) and administration must be 
resumed at a lower dose (Section 4.1.3). 


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Table 5: 
DLT Definitions 
TOXICITY 
DLT DEFINITION CRITERIA 
Dose delays 
Failure to meet re-treatment criteria within the specified timeframe 
Hematology 
• 
CTCAE Grade 4 neutropenia ≥ 7 days. 
• 
CTCAE Grade 3 or 4 neutropenia with single temperature reading  ≥ 
38.3°C or sustained temperature reading of > 38°C for > 1 hour 
• 
CTCAE Grade 3 thrombocytopenia, associated with clinically-
significant bleeding that requires transfusion therapy 
• 
CTCAE Grade 4 thrombocytopenia  
Non-hematologic and 
other DLTs 
• 
≥ CTCAE Grade 3 nausea or vomiting despite the use of optimal anti-
emetic treatments 
• 
≥ CTCAE Grade 3 diarrhea despite the use of optimal anti-diarrheal 
treatments 
• 
Other non-hematologic toxicities of CTCAE ≥ Grade 3 except for the 
following: 
o AEs related to underlying disease 
o Alopecia 
o CTCAE Grade 3 fatigue 
o Lymphopenia is not considered DLT unless accompanied by 
clinically-significant infection 
o Isolated, asymptomatic Grade 3 abnormalities in biochemistry 
laboratory values that last for ≤ 7 days.  This includes 
electrolyte abnormalities that respond to medical 
intervention. 
For any dose limiting hepatic toxicity that does not resolve to baseline within 7 days, an abdominal CT 
scan must be performed to assess whether it is related to disease progression. 
4.1.5. 
Dose Expansion Cohorts 
Once the MTD is established, additional patients will be treated in a dose expansion phase that is 
designed to further evaluate safety and tolerability, assess preliminary efficacy at the MTD, and 
characterize IMGN853 Pd.  
Data obtained in the dose expansion phase will help define the RP2D.   
Expansion Cohort #1 will enroll 40 patients with platinum-resistant EOC, primary peritoneal 
cancer or fallopian tube cancer who have tumors that meet the requirement of FOLR1 positivity 
by IHC (≥25% of tumor staining at ≥2+ intensity).  The size of this cohort was increased to 


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better define the frequency and assess the impact of the proposed management guidelines for 
ocular adverse events.   
Expansion Cohort #2 will enroll 20 patients with advanced, recurrent uterine cancer; eligible 
patients will have tumors with an H score ≥100 for FOLR1 expression by IHC.  
Expansion Cohort #3 will enroll 20 patients with relapsed EOC; eligible patients will have 
tumors that meet the requirement of FOLR1 positivity by IHC (≥25% of tumor staining at ≥2+ 
intensity).   
Expansion Cohort #4 will enroll 20 patients with relapsed/refractory NSCLC adenocarcinoma 
or BAC; eligible patients will have tumors that meet the requirement of FOLR1 positivity by 
IHC (≥25% of tumor staining at ≥1+ intensity).   
Expansion Cohort #5 will enroll 40 patients with relapsed EOC, primary peritoneal cancer or 
fallopian tube cancer who have tumors that meet the requirement of FOLR1 positivity by IHC 
(≥25% of tumor staining at ≥2+ intensity).  Patients enrolled into this cohort will self-administer 
corticosteroid eye drops four times daily, for the first 10 days of each cycle, to assess whether 
prophylaxis with topical steroids prevents or lessens severity of ocular toxicity. 
In addition to FOLR1-positivity, all patients enrolled in the expansion cohorts must meet all 
other eligibility criteria (Section 3.1.1).  Safety will be evaluated continuously, separately, and in 
aggregate in the expansion cohorts.  If at any time ≥ 33% of patients treated in an expansion 
cohort experiences a Cycle 1 DLT, further enrollment to that cohort will stop and a CRC will be 
convened.  The CRC will review all available safety data and PK data to determine how further 
dosing should proceed.  If it is decided that a new dose should be investigated, enrollment to the 
cohort will begin anew. 
 


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5. 
STUDY TREATMENT 
5.1. 
Description of Study Treatment 
The investigational study drug, IMGN853, will be provided by ImmunoGen, Inc. at a protein 
concentration of 5.0 mg/mL in an aqueous pH 5.0 buffered solution.  IMGN853 will be available in a 20 
mL glass vial with 20 mL deliverable volume.  IMGN853 should be stored upright at 2-8°C.  
5.2. 
IMGN853 Packaging  
The IMGN853 will be provided in a 20 mL Type I glass vial.  The container closure for the Type 
I glass vials will consist of a 20 mm ETFE-coated serum stopper (Flurotec®) on the top and 
product contact surface with a 20 mm aluminum TruEdge® seal with blue Flip-off® top.  Refer to 
the Pharmacy Manual for labeling information. 
5.3. 
Storage, Handling and Compatibility 
Specific details regarding storage and handling can be found in the Pharmacy Manual. 
All IMGN853 supplied for the study will be accompanied by accountability and shipping 
documents that must be maintained by the Principal Investigator or designee (e.g., the study 
pharmacist).  The Investigator or designee must maintain an accurate record of the receipt and 
dispensing of IMGN853 in a drug accountability log.  These records must always be available 
for inspection, and a copy will be supplied to ImmunoGen, Inc., on request.  Information 
recorded on these accountability and shipping documents will include quantities received, dates 
and amount dispensed, the recorder’s initials, patient number and initials to whom administered, 
lot number of drug administered, and drug lost, damaged or destroyed.  
Upon completion of the study, all IMGN853 dispatched to a site must be accounted for and 
unused supplies destroyed according to the site’s Standard Operating Procedures (SOPs). If the 
site cannot destroy onsite, return of unused supplies to ImmunoGen, Inc. can be arranged.  The 
original drug reconciliation records shall be maintained at the site and a copy collected and sent 
to ImmunoGen once a representative of the company has confirmed the drug accountability.  The 
pharmacy shall maintain accurate records of all study drugs that have been received, stored, 
dispensed, destroyed, and used.  The eCRF shall also record details of IMGN853 administration 
such as date and time of administration. 
Drug accountability will be monitored regularly. 
5.4. 
Study Treatment Compliance 
The IMGN853 supplied for the study may not be used for any purpose other than the study or 
administered other than as described in this protocol.   
Study drug from two different drug lots cannot be mixed in a single dose administration. 
Under no circumstances is the Investigator allowed to release study drug supplies to any 
physician not named in the Form FDA 1572 or to administer these supplies to a patient not 
enrolled in this study.  If investigational supplies are to be dispensed from any facility other than 
that supervised directly by the Principal Investigator (i.e., hospital pharmacy, satellite pharmacy), 


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it is the responsibility of the Principal Investigator to ensure that all study drug is maintained in 
the manner described. 
5.5. 
Assignment of Patient Number 
Patient numbers are assigned in sequential order as patients sign informed consent to participate.  
Patients are to be registered by faxing or emailing a completed eligibility checklist and 
enrollment form to the Clinical Manager or designee.  The checklist will be verified and a dose 
level will be assigned as instructed by ImmunoGen, Inc. or designee.  A confirmation of 
registration form will be faxed or emailed back to the site to complete the registration process. 
The Investigator will certify that the patient satisfies all eligibility criteria at screening and 
continues to satisfy all inclusion and exclusion criteria on Cycle 1, Day 1 prior to dosing.   
5.5.1. 
Enrolled Patient Definition 
Patients who receive at least one dose of IMGN853 will be considered enrolled.  Patients who 
are issued a patient number, but who do not successfully complete the screening process and who 
do not receive a dose of IMGN853 will be considered a screen failure.  Patient numbers for 
patients who screen fail will not be re-issued. 
5.5.2. 
Patient Assignment to Dosing Schedules 
Patients will be assigned to Schedule A or B based on eligibility criteria and slot availability. 
5.6. 
Blinding 
Not applicable as this is an open-label study. 
5.7. 
Study Treatment Administration 
5.7.1. 
Study Treatment Overview and Schedule 
IMGN853 is an experimental anticancer drug, and as with other potentially toxic compounds, 
caution should be exercised when handling this compound.  It is recommended that gloves and 
protective garments be worn during preparation. 
5.7.1.1. 
Every 3-Week Schedule (Q3W) 
For logistical reasons such as holidays, delays in the scheduled study treatment for up to 3 days.  
Additionally, shifts in the start of a new cycle by -1 or +3 days will be permitted in Cycles ≥ 3. 
5.7.1.2. 
Modified Weekly  Schedule (Days 1, 8 and 15, Every 28 Days) 
For logistical reasons such as holidays, Day 1 delays in the scheduled study treatment for up to 3 
days is permitted.  Additionally, shifts in the start of a new cycle by -1 or up to +3 days will be 
permitted in Cycles ≥ 3.  If patients do not meet retreatment criteria on Days 8 and 15 of a given 
cycle, the dose should be omitted.  A delay of 1 day in the dosing of Days 8 and 15 is permitted; 
if a delay occurs, subsequent dosings on that cycle should be shifted by 1 day.  Intervals <7 days 
between dosings are not permitted.  The start of the next cycle should remain the same.   


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5.8. 
IMGN853 Preparation and Administration 
5.8.1. 
Premedication to Prevent Infusion Reaction 
5.8.1.1. 
Schedule A 
Patients should receive 10 mg IV dexamethasone, 25-50 mg diphenhydramine (IV or PO) and 325-650 
mg acetaminophen (IV or PO) approximately 30 minutes prior to each infusion.  If individual patients 
require more intensive treatment to prevent infusion reaction, investigators may modify the regimen 
accordingly.  
5.8.1.2. 
Schedule B 
Premedication with corticosteroids will not be employed initially.  For individual patients who 
experience signs of infusion-related reactions, the premedication regimen outlined in Section 
5.8.1.1 should be administered prior to all subsequent IMGN853 infusions.  All patients dosed 
according to Schedule B should receive 325-650 mg of acetaminophen (PO or IV) approximately 
30 minutes prior to each infusion of IMGN853 to prevent infusion-related headaches. 
5.8.2. 
Premedication with Corticosteroid Eye Drops (Dose Expansion Cohort#5 
ONLY) 
All patients enrolled into Cohort Expansion 5 will be instructed to self-administer 1% 
prednisolone (Pred Forte® or generic equivalent) six times daily on Days 1-5 and four times daily 
on Days 6-10 of each cycle during the study (Figure 4).  
These medications will be prescribed by the treating physician and will be sourced by the 
site.  Patients will record their eye drop administration in a patient diary, which will be entered 
on the CRF. 
5.8.3. 
Lubricating Eye Drops 
In order to prevent dry eye, which may predispose a patient to corneal irritation, patients will be 
required to use preservative-free, lubricating artificial tears  on a daily basis (as directed by the 
product label or the treating physician) for the duration of their IMGN853 treatment.   
Patients in Cohort#5 will use the corticosteroid eye drops as described in Section 5.8.2 and will 
use the lubricating eye drops for the remainder of the cycle (Days 11 through 21 inclusive). If 
patients need to use lubricating drops during Days 1-10, while steroid eye drops are being 
administered, they should be advised to wait at least 15 minutes following steroid administration 
before instilling lubricating eye drops.  
Figure 4: 
Co-Administration of Steroid Eye Drops and Lubricating Eye Drops 
(Schema) 
 


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As with the corticosteroid eye drops, patients will record their eye drop administration in a 
patient diary, which will be recorded on the CRF. 
5.8.4. 
Calculation for Adjusted Ideal Body Weight 
Based on the results of the PK modeling, as described in Section 1.10.1, which suggested that 
dosing according to adjusted ideal body weight (AIBW) may reduce the variation in exposure 
within dosing cohorts, the adjusted ideal body weight calculation will be used to dose IMGN853 
going forward.  
The total dose of drug will be calculated based on each patient’s adjusted body weight using the 
following formula: 
 
Adjusted Ideal Body Weight (AIBW)  
1. IBW1 + 0.4 ( Actual weight – IBW1) 
Where: 
Ideal Body Weight (IBW)  
1. IBW1 (male) = 0.9H1-88 
2. IBW1 (female) = 0.9H1-92 
 
(1H=height in cm; W=weight in kg) 
The weight used for calculation should be obtained prior to first treatment and thereafter should 
only be modified for significant (≥ 10%) changes in body weight (not influenced by weight gain 
or loss attributed to fluid retention).  The desired amount should be withdrawn from the vial(s) 
and diluted using 5% dextrose to a final concentration as outlined in the Pharmacy Manual.  
Note: IMGN853 is incompatible with saline (0.9% sodium chloride).  Therefore, dilutions 
should be made using 5% dextrose.  Infusion bags must be labeled with the protocol number, 
patient number, storage temperature, dose, and volume of IMGN853 filtered into the bag, or 
according to institutional protocol.  Once the solution is prepared, the infusion bag must not be 
left in direct sunlight, and the infusion must be completed within 8 hours of preparation. 
Study drug from two different drug lots cannot be mixed in a single dose administration. 
5.8.5. 
IMGN853 Administration   
During the dose escalation phase, the starting dose of IMGN853 was 0.15 mg/kg for patients 
enrolled to Schedule A and 1.1 mg/kg for patients enrolled to Schedule B.  Following 
Amendment 10 implementation, IMGN853 will be administered to all patients at the MTD of 6 
mg/kg every three weeks. (Note: Available safety data indicate that the MTD is equal to the 
RP2D). IMGN853 will be administered as an IV infusion following preparation as outlined in 
the Pharmacy Manual.  An IV tubing administration set with a 0.22 micron in-line filter must be 
used for infusion.  Initially the study drug should be administered at a rate of 1 mg/min; after 30 
minutes, the rate can be increased to 3 mg/min if well tolerated.  If well tolerated after 30 


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minutes at 3 mg/min, the IMGN853 infusion rate may be increased to 5mg/min. Subsequent 
infusions may be delivered at the tolerated rate.  Therefore, the overall length of infusion will 
vary depending on dose and patient tolerability.  Following infusion, the IV line should be 
flushed with 5% dextrose as needed to ensure delivery of the full dose.   
Patients will be carefully observed during each infusion and vital signs taken as outlined in the 
Schedule of Clinical Assessments (Appendix A and Appendix B).  They will remain in the clinic 
under observation for 4 hours after the first infusion, and for at least 1 hour after each subsequent 
infusion.   
5.8.6. 
Management of Potential IMGN853 Infusion-related Reactions  
Some patients treated with IV infusions of therapeutic antibodies have experienced concurrent infusion-
related reactions with signs or symptoms that can be classified as acute allergic/hypersensitivity 
reactions (see NCI CTCAE, Version 4.03).  The signs and symptoms may include headache, fever, facial 
flushing, pruritus, myalgia, nausea, chest tightness, dyspnea, vomiting, erythema, abdominal discomfort, 
diaphoresis, shivers, lightheadedness, hypotension, palpitations, and somnolence.  Anaphylaxis might 
occur at any time during an infusion.  Before any infusion is started, appropriate medical personnel, 
medication (e.g. epinephrine, inhaled beta agonists, antihistamines, and corticosteroids), and other 
required resources to treat anaphylaxis must be readily available.  In general, Investigators should 
manage acute hypersensitivity reactions according to Institutional practices.  General guidelines for 
management of acute reactions and subsequent retreatment with IMGN853 are provided in Table 6 
below.  Due to long half-life of the antibody, the potential exists for infusion–related reactions to recur 
after appropriate treatment; therefore, patients should be advised to seek immediate medical 
treatment if symptoms recur after discharge from clinic. 
Patients who experience an infusion-related reaction during or immediately following administration of 
IMGN853 will have blood drawn for determination of drug concentration, antibodies to IMGN853 
(HADA, HAHA).  The sample should be obtained within three hours of the onset of the reaction and 1 
week later.  Such patients should undergo all scheduled efficacy and safety evaluations. 
Table 6: 
Management Guidelines for Potential Infusion Reactions 
Infusion Reaction CTCAE v4.03 
Grade 
Management 
Grade 1: Mild, transient reaction 
• 
Maintain infusion rate unless progression of symptoms to ≥ Grade 2; if 
symptoms worsen, refer to guidelines below 
• 
Promethazine (or equivalent) 150 mg PO prn nausea 
• 
Diphenhydramine (or equivalent) 25-50 mg PO or IV prn 
• 
Methylprednisolone 125 mg (or equivalent) IV prn 


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Infusion Reaction CTCAE v4.03 
Grade 
Management 
Grade 2: Moderate  
• 
Interrupt infusion and disconnect infusion tubing from subject 
• 
Promethazine (or equivalent) 150 mg PO prn nausea 
• 
Diphenhydramine (or equivalent) 25-50 mg PO or IV prn 
• 
Acetaminophen (or equivalent) 650 mg PO prn 
• 
Methylprednisolone 125 mg (or equivalent) IV prn 
• 
After recovery from symptoms, resume the infusion at 50% of the 
previous rate and if no further symptoms appear, gradually increase rate 
until infusion is completed. 
• 
For subsequent dosing in future cycles, subjects should be pre-medicated 
with Dexamethasone 8 mg PO BID the day prior to IMGN853 
administration and Acetaminophen 650 mg PO and Benadryl 25-50 mg 
PO 30-60 minutes prior to dosing.   
Grade 3: Severe, prolonged 
reaction not rapidly responsive to 
symptomatic medication and/or 
brief interruption of infusion; 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for 
clinical sequelae 
• 
Stop infusion and disconnect infusion tubing from subject 
• 
Administer Diphenhydramine (25-50 mg) IV 
• 
Administer normal saline, epinephrine (0.2-0.5 mL of a 1:1000 dilution 
(0.2-0.5 mg)SQ or IM) and bronchodilators (nebulized albuterol, 2.5-5 mg 
in 3 mL of saline) as medically indicated 
• 
Consider IV steroids (methylprednisolone (or equivalent) up to 0.5mg/kg 
Q 6h) to prevent recurrent or ongoing reactions 
• 
Advise patient to seek emergency treatment and notify investigator/clinic 
if the infusion-related symptoms recur after discharge from clinic. 
• 
Report as a serious adverse event (see Section 9.1.1.2) 
• 
Investigators should confer with the sponsor regarding retreatment of 
the subject with IMGN853.  If the investigator and sponsor agree that the 
subject could be rechallenged with IMGN853 then prophylaxis for an 
infusion-related reaction should occur in all subsequent cycles.  For this, 
subjects should be pre-medicated with Dexamethasone 8 mg PO BID the 
day prior to IMGN853 administration and Acetaminophen 650 mg PO and 
Diphenhydramine 25-50 mg PO 30-60 minutes prior to dosing. 


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Infusion Reaction CTCAE v4.03 
Grade 
Management 
Grade 4: Life-threatening 
consequences, urgent intervention 
indicated  
• 
Immediately stop infusion and disconnect infusion tubing from subject 
• 
Permanently discontinue study medication treatment 
• 
Administer Diphenhydramine (or equivalent) 50 mg IV 
• 
Administer normal saline, epinephrine (0.2-0.5 mL of a 1:1000 dilution 
(0.2-0.5 mg)SQ or IM)  
• 
Administer bronchodilators (nebulized albuterol, 2.5-5 mg in 3 mL of 
saline) as medically indicated 
• 
Administer IV steroids (methylprednisolone (or equivalent) up to 
0.5mg/kg Q 6h) to prevent recurrent or ongoing reactions 
• 
Report as a serious adverse event (see Section 9.1.1.2)  
• 
Remove patient from study. 
5.8.7. 
Monitoring and Management of Infusion-Associated Headaches 
Infusion-associated headaches have been shown to be common in patients receiving IMGN853 
under Schedule B. Patients should be advised of the risk of headache and should inform their 
treating physician if they develop an infusion-associated headache, to allow for appropriate 
evaluation and treatment.  All patients dosed according to Schedule B should receive 325-650 
mg of acetaminophen (PO or IV) approximately 30 minutes prior to each infusion of IMGN853. 
5.8.8. 
Monitoring and Management of Treatment-emergent Eye Disorders 
5.8.8.1. 
Monitoring - Potential Ocular Disorders 
Changes in visual acuity, resulting from reversible keratopathy have been reported in other 
studies of DM4-containing immunoconjugates that use the SPDB linker (Younes  2012).  Due to 
the observation of ocular disorders in patients treated with IMGN853 at the 5.0 and 7.0 mg/kg 
dose levels, (Section 1.9) ocular function is being carefully monitored.  Complete 
ophthalmologic exams and ocular symptom assessments will be performed in all patients at 
baseline and post-treatment as described in the following schedule: 
 
Table 7: 
Schedule for Ophthalmologic Assessments 
Assessment 
Screening 
Day 1 
(All Cycles) 
Prior to Day 1 
Dose 
(Every other 
Cycle)4 
End of 
Treatmen
t 
28-Day 
Follow Up 
Ophthalmologic history – patients will be 
asked about ocular symptoms such as history 
of dry eye, and contact lens use 
X 
 
 
 
 


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Assessment 
Screening 
Day 1 
(All Cycles) 
Prior to Day 1 
Dose 
(Every other 
Cycle)4 
End of 
Treatmen
t 
28-Day 
Follow Up 
Complete Exam1: 
- 
Visual acuity (with/without 
corrective lenses; whichever best 
reflects the patient’s usual 
functioning) 
- 
Slit lamp examination 
- 
Intraocular pressure measurement 
- 
Indirect fundoscopy 
- 
 
X2 
 
Patients who report 
treatment- emergent 
ocular AEs 
X  
X  
Schirmer’s test4 
X 
 
 
 
 
Ocular symptom assessment (blurred vision, 
ocular discomfort, etc.) 
X 
X 
 
X 
X 
Prescribe 1% prednisolone (Cohort 5 Patients 
Only)5 
X 
 
 
 
 
1 Performed by a board-certified ophthalmologist 
2 Within 14 days prior to Cycle 1, Day 1 
3 Within 2 weeks prior to Day 1 Dose of every other cycle, required for patients who have experienced signs or 
symptoms of ocular toxicity and for those with blurred vision but normal eye exams. 
4 For patients experiencing ocular symptoms, the Schirmer’s test (with and without topical anaesthetic) will be 
repeated at the first ophthalmology exam and in subsequent ophthalmologic exams if clinically indicated. 
5 Patients enrolled to Expansion Cohort 5 will receive primary prophylaxis with 1% prednisolone six times daily on 
Days 1-5 of each treatment cycle, followed by four times daily on Days 6-10 of each treatment cycle. 
 
If a subject develops ocular symptoms of any grade, the subject will be referred to an ophthalmologist 
for a complete examination. If a subject develops ≥ Grade 2 ocular symptoms, treatment with IMGN853 
will be interrupted. In patients with clinical benefit, therapy may resume if ocular symptoms  improve to 
Grade 1 or baseline within 21 days of the next scheduled IMGN853 dose. Subsequent examinations will 
be scheduled to occur in every other cycle going forward, from the time that the AE was initially 
reported, and at either the end of study or 28-day follow up visit.  In the event of therapy being held for 
more than 14 days due to ocular symptoms, a subject showing clinical benefit prior to the onset of an 
ocular treatment-emergent adverse event may be allowed to resume therapy at a reduced dose after 
approval from the Sponsor. 
5.8.8.2. 
Management Guidelines for Eye Disorders 
Patients should also be firmly advised to avoid using contact lenses while on study.  Baby 
shampoo and a soft cloth should be used to clean the eyes, and a warm compress at bedtime may 
be used to decrease any possible inflammation on the eyelid’s surface.  The use of UVA/UVB 
sunglasses is recommended for use outside in full daylight during the course of the study.  If 
patients report signs or symptoms of ocular disorders, including, but not limited to, blurred 


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vision or eye irritation, the management and dose modification guidelines outlined in Table 8 
should be followed.  
Patients who have experienced study drug-related blurred vision symptoms, including those with 
including those with no obvious clinical findings on examination, will have a complete 
ophthalmic examination performed prior to the start of every other cycle and at the end of study 
or follow up visit following study discontinuation.  Management of treatment emergent eye 
disorders with inflammatory characteristics should include corticosteroid eye drops and/or other 
measures as indicated by an ophthalmologist. 
Table 8: 
Management of Ocular Disorders 
Severity Grade 
(CTCAE v4.03 
Grade) 
Management 
Guidelines for IMGN853 Dose 
Modifications 
Grade 1 
• 
Complete eye exam as outlined in Table 7. 
• 
Monitor for worsening symptoms 
• Continue IMGN853 dosing 
Grade 2 
• 
Complete eye exam as outlined in Table 7. 
Repeat complete exam as clinically indicated.  
• 
Patients should have weekly symptomatic 
ocular assessments until the symptoms 
resolve to grade 1 or baseline (Section 5.9.1) 
or are deemed to be irreversible by the 
investigator 
• Hold IMGN853 dosing.  
• Patients may be allowed to 
resume therapy at the same 
dose level unless there is a 
dosing delay > 14 days, in 
which case they should 
resume treatment at a reduced 
dose level (see Table 11)  
Grade 3 
• 
Complete eye exam as outlined in Table 7. 
Repeat complete exam as clinically indicated. 
• 
Patients should have weekly symptomatic 
ocular assessments until the symptoms 
resolve to grade 1 or baseline (Section 5.9.1) 
or are deemed to be irreversible by the 
investigator. 
• Hold IMGN853 dosing.  
• Patients may be allowed to 
resume therapy at a lower 
dose than the one they were 
receiving when their 
symptoms began (see Table 
11). 
Grade 4 
• 
Complete eye exam as outlined in Table 7. 
Repeat complete exam as clinically indicated. 
• 
Patients should have weekly symptomatic 
ocular assessments until the symptoms 
resolve to grade 1 or baseline (Section 5.9.1) 
or are deemed to be irreversible by the 
investigator. 
• Permanently discontinue 
IMGN853 dosing. 
 
5.8.9. 
Management of Non-Infectious Pneumonitis 
Non-infectious pneumonitis has been observed following the administration of IMGN853 and 
may result in fatigue, shortness of breath, cough or respiratory distress.  Drug-induced 
pneumonitis may be immediately life-threatening.  If a patient presents with signs or symptoms 
consistent with pneumonitis and/or a clinically meaningful change in pulse oximetry value, the 


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patient should be immediately evaluated according to institutional guidelines/practice.  Patients 
are advised to notify their treating physician immediately if they experience new or worsening 
shortness of breath, cough or respiratory distress. 
For patients diagnosed with pneumonitis without an infectious etiology, the management and 
IMGN853 treatment guidelines outlined in Table 9 should be followed. 
Table 9: 
Management of Non-Infectious Pneumonitis 
Severity Grade 
(CTCAE v4.03 
Grade) 
Medical Management of Pneumonitis 
Guidelines for Dose Modifications 
Grade 1 
• 
Radiologic assessments (CT scan 
and/or chest x-ray) should be 
performed as clinically indicated.  
• Monitor for pulmonary symptoms 
• Continue dosing after 
discussion with the Sponsor.  
Grade 2 
• 
Radiologic assessments (CT scan 
and/or chest x-ray) should be 
performed as clinically indicated. 
• 
Patient must be evaluated by a 
pulmonary specialist.  
• Treatment with corticosteroids may be 
indicated as recommended by a 
pulmonary specialist and/or 
institutional guidelines. 
• 
Hold dosing until symptoms 
improve.  
• IMGN853 may be resumed at 
same dose level after discussion 
with the Sponsor. 
Grade 3 
• 
Radiologic assessments (CT scan 
and/or chest x-ray) should be 
performed as clinically indicated.  
• 
Patient must be evaluated by a 
pulmonary specialist.  
• 
Treatment with corticosteroids until 
resolution of symptoms may be 
indicated as recommended by a 
pulmonary specialist and/or 
institutional guidelines.   
• 
Bronchoscopy with lavage and/or 
biopsy when clinically feasible should 
be performed.   
• The pneumonitis event must be 
followed until resolution  
• 
Hold IMGN853 dosing until 
symptoms resolve 
• 
IMGN853 may be resumed at a 
lower dose level after discussion 
with the Sponsor. 
 


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Severity Grade 
(CTCAE v4.03 
Grade) 
Medical Management of Pneumonitis 
Guidelines for Dose Modifications 
Grade 4 
• 
Radiologic assessments (CT scan 
and/or chest x-ray) should be 
performed as clinically indicated.  
• 
Patient must be evaluated by a 
pulmonary specialist.  
• 
Treatment with corticosteroids until 
resolution of symptoms may be 
indicated as recommended by a 
pulmonary specialist and/or 
institutional guidelines.   
• 
Bronchoscopy with lavage and/or 
biopsy when clinically feasible should 
be performed.   
• The pneumonitis event must be 
followed until resolution 
• 
Permanently discontinue 
IMGN853 dosing. 
  
5.8.10. 
Monitoring and Management of Diarrhea 
Mild to moderate diarrhea has been commonly reported in patients treated with IMGN853 
(refer to IMGN853 Investigator’s Brochure).  Patients should be advised to contact their 
treating physician at the first sign of diarrhea.  Patients may then be treated according to 
standard institutional practice.  One suggested regimen would be the administration of 2 mg 
loperamide at the first sign of loose stool, with repeat dosing every 2 hours until symptoms 
resolve (Wadler 1998). 
5.8.11. 
Monitoring and Management of Nausea and Vomiting 
Nausea and vomiting have been reported in patients treated with IMGN853 in both dosing 
schedules.  Patients should be advised to contact their treating physician at the first sign of 
vomiting or worsening nausea.  Patients should be treated according to the ASCO Clinical 
Practice Guidelines for the use of antiemetics (Basch 2011) outlined in Table 10. 
 


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Table 10: 
Management of Nausea and Vomiting 
Severity Grade 
(CTCAE v4.03 Grade) 
Management 
Grade 1 
• 
No premedication required as patients are already receiving 8 
mg dexamethasone as part of their premedication for 
prevention of infusion reaction. 
Grade 2 
• 
Administer a 5- HT3 receptor antagonist on day 1 (e.g. 
palonosetron, granisetron, or ondansetron) in combination 
with dexamethasone on days 1-3 or treat as per institutional 
guidelines.  Aprepitant may be added to the combination. 
Grades 3 and 4 
• 
Administer a neurokinin 1 receptor antagonist (e.g. aprepitant 
on days 1-3 or fosaprepitant on day 1), in combination with a 
5- HT3 receptor antagonist on day 1 only, and dexamethasone 
on days 1-3 or 1-4 or treat as per institutional guidelines. 
5.9. 
Treatment Guidelines 
5.9.1. 
Re-treatment Criteria 
5.9.1.1. 
To Begin a New Cycle of Treatment 
In the absence of otherwise dose-limiting toxicity, for a patient to begin a new cycle of therapy, 
the following criteria must be met. 
• ANC must be ≥ 1.5x109/L (1,500/µL) 
• Platelet count must be ≥ 75 x 109/L (75,000/µL) 
• All non-hematologic toxicities for which a causal association to study treatment 
cannot be ruled out, must be ≤ Grade 2 (except alopecia) or returned to baseline; the 
exception to this rule is treatment-emergent ocular symptoms, which must have 
recovered to < Grade 1 or baseline 
If the patient does not meet these criteria, dosing will be delayed and the patient should be re-
evaluated within 48-72 hours.  Dosing may resume if these criteria have been met.  However, if 
the next cycle is delayed by greater than 14 days because of insufficient recovery from a 
treatment-related toxicity, this will be viewed as a dose-limiting event (Section 4.1.4).  For 
patients treated on either dosing schedule, if the next cycle is delayed due to treatment-related 
toxicity by greater than 21 days then the patient should be removed from study treatment.  In 
such cases, continuation of study treatment may be considered for those patients who have 
experienced clinical benefit if agreed upon between the Sponsor and the Investigator. 
The use of granulocyte growth factors in accordance with ASCO guidelines may be implemented 
at the discretion of the treating physician after Cycle 1. 


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5.9.1.2. 
To Continue Treatment within a Cycle- Schedule B (modified weekly) 
Amendment 10 Update: Following completion of the Schedule B Dose Escalation portion of the 
study, the CRC reviewed safety, PK and efficacy data from both dosing schedules and based this 
review, made the decision to discontinue further investigation of Schedule B dosing. While 
patients currently receiving IMGN853 study treatment according to Schedule B will continue to 
do so, new patients enrolled to the study will receive treatment according to Schedule A only. 
In the absence of otherwise dose-limiting toxicity, for a patient to continue treatment within a 
cycle, the following criteria must be met. 
• ANC must be ≥ 1.0x109/L (1,000/µL) 
• Platelet count must be ≥ 75 x 109/L (75,000/µL) 
• All non-hematologic toxicities for which a causal association to study treatment 
cannot be ruled out, must be ≤ Grade 2 (except alopecia) or returned to baseline; the 
exception to this rule is treatment-emergent eye disorders, which must have recovered 
to < Grade 1 or baseline 
• A minimum of 7 days (~168 hours) must have elapsed between IMGN853 doses 
If the patient does not meet these criteria, dosing will be delayed and the patient should be re-
evaluated within 72 hours.  Dosing may resume if these criteria have been met.  If the criteria are 
not met due to insufficient recovery from a treatment-related toxicity, then that week’s dose will 
be considered “missed”.   
The use of granulocyte growth factors in accordance with ASCO guidelines may be implemented 
at the discretion of the treating physician after Cycle 1. 
5.9.2. 
Follow-up for DLTs and AEs Leading to Discontinuation 
Patients who experience a non-laboratory DLT must be evaluated weekly, at a minimum, until 
resolution to ≤ Grade 1 or baseline and then at least monthly until return to baseline or 
stabilization of the event, whichever comes first.  For abnormal laboratory values that qualify as 
a DLT, patients will be followed twice weekly until values return to < Grade 1 or baseline, 
whichever comes first.  
Patients who discontinue the study for AE or an abnormal laboratory value must be followed at 
least once a week for 4 weeks, and subsequently at 4-week intervals until resolution or 
stabilization of the adverse event or laboratory abnormality, whichever occurs first.   
5.9.3. 
Criteria for Re-Initiation of Study Treatment Following Occurrence of a DLT  
Study treatment will be stopped if a patient experiences a DLT at any time during the study.  It 
may resume, with applicable dose adjustments (Section 5.9.4.1) if the following criteria are met: 
• ANC must be ≥ 1.5 x109/L (1500 /µL) 
• Platelet count must be ≥ 75 x 109/L (75,000/µL) 
• All clinically-significant non-hematologic toxicities for which a causal association to 
study treatment cannot be ruled out must be ≤  Grade 1 (except alopecia) or returned 
to baseline 


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If the patient does not meet these criteria, dosing will be delayed and the patient should be re-
evaluated within 48-72 hours.  Dosing may resume if these criteria have been met.  However, if 
the next cycle is delayed by greater than 14 days because of insufficient recovery from a 
treatment-related toxicity, this may be viewed as a dose-limiting event (Section 4.1.4).  For 
patients treated on either schedule, if the next cycle is delayed due to treatment-related toxicity 
by greater than 21 days then the patient should be removed from study treatment.  In such cases, 
continuation of study treatment may be considered for those patients who have experienced 
clinical benefit if agreed upon between the Sponsor and the Investigator. 
5.9.4. 
Dose Modification Guidelines 
5.9.4.1. 
Dose Reduction Following DLT 
Patients who develop DLTs or adverse events requiring holding of the study drug may resume 
treatment at a reduced dose level as shown in Table 11 provided the criteria outlined in 
Section 5.9.4.2 are met.  
Table 11: 
Dose Modification Guidelines 
Dosing Schedule 
If the patient was receiving IMGN853 at: 
Dose should be reduced to: 
Schedule A 
6.0 mg/kg 
5.0 mg/kg 
5.0 mg/kg 
4.0 mg/kg 
Schedule B* 
2.0 mg/kg 
1.8 mg/kg 
1.8 mg/kg 
1.1 mg/kg 
*IMGN853 should be dose-reduced one dose level; a second dose reduction may be allowed as needed.  Dose 
reductions to intermediate dose levels may be allowed based on emerging data with the approval of the Sponsor. 
Amendment 10 Update: Schedule B will not be evaluated further in the current study. 
5.9.4.2. 
Criteria for Re-initiation of Study Treatment Following Occurrence of a DLT 
The AE reverts to baseline or ≤ Grade 1 within 14 days of the next scheduled Day 1 dose; the 
patient is clearly deriving clinical benefit, and the patient has an otherwise favorable risk/benefit 
profile. 
Once a dose level reduction has occurred, patients must remain at this reduced dose.  
5.9.5. 
Discontinuation of Study Treatment Due to Toxicity 
Study treatment should not be resumed in the case of the following treatment-related events. 
• ≥ Grade 3 cardiac event 
• other non-hematologic events of Grade 4 severity 
• Failure to meet re-treatment criteria within 21 days due to insufficient recovery from 
a treatment-related toxicity.  In such cases, continuation of study treatment may be 
considered for those patients who have experienced clinical benefit if agreed upon 
between the Sponsor and the Investigator. 


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5.10. 
Removal of the Patients from the Trial or Study Drug 
The patient or legal guardian acting on behalf of the patient is free to withdraw consent and 
discontinue participation in the study at any time without prejudice to further treatment.  For this 
protocol, patients withdrawn for reasons other than toxicity during Cycle 1 may be replaced. 
Patients will be removed from the study when their disease worsens, and show no clinical 
benefit.  Additionally, a patient’s participation in the study may be discontinued at any time at 
the discretion of the Investigator.  The following may be justifiable reasons for the Investigator 
to remove a patient from the study: 
• The patient suffers an intolerable adverse event 
• Non-compliance, including failure to appear at one or more study visits 
• The patient was erroneously included in the study 
• The study is terminated by the Sponsor 
If a patient or the patient’s legal guardian(s), acting on behalf of the patient, discontinues 
participation in the study, or the patient is discontinued by the Investigator, the reason for 
discontinuation must be captured in the eCRF.  Any AEs experienced up to the point of 
discontinuation must be documented on the AE eCRF.  All SAEs, and those AEs assessed by the 
Investigator as at least possibly related to study drug should continue to be followed until they 
resolve or stabilize, whichever comes first. 
5.10.1. 
Replacement of Patients who are Withdrawn Prior to the End of Cycle 1 
Only patients who sign the informed consent and receive any study treatment will be considered 
enrolled.  If an enrolled patient is discontinued from study treatment for reasons other than safety 
(e.g., withdrawal of consent, non-compliance, death due to disease progression) prior to the end 
of Cycle 1, he or she will be replaced (i.e., an additional patient will be added to the cohort).  
Patients who do not complete Cycle 1 due to an AE will not be replaced.  Patients who are 
replaced will not be considered in making dose-escalation decisions, but if possible, will be 
followed for safety and other assessments according to the protocol. 
5.11. 
Period of Observation 
For purposes of this study, the period of safety observation extends from the time of first dosing 
until the final evaluation during the study, including the 28-day follow-up safety visit.  Short-
term follow-up for patients who discontinue study therapy without documented progressive 
disease will continue every three months until the patient’s disease worsens, until the patient 
begins subsequent anti-cancer treatment, or until the patient dies, whichever comes first. 
5.12. 
Concomitant Medications and Procedures 
All concomitant medications and supportive therapy taken within 4 weeks of Cycle 1, Day 1 and 
through 28 days after last study treatment must be recorded on the appropriate electronic case 
report form (eCRF).  The identity of all medications, dosage, and route of administration, 
frequency, duration of administration, and indication for use will be recorded in the appropriate 
sections of the eCRF. 


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5.12.1. 
Lubricating Artificial Tears 
Patients will be required to use preservative-free, lubricating artificial tears on a daily basis, as 
directed by the product label or the treating physician (Section 5.8.3).    
5.12.2. 
Corticosteroid Eye Drops 
All patients enrolled in Cohort 5 will be required to self-administer corticosteroid eye drops (1% 
prednisolone; Pred Forte® or generic equivalent) during active study treatment (Section 5.8.2). 
Patients will record their eye drop administration in a patient diary, which will be entered on the 
CRF. 
5.12.3. 
Antiemetic and antidiarrheal medications 
Antiemetic (e.g. 5-HT3 serotonin receptor antagonists such as palonosetron, granisetron or 
ondansetron) and antidiarrheal (e.g. loperamide) medications may be used at the discretion of the 
treating physician, but they are not to be used prophylactically. 
5.12.4. 
Acetaminophen  
All patients dosed according to Schedule B should receive 325-650 mg of acetaminophen (PO or 
IV) approximately 30 minutes prior to each infusion of IMGN853. 
5.12.5. 
Folate-Containing Vitamins 
Folate-containing vitamins are not to be taken during the course of the study. 
5.12.6. 
Antineoplastic Therapy 
Other chemotherapy, investigational agents, or biologic therapy will not be permitted during the 
study. 
Palliative radiotherapy for local peripheral metastases not being used as target lesions is allowed.  
However, the need for such therapy may be an indication of disease progression and should be 
discussed with the Sponsor prior to implementation.  Radiotherapy for central metastases (e.g. 
vertebral, meditational) will not be allowed; the need for such radiotherapy while on study will 
be seen as an indication of disease progression and the patient should be withdrawn from 
therapy. 
5.12.7. 
Hematopoietic Growth Factors 
Patients receiving recombinant erythropoietin or darbepoietin-α prior to study start may continue 
to receive pre-treatment doses.  
The use of erythropoietic and granulocyte growth factors in accordance with ASCO guidelines 
may be implemented at the discretion of the treating physician after Cycle 1. 
5.12.8. 
Anticoagulants 
The use of low dose anticoagulants for maintenance of line patency is allowed.  Thrombosis 
prophylaxis is allowed. 


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5.12.9. 
Other Concomitant Medications 
Medications for the treatment of adverse events or cancer symptoms (e.g. packed red blood cells 
and pain medications), are allowed.  Prophylactic use of steroids and/or antihistamines will be 
considered if needed to alleviate mild-moderate infusion reactions.  Additionally medications 
(not addressed above) used to treat underlying medical conditions at study entry including anti-
emetics and anti-diarrheals will be allowed to continue.  
5.13. 
Overdose and Medication Error 
Overdose – There is no known treatment/antidote available for IMGN853.  Supportive measures 
should be instituted if an instance arises in which a patient suffers an overdose of study drug. 
Medication Error – The Sponsor must be immediately notified in the event of error in 
prescribing, dispensing, administering and/or use of IMGN853, and the event must be reported 
on the eCRF. 


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6. 
PHARMACOKINETIC (PK ASSESSMENTS) 
6.1. 
Overview 
Serial analyses of patient plasma will be performed to define the PK properties of IMGN853 
when administered intravenously once every 3 weeks.  Plasma will be analyzed for levels of 
IMGN853, free DM4, and total M9346A antibody to assess IMGN853 stability. 
6.2. 
PK Schedule 
6.2.1. 
Schedule A 
Blood samples for PK measurements will be taken in Cycles 1 and 3, at the following time 
points: 
Day 1 – predose, and following completion of infusion at the following timepoints: 0-10 
minutes, and 2, and 4 hours (±10 minutes) 
Day 2 – 24 hours after completion of infusion (±2 hours) 
Day 3 – 48 hours after completion of infusion (±2 hours) 
Day 4 or 5, Day 8 and Day 15 – a single blood sample will be drawn for PK (±24 hours) 
Additionally, a single pre-dose sample will be collected before the IMGN853 infusion and 
following completion of the infusion in Cycles 2, 4, 5 and 6.  A single blood sample for analysis 
of HAHA and HADA will be taken on Day 1 of Cycles 2, 4, and 5 and at the End of Treatment 
and Follow-up visits.  
The sample for HAHA and HADA analysis will be taken from the PK tube; no additional blood 
draw is necessary.   
6.2.2. 
Schedule B 
Blood samples for PK measurements will be taken in at the following time points: 
Cycle 1 & 3: 
Day 1 – predose, and following completion of infusion at the following timepoints: 0-10 
minutes, and 2 and 4 hours (±10 minutes) 
Day 2 – 24 hours after completion of infusion (±2 hours) 
Day 8 – predose and within 10 minutes of completion of the infusion 
Day 15 – predose, and following completion of infusion at the following timepoints: 0-10 
minutes, and 2 and 4 hours (±10 minutes) 
Day 16 – 24 hours after completion of infusion (±2 hours) 
Day 22 – a single blood sample will be drawn for PK (±24 hours) 
 
Additionally, a single pre-dose sample will be collected before the IMGN853 infusion and 
following completion of the infusion in Cycles 2, 4, 5 and 6.  A single blood sample for analysis 


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of HAHA and HADA will be taken on Day 1 of Cycles 2, 4, and 5 and at the End of Treatment 
and Follow-up visits.  
The sample for HAHA and HADA analysis will be taken from the PK tube; no additional blood 
draw is necessary.   
Details of sample preparation and shipping are provided in the Laboratory Manual. 
6.2.3. 
Additional PK Samples  
Any patient who experiences a Grade 2 or greater infusion reaction during the administration of 
IMGN853 will have blood drawn within 3 hours of the onset of the reaction and one week later 
for determination of drug concentration, antibodies to IMGN853 and factors that may be related 
to hypersensitivity reactions (see Section 5.8.6). 
PK samples may also be obtained as feasible any time during the treatment period for assessment 
of study drug related SAEs if deemed appropriate by the Investigator and Sponsor. 
6.3. 
Immunogenicity Assessments 
To assess for potential immunogenicity against IMGN853 or DM4, plasma samples taken for PK 
assessment in cycles 1 through 6 will be taken as outlined in Sections 6.2.1 and 6.2.2, using the 
same tube that is used for the PK assessment.  The study will evaluate the potential impact of 
immunogenicity on PK, Pd, safety, and efficacy of IMGN853 and total M9346A antibody.  
Specifically, clinical characteristics such as PK, safety and efficacy of immune positive patients 
will be compared to the immune negative population.  


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7. 
TRANSLATIONAL RESEARCH STUDIES 
Translational research studies will be performed to generate data that will demonstrate proof-of-
mechanism and characterize pharmacodynamics and anti-tumor effects of IMGN853.  In 
addition, several biomarkers, including FOLR1, will be evaluated as potential biomarkers of 
clinical response to IMGN853.  These will help guide further clinical development of IMGN853. 
7.1. 
Correlation between FOLR1 Expression and IMGN853 anti-tumor 
activity 
FOLR1 expression varies with tumor histology, as reported in the literature and demonstrated in 
our pre-clinical studies (Sections 1.1 and Investigators’ Brochure).  Based on the hypothesis that 
tumors expressing higher levels of FOLR1 are more likely to be susceptible to anti-tumor 
activity of IMGN853, a threshold for FOLR1 expression was determined for each tumor 
histology studied in the expansion cohorts.  This was done based on molecular epidemiology 
data generated in a number of patient samples representative of different tumor types, as well as 
pre-clinical efficacy data. 
7.1.1. 
Evaluation of FOLR1 Expression in Tumor Tissue During Dose-Escalation and 
Dose Expansion 
FOLR1 expression in tumors will be analyzed via IHC.  All patients must submit archived tumor 
tissue, formalin-fixed, paraffin embedded (FFPE) slides for analysis of FOLR1 expression by 
IHC.  For dose escalation, patients with tumors known to have high incidence of FOLR1 
expression (serous and endometrioid ovarian cancer, serous and endometrioid endometrial 
cancer and NSCLC adenocarcinoma or BAC) may submit archived tumor tissue for retrospective 
analysis after enrollment.  All other patients must submit archived tumor tissue for 
documentation of FOLR1 positivity by IHC prior to enrollment.  Any level of FOLR1 expression 
(i.e., ≥1% of tumor staining at ≥1+ intensity) is acceptable for enrollment in the dose escalation 
portion of the study.  If a patient does not have archival material available for analysis, the 
patient may alternatively undergo a biopsy to assess FOLR1 expression.  The decision to biopsy 
will be made once patient eligibility has been determined and on the basis of tumor accessibility 
and patient safety. 
Only patients with the required FOLR1 expression levels by IHC will be eligible to enroll in the 
dose expansion cohorts.  If a patient wishes to enroll and does not have archival material 
available for analysis, he or she must undergo a biopsy to assess FOLR1 expression.  In the 
ovarian cancer cohorts (Cohort #s 1 and 3) eligible patients must meet the minimum requirement 
of FOLR1 positivity by IHC (≥25% of tumor staining at ≥2+ intensity), and in the uterine cancer 
and NSCLC cohorts, patients will be required to have an H score ≥ 100 for FOLR1 expression  
in order to be eligible to enroll.   
The tumor samples will be analyzed for folate receptor alpha (FOLR1) expression in the Companion 
Diagnostics Pharma Services CAP-accredited and CLIA-certified laboratory and Pathology Services at 
Ventana Medical Systems, Inc. 
 


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IHC data will be used to define any potential associations between FOLR1 expression and 
clinical response. 
7.2. 
Exploratory Biomarker Studies 
Studies in tumor tissue and blood will be performed to explore potential markers of IMGN853 
sensitivity and resistance.  The sections below describe specific activities that are planned, but 
other additional biomarkers/biological pathways may be investigated based on emerging data. 
7.2.1. 
Potential Markers of Drug Sensitivity 
As IMGN853 targets proliferating cells, Ki67 IHC staining will be assessed as a marker of cell 
proliferation on fresh biopsy samples from patients in Expansion Cohort 3.  Potential 
associations between Ki67 levels and clinical response will be examined. 
IMGN853 retains the ADCC activity of the parental M9346A antibody.  FcγR is the principle 
leukocyte receptor that mediates ADCC and FcγR polymorphisms modulate leukocyte ADCC 
activity.  Therefore, all patients will be genotyped for FcγR alleles via PBMC analysis at 
screening.  Potential associations between FcγR genotype and clinical response will be 
examined. 
7.2.2. 
Potential Markers of Drug Resistance 
Drug efflux transporters and p-glycoprotein (PgP) in particular play an important role in cancer 
cell resistance to cytotoxic agents, including microtubule-targeting agents.  Therefore, PgP IHC 
staining will be assessed as a marker of drug resistance in archived tumor tissues for all patients 
and on fresh biopsy samples obtained from patients in the Expansion Cohorts.  Potential 
associations between PgP levels and clinical response will be examined. 
7.2.3. 
Folate Pathway Markers 
Preclinical studies suggest that FOLR1 is upregulated in folate deficiency and downregulated 
following folate repletion (Zhu 2001, Sadasivan 2002).  Because folate deficiency can enhance 
FOLR1 expression via a homocysteine-dependent upregulation of FOLR1 mRNA translation 
(Antony 2004), plasma total homocysteine levels will be assessed in all patients at baseline, 
during Cycle 2 and at the end of treatment visit.  Increased homocysteine levels correlate with 
low serum and RBC folate levels and suggest folate deficiency.  Vitamin B12 deficiency 
similarly elevates homocysteine levels and also elevates plasma methylmalonate (MMA) levels.  
Plasma MMA will therefore be analyzed in parallel with plasma total homocysteine to 
differentiate folate and B12 status.  Potential associations between plasma total 
homocysteine/MMA, FOLR1 expression, and clinical response will be examined. 
7.3. 
Pharmacodynamic (Pd) and Proof of Mechanism (POM) Analyses 
7.3.1. 
Pd and PoM studies in Tumor Biopsies (EOC Expansion Cohort #3 Only) 
For this, patients with biopsy-accessible tumors will undergo core tumor biopsy at baseline and 
at Cycle 2, Day 8±3 days.  The patient must sign consent to undergo the biopsy procedure.  The 
decision to biopsy will be made once patient eligibility has been determined and on the basis of 
tumor accessibility and patient safety.  


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Biomarkers to characterize mechanisms involved in the anti-tumor activity of IMGN853 will be 
evaluated.  
Binding of IMGN853 to FOLR1 on the surface of tumor cells results in internalization of the 
folate receptor.  Changes in FOLR1 expression levels will be examined via pre- and post-dose 
tumor biopsy samples.  The presence of IMGN853 will also be detected in tumor cells using IHC 
methods directed at the maytansinoid payload of IMGN853 (using an anti-maytansinoid 
antibody).  Changes in Ki67 and other markers describing anti-proliferative and/or apoptotic 
effect of IMGN853 may also be investigated.   


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8. 
STUDY PROCEDURES 
8.1. 
Informed Consent 
Each patient or legally authorized representative must provide written informed consent before 
any study-required procedures are conducted, unless those procedures are performed as part of 
the patient’s standard care.   
8.2. 
Inclusion and Exclusion Criteria 
The inclusion and exclusion criteria will be assessed during screening (within 28 days prior to 
the first dose of any study drug on Cycle 1, Day 1).  A patient is considered enrolled when 
administered the first dose of any study drug. 
Procedures for completion of enrollment information, and requirements to communicate with the 
Sponsor about enrollment, are detailed in the Study Manual. 
8.3. 
Confirmation of Disease Diagnosis 
At screening, disease diagnosis, and current disease status will be confirmed from information in 
the source record. 
8.4. 
Demographic/Medical History 
The age, race, and gender of the patient are to be recorded during screening. 
During the Screening period, a complete medical history will be compiled for each patient.  The 
history will include the background and progress of the patient’s primary malignancy and 
include a description of all prior therapies for the primary malignancy. 
8.5. 
Physical Examination, Weight and Height 
Physical examination, height (screening only) and weight must be performed as indicated in the 
Schedule of Clinical Assessments (Appendix A and Appendix B).  A complete physical 
examination - including assessments of general appearance, skin, head (eyes, ears, nose, and 
throat), neck, lungs, heart, abdomen, back, lymph nodes, extremities, and neurological system - 
will be completed at screening and end of treatment.  Directed physical examinations will be 
completed at additional time points as specified in the Schedule of Events and Section 10. 
Weight will be measured at screening and at other times specified in the Schedule of Clinical 
Assessments (Appendix A and Appendix B). 
 
 


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8.6. 
Vital Signs 
Vital signs will be measured as outlined below and in Appendix A and Appendix B: 
Table 12: 
Vital Sign Measurements 
 
Screening 
Day 1 of all 
Cycles 
(Predose)a 
Every 30 
Minutes 
During 
IMGN853 
Infusionb,d 
Following 
Completion 
of IMGN853 
Infusionc 
4-hours Post 
End of 
Infusiond 
At Same 
Time as 
ECG 
Assessments
e 
End of 
Study and 
FUP Visits 
Blood 
Pressure 
● 
● 
● 
● 
● 
● 
● 
Pulse 
● 
● 
● 
● 
● 
● 
● 
Respiratory 
Rate 
● 
● 
● 
● 
● 
● 
● 
Temperature 
● 
● 
● 
● 
● 
 
● 
a Within 10 minutes prior to start of infusion 
b ± 10 minutes 
c Within 10 minutes following completion of infusion 
d Cycles 1 and 2 only.  If the patient's infusion was well-tolerated, the 4-hour post infusion assessment will not be 
required in Cycles ≥3. 
e Measured predose and within 10 minutes of completion of each set of triplicate ECG readings (predose, end of 
infusion to coincide with Cmax PK draw (+10 minute window) and 24 hrs post infusion (±2 hours) – See also 
Section 8.7. 
8.7. 
Electrocardiogram (ECG) 
A standard, single 12-lead electrocardiogram (ECG) will be performed within 14 days prior to 
first dose to determine study eligibility.  
On study ECGs will be performed in triplicate at the following timepoints in Cycles 1 and 3: 
• Baseline ECG: Within one hour prior to the first dose 
• Post Dose ECGs:  
o End-of-infusion to coincide with Cmax and PK blood draw (within one hour from 
this blood draw ) 
o  24 ± 2 hours post infusion to coincide with PK blood draw 
Triplicate ECGs will be performed at 2-5 minute intervals.  A single ECG will also be performed 
at the end of treatment visit and as clinically indicated (Appendix A and Appendix B). 
Vital signs (blood pressure, pulse, and respiratory rate) will be measured within 10 minutes of 
completion of each set of triplicate ECG readings. 


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8.8. 
Pulse Oximetry 
Pulse oximetry will be performed prior to dosing on Day 1 of every cycle and as indicated in 
Section 10 (Study Activities) and Appendix A and Appendix B (Schedule of Clinical 
Assessments for Schedules A and B, respectively). 
8.9. 
Pulmonary Function Tests 
Pulmonary function tests (PFTs) should include spirometry, diffusion capacity, and lung volume 
tests. PFTs will be performed within two weeks prior to Cycle 1 Day1 and in the event of 
pulmonary symptoms as clinically indicated (Appendix A).  
8.10. 
Laboratory Assessments 
Patients should be in a seated or supine position during blood collection.  Screening labs 
(hematology, clinical chemistry, and urinalysis) may be performed within 14 days of first dose.  
Repeat testing on Cycle 1, Day 1 is not required if tests were obtained within 4 days of dosing 
and are within acceptable ranges.  Repeat testing will be performed as outlined in the Schedule 
of Clinical Assessments (Appendix A and Appendix B) and as clinically indicated.   
Note that prior to each administration of IMGN853, laboratory results must be reviewed to 
evaluate for potential toxicity.   
8.10.1. 
Clinical Laboratory Panels 
Table 13: 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Coagulation 
Tests 
Urinalysis 
Other 
• 
Hematocrit 
• 
Hemoglobin 
• 
WBC       
(w/5-part 
differential) 
• 
RBC 
• 
Platelet count 
• 
Albumin 
• 
Alkaline 
phosphatase 
• 
ALT 
• 
AST 
• 
BUN 
• 
Calcium 
• 
Carbon dioxide 
• 
Chloride 
• 
Creatinine 
• 
Glucose 
• 
LDH 
• 
Magnesium 
• 
Phosphorus 
• 
Potassium  
• 
Sodium 
• 
Total bilirubin 
• 
PT 
• 
aPTT 
• 
INR 
• 
pH 
• 
Ketones 
• 
Protein 
• 
Glucose 
• 
Occult blood 
• 
Leukocyte 
    esterase 
• 
Nitrite 
(microscopic 
examination of 
sediment will be 
performed only if 
results of urinalysis 
dipstick are positive) 
β-hcG 
homocysteine 
methylmalonate 
 
WBC, white blood cell count; RBC, red blood cell count; ALT, alanine aminotransferase; AST, aspartate 
aminotransferase; BUN, blood urea nitrogen; LDH, lactic acid dehydrogenase; GFR, glomerular filtration rate; INR, 
International Normalized Ratio; PT, Prothrombin time; aPTT, Activated partial thromboplastin time 


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8.11. 
Pregnancy Screen 
All female patients of child-bearing potential will complete a serum beta-human chorionic 
gonadotropin (β-hCG) or urine pregnancy test (not more than 3 days before the first dose of 
IMGN853); this test must be negative for the patient to be enrolled and to receive the study drug. 
If a female patient becomes pregnant or suspects pregnancy while participating in this study, the 
Investigator and Sponsor must be informed immediately and the patient will be withdrawn from 
study treatment. 
8.12. 
Eastern Cooperative Oncology Group Performance Status 
Eastern Cooperative Oncology Group (ECOG) performance status (Appendix D) will be 
assessed during screening and at other times specified in the Schedule of Clinical Assessments 
(Appendix A and Appendix B).  An assessment is not necessary on Day 1 of Cycle 1 if the 
screening assessment was obtained within 3 days prior to Day 1. 
8.13. 
Radiologic Imaging 
Radiographic tumor evaluation by computed tomography (CT) or MRI of chest, abdomen, and 
pelvis (EOC patients only) will be performed within 28 days prior to first dose and 
approximately every second cycle, from the date of first dose until the 28-day Follow-up visit.  
The same radiographic assessment used at screening must be used at all subsequent radiographic 
evaluations.  
8.14. 
Tumor Response Assessment 
Tumor response for patients with measurable lesions should be assessed using RECIST 1.1 
(Eisenhauer 2009, Appendix E).  Patients with ovarian and uterine cancer will have CA125 
measured at approximately the same time they undergo radiologic assessment.  Patients will have 
a baseline tumor assessment done within the 28 days prior to Cycle 1, Day 1.  Patients with 
measurable lesions should be assessed using CT scan approximately every second cycle, from 
the date of first dose until the 28-day Follow-up visit.  Although progression may be determined 
by the investigator based upon clinical deterioration, every effort should be made to document 
progression using radiographic methods.  The basis for determination of progression per clinical 
deterioration should be documented.  
Patients experiencing CA125 response must have a confirmatory test performed at least 28 days 
after initial response is documented.  In the case of stable disease (SD), follow-up measurements 
must have met the SD criteria at least once after study entry at a minimum interval of 6 weeks. 
Electronic copies of radiologic images with tumor size measurements, including baselines 
assessment, must be sent to the sponsor within 4 weeks after PR/CR has been documented, 
together with a copy of the corresponding radiology report and tumor assessment worksheets.  
Scans must be in Digital Imaging and Communications in Medicine (DICOM) format.  
Electronic transfer of scan files (via FTP, HTTP, or similar means) is preferred, although transfer 
on physical media (such as DVD or CD) is acceptable.  For digital media, one time 
point/patient/disk is expected.  The site is expected to maintain a copy of digital data for the 
retention period applicable to the protocol, Good Clinical Practices (GCP), and federal, 
international, and/or state legal and medical requirements.  ImmunoGen will retain the media for 


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a period of 2 years following the date a marketing application is approved or, if no application is 
to be filed or if the application is not approved for such indication, until 2 years after the 
investigation is discontinued. 
Note: It is very important that the same method of radiologic assessment be used 
throughout the study and that the same lesions are followed.  
8.15. 
Eligibility based on FOLR1 Expression  
Instructions regarding processing and shipment of biopsy samples and archival tissues are 
detailed in the Laboratory Manual. 
8.15.1. 
Dose Escalation Cohorts 
Patients with serous or endometrioid ovarian cancer, uterine cancer or NSCLC adenocarcinoma 
or BAC, tumors known to have a high incidence of FOLR1 expression do not require IHC 
screening prior to enrollment (Section 1.1 and Section 7.1.1, and the Investigators’ Brochure).  
Archival tumor tissue should be submitted for retrospective analysis of FOLR1 expression.  
Patients with other tumor types may be eligible, but require documented expression of FOLR1 
by IHC (≥1% of tumor staining at ≥1+ intensity) on archival tissue prior to enrollment.  If 
archival tissue is not available, then a fresh tumor biopsy must be obtained to confirm FOLR1 
expression by IHC prior to enrollment.  De-identified pathology reports should be included with 
sample shipment to ImmunoGen or designee.  
8.15.2. 
Dose Expansion Cohort #1, Platinum Resistant Ovarian Cancer  
Patients must meet the minimum requirement of FOLR1 positivity by IHC (≥25% of tumor 
staining at ≥2+ intensity) prior to enrollment.  IHC may be performed on archival tissue to 
determine eligibility.  If archival tissue is not available, then a fresh tumor biopsy must be 
obtained to confirm FOLR1 expression by IHC prior to enrollment. 
8.15.3. 
Dose Expansion Cohort #2, Advanced/Recurrent Uterine Cancer 
Patients must have documented expression of FOLR1 by IHC (H score ≥ 100) prior to 
enrollment.  IHC may be performed on archival tissue to determine eligibility.  If archival tissue 
is not available, then a fresh tumor biopsy must be obtained to confirm FOLR1 expression by 
IHC prior to enrollment. 
8.15.4. 
Dose Expansion Cohort #3, Relapsed Ovarian Cancer 
Patients must meet the minimum requirement of FOLR1 positivity by IHC (≥25% of tumor 
staining at ≥2+ intensity) prior to enrollment.  IHC may be performed on archival tissue to 
determine eligibility.  If archival tissue is not available, then a fresh tumor biopsy must be 
obtained to confirm FOLR1 expression by IHC prior to enrollment. 
If the patient meets all eligibility criteria and enrolls in the study, then a fresh tumor biopsy must 
be obtained prior to their first dose of IMGN853 and at Cycle 2 day 8±3 for pharmacodynamic 
analyses (Section 7.3).  Patients who relapse after showing clinical benefit will be asked to 
undergo an optional biopsy to help understand the mechanism of resistance to IMGN853.  


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8.15.5. 
Dose Expansion Cohort #4, Relapsed/Refractory NSCLC Adenocarcinoma 
Patients must have documented expression of FOLR1 by IHC (≥ 1 hetero - ≥25% of tumor 
staining at ≥1+ intensity) prior to enrollment.  IHC may be performed on archival tissue to 
determine eligibility.  If archival tissue is not available, then a fresh tumor biopsy must be 
obtained to confirm FOLR1 expression by IHC prior to enrollment. 
8.15.6. 
Dose Expansion Cohort #5, Relapsed Ovarian Cancer  
Patients must have documented expression of FOLR1 by IHC ( ≥25% of tumor staining at ≥2+ 
intensity) prior to enrollment.  IHC may be performed on archival tissue to determine eligibility.  
If archival tissue is not available, then a fresh tumor biopsy must be obtained to confirm FOLR1 
expression by IHC prior to enrollment. 
 


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9. 
ASSESSMENT OF SAFETY 
9.1. 
Adverse and Serious Adverse Events 
Treatment-emergent AEs (including SAEs) will be documented on the AE eCRF and monitored 
continuously throughout the study from the time of the first dose of study treatment until 28 days 
after the patient’s last dose of study drug or until the event has resolved, stabilized or an outcome 
has been reached, whichever comes first.   
If the Investigator considers it necessary to report an AE in a study patient occurring after the 
end of study, he or she should contact the Sponsor to determine how the AE should be 
documented and reported.  Pre-treatment AEs attributed to study procedures, including those 
events which occur prior to the first dose, should also be documented on the AE eCRF.  Any 
other change in medical condition which occurs during the interval between consent and first 
dose will be documented on the medical history eCRF. 
9.1.1. 
Definition of Adverse Events 
9.1.1.1. 
Adverse Event (AE) 
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
any phase of a clinical study, whether or not considered study drug-related.  This includes an 
exacerbation of a pre-existing condition.  AEs include: 
• Worsening (change in nature, severity, or frequency) of conditions present at the 
onset of the study 
• Intercurrent illnesses 
• Drug interactions 
• Events related to or possibly related to concomitant medications 
• Abnormal laboratory values (this includes significant shifts from baseline within the 
range of normal that the Investigator considers to be clinically important) 
• Clinically significant abnormalities in physical examination, vital signs, and weight 
Note that progressive disease should not be reported as an AE. 
Pre-treatment AEs occurring from the time of consent until the time of the first dose of study 
treatment, which are attributed to study procedures, must be reported on the designated AE 
eCRF.  All treatment-emergent AEs, including AEs attributed to study procedures, occurring 
from the first dose of study treatment until 28 days after last study treatment or until the event 
has resolved, stabilized or an outcome has been reached  must be reported on the AE eCRF, 
regardless of the severity or relationship to study drug.  The Investigator should treat patients 
with AEs appropriately and observe them at suitable intervals until the events stabilize or 
resolve.  AEs may be discovered through observation or examination of the patient, questioning 
of the patient, complaint by the patient, or by abnormal clinical laboratory values. 
In addition, AEs may also include laboratory values that become significantly out of range.  Such 
abnormal laboratory values or test results constitute AEs if they induce clinical signs or 


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symptoms, are considered clinically significant (e.g., cause study discontinuation or constitutes 
in and of itself a Serious Adverse Event, or require therapy, e.g., any hematologic abnormality 
that requires transfusion or cytokine treatment); and should be recorded on the AE eCRF under 
the signs, symptoms or diagnosis associated with them.  In the event of an out-of-range value, 
the laboratory test should be repeated until it returns to normal or can be explained and the 
patient’s safety is not at risk.   
9.1.1.2. 
Serious Adverse Event (SAE) 
A SAE is any AE occurring at any dose that results in any of the following outcomes: 
• Death 
• Is life-threatening 
• Requires inpatient hospitalization 
• Requires prolongation of existing hospitalization 
• A persistent or significant disability or incapacity or substantial disruption of the 
ability to conduct normal life functions 
• A congenital anomaly or birth defect 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization. 
Note that hospitalization is defined as admission to treat a clinical adverse event.  The following 
events would not be considered hospitalizations for SAE reporting purposes: 23-hour hold for 
observation, admission to a hospice facility or nursing home, respite care, outpatient surgery, 
social admission (e.g., a homeless patient) or admission not associated with a precipitating 
clinical adverse event (e.g., elective ore pre-planned surgery, or in-patient administration of 
subsequent chemotherapy, etc.). 
All AEs will be evaluated according to the NCI CTCAE version 4.03 (effective 14 June 2010).  
If the AE is not listed in the CTCAE version 4.03, it should be graded based on the description 
given in Table 14. 
 
 
 
 


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Table 14: 
Adverse Event Severity  
Severity 
Definition 
Grade 1 (Mild) 
No limitation of usual activities. 
Grade 2 (Moderate) 
Some limitation of usual activities. 
Grade 3 (Severe) 
Inability to carry out usual activities. 
Grade 4 (Life-threatening or disabling ) 
Immediate risk of death. 
Grade 5 (Fatal) 
Resulting in death 
 
Relationship of an AE or SAE to study medication is to be determined by the Investigator based 
on the definitions in Table 15: 
 
Table 15: 
Adverse Event Relatedness  
Relationship to Product(s) 
Definition 
Not Related 
No relationship between the event/laboratory abnormality and the 
administration of study drug.   
Possibly Related 
A clinical event/laboratory abnormality with a reasonable time 
sequence to administration of study drug, but which could also be 
explained by concurrent disease or other drugs/chemicals. 
Definitely Related 
A clinical event/laboratory abnormality with a reasonable time 
sequence to administration of study drug and follows a known 
response pattern to the study drug and can be confirmed with a 
positive re-challenge test or supporting laboratory data.   
9.2. 
Recording Adverse Events 
9.2.1. 
Reporting Serious Adverse Events 
Any SAE, regardless of relationship to study medication, which occurs in a patient from the time 
of the first dose of study treatment until 28 days after the last study treatment, should be recorded 
by the clinical site on an SAE form.  This reporting requirement also includes SAEs that are 
attributed to a study procedure performed during the screening period (from the time of consent 
until the time of the first dose of study treatment).  The SAE must be completely described on 
the patient’s CRF, including the judgment of the Investigator as to the relationship of the SAE to 
the study drug.  The Investigator will promptly supply all information identified and requested 
by the Sponsor (or contract research organization [CRO]) regarding the SAE.  
The Investigator must report the SAE to the ImmunoGen Medical Director or designee on an 
SAE report form.  This form must be completed and submitted within 24 hours of the 
Investigator’s learning of the event to the contact persons listed in the Study Manual provided to 
each site and maintained in the Investigator study files.  Any follow-up information must also be 
completed on an SAE form and submitted to the same contacts. 
When reporting SAEs, the following additional points should be noted.  


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• The underlying diagnosis or syndrome should be reported as the primary SAE term, 
rather than the signs or symptoms (signs and symptoms may be described in the 
narrative). 
• Death should not be reported as an SAE, but rather as an outcome of a specific SAE, 
unless the event preceding the death is unknown.  In these exceptional cases, death 
may be used as an event term.  If an autopsy was performed, the autopsy report 
should be provided. 
It is the responsibility of the Sponsor to ensure that each Investigator receives a copy of any 
CIOMS/MedWatch report that has been submitted to the appropriate national regulatory agencies as 
notification of a suspected unexpected serious adverse reaction (SUSAR).  The Investigator (or Sponsor 
or Sponsor’s representative if so designated) must promptly report all SUSARs to the Institutional 
Review Board/Independent Ethics Committee (IRB/IEC) for review in accordance with national 
regulations.  IRB/IEC notification of the SUSAR may take the form of a submission of a copy of the 
CIOMS/MedWatch report or other format accepted by the IRB/IEC.  A copy of the CIOMS/MedWatch 
report and notification to IRB/IEC should be retained in the site’s study files.  
In addition to CIOMS/MedWatch reports, the Sponsor will also notify the Investigators and 
IRBs/IECs of all deaths that occur during the study, irrespective of relationship to study 
medication through annual updates to the IB. 
Disease progression and/or progression of the disease under study are anticipated occurrences in 
oncology drug development, and as such, are considered expected as per the current 
investigator’s brochure for the compound.  If a patient expires from progression of disease and/or 
from the disease under study during the period of obligation to report serious adverse events, 
disease progression and/or progression of the disease under study with a fatal outcome do not 
need to be reported as serious adverse events.  The applicable protocol CRF page(s) pertaining to 
death should be appropriately completed however, as disease progression. 
9.2.2. 
Reporting a Pregnancy 
Pregnancy and lactation are exclusion criteria.  The Sponsor must be notified in the event of a 
pregnancy occurring during the course of the study and through 28 days after the patient’s last 
dose of study drug.  Pregnancy is not to be reported as an AE; the pregnancy reporting form 
should be used to report the pregnancy.  The pregnancy will be followed through delivery or 
final outcome. 


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10. 
STUDY ACTIVITIES 
10.1. 
Screening Visit (Days -28 to -1) 
The Investigator is responsible for keeping a record of all patients screened for entry into the 
study and subsequently excluded.  The reason(s) for exclusion must also be recorded.  The 
following screening procedures must be performed within 28 days prior to Day 1, unless 
otherwise specified.  
• Obtain written informed consent prior to the undertaking of study-specific procedures 
unless those procedures are performed as part of the patient’s standard care   
• Collect and record demographic and medical information; include all prior treatments 
for their disease with dates of therapy and best response, when available   
• Perform complete physical examination (Appendix A and Appendix B) 
• Vital signs (Section 8.6, Appendix A and Appendix B)  
• Height (Appendix A and Appendix B) 
• Weight (Appendix A and Appendix B) 
• ECOG performance status (Appendix A and Appendix B)  
• Clinical laboratory tests – within 14 days prior to first dose (Section 8.10, 
Appendix A and Appendix B):   
o Serum chemistry 
o Hematology 
o Coagulation profile 
o Urinalysis 
• Complete Ophthalmic Examination (performed by a board-certified ophthalmologist): 
o Schirmer test, Slit lamp examination under dilatation, visual acuity, 
intraocular pressure assessment, and indirect fundoscopy.  (Section 5.8.8) 
o Performed within 14 days of Cycle 1, Day 1 
• Pulmonary Function Tests (Section 8.9) – within 14 days prior to first dose 
• Pregnancy test for WCBP (Appendix A and Appendix B) 
• Radiologic imaging, disease staging, and prognostic index evaluation (Appendix A 
and Appendix B) 
o Confirm disease diagnosis and current disease status 
o CA125 - for patients with EOC, primary peritoneal cancer, fallopian tube cancer or 
uterine cancer whose baseline levels are ≥ 2.0 times the UNL – to be performed 
within 14 days prior to starting treatment (Appendix F) 
• 12-lead electrocardiogram (a single ECG – within 14 days of first treatment)  


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• Directed neurological examination will be performed, to include light touch, pinprick, 
proprioception, and deep tendon reflexes (DTRs) of the upper and lower extremities; 
and questioning for symptoms of paresthesia and numbness.  If abnormal, an NCI 
CTAE grade will be recorded and if warranted a neurologist will be consulted 
(Appendix A and Appendix B) 
o FACT/GOG-Neurotoxicity Questionnaire (FACT/GOG NTx), Version 4.0 
(Appendix G ) 
• Record baseline signs and symptoms (Appendix A and Appendix B) 
• Record concomitant medications (Appendix A and Appendix B) 
• Review and document inclusion and exclusion criteria (Appendix A) 
• Record AEs and SAEs which resulted from study procedures 
• PFTs (within 14 days of Cycle 1 Day 1, and as clinically indicated) (Appendix A) 
• Fresh tumor biopsy (Section 7.1.1 and Appendix C)  
o Patients requiring FOLR1 documentation who do not have archival tissue 
available 
o All patients in MTD Expansion Cohort #3 (relapsed EOC) 
• For patients with EOC, uterine cancer or NSCLC only: 
o Identify and ship fresh or archival tumor tissue (Section 8.15) 
10.1.1. 
Standard of Care Assessments 
In some cases, clinical assessments performed prior to obtaining informed consent may be used 
to qualify the patient for the study.  These include radiological tumor assessment, physical 
examinations, hematology, serum chemistry results, coagulation studies, urinalysis, or other 
assessments which may be considered part of normal standard of care.  In these cases, repeat 
assessments may not be necessary prior to enrollment, unless individual parameters require 
further study or confirmation and are clinically appropriate. 
10.2. 
Cycle 1 Assessments 
10.2.1. 
Cycle 1, Day 1 
The following procedures must be performed or initiated as indicated prior to the start of 
treatment to establish the patient’s baseline condition.  The patient will remain in the clinical 
research unit/treatment area for at least 4 hours following the initial dose of IMGN853.  
Subsequent IMGN853 infusions require at least a 1-hour post-dose observation period (if the 
initial infusion is well tolerated).  While in the treatment area, patients will be closely monitored 
for toxicity. 
The following should be completed prior to dosing on Day 1 of Cycles 1 and 2 except as noted.  
Note that safety blood tests, and physical examination do not need to be repeated if normal and 
conducted within 4 days prior to Cycle 1, Day 1. 


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• Confirm that the patient continues to satisfy all inclusion and exclusion criteria 
(Appendix A and Appendix B) 
• Symptom-directed physical examination (Appendix A and Appendix B) 
• Vital signs (Section 8.6, Appendix A and Appendix B)  
• Pulse oximetry (Section 8.8) 
• Weight (Appendix A) 
• ECOG performance status (Appendix A and Appendix B) 
• Clinical laboratory tests (Section 8.10, Appendix A and Appendix B): 
o Serum chemistry 
o Hematology  
o Coagulation profile 
o Urinalysis  
• Ocular symptom assessment (Section 5.8.8) 
• Pregnancy test for WCBP (Appendix A and Appendix B) 
• ECG – performed in triplicate as outlined in Section 8.7 (Appendix A and 
Appendix B) 
• Directed neurological examination will be performed, to include light touch, pinprick, 
proprioception, and deep tendon reflexes (DTRs) of the upper and lower extremities; 
and questioning for symptoms of paresthesia and numbness.  (Appendix A and 
Appendix B) 
o Neurotoxicity Questionnaire (FACT/GOG NTx), Version 4.0 (Appendix G) 
• Record baseline signs and symptoms that have emerged since the screening visit 
(Appendix A and Appendix B) 
• IMGN853 administration (Appendix A and Appendix B) 
• AEs and SAEs (Appendix A and Appendix B) 
• Concomitant medications (Appendix A)  
• Blood sample for measurement of homocysteine and methylmalonate as outlined in 
Section 7.2.3 and Appendix C 
• Blood sample for measurement of FcγR polymorphisms as outlined in Section 7.2.1 
and Appendix C  
• Record known molecular pathology data (Appendix C), for example: 
o Ovarian Cancer: BRCA1/BRCA2 status 
o NSCLC: EGFR mutation/amplification, ALK translocation, Ras 
mutation/amplification 


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o Renal Cell Carcinoma (RCC): Von Hippel Lindau (VHL) mutation 
• PK sample collection as outlined in Section 6 and Appendix C  
• HAHA and HADA sample collection as outlined in Section 6 and Appendix C 
10.2.2. 
Cycle 1, Day 2 
• PK sample collection as outlined in Section 6 and Appendix C 
• ECG performed in triplicate as outlined in Section 8.7 (also Appendix A and 
Appendix B) 
• Vitals signs; blood pressure, pulse, temperature and respiratory rate as outlined in 
Section 8.6, Appendix A and Appendix B 
• Pulse oximetry (Section 8.8) 
10.2.3. 
Cycle 1, Day 3 and Day 4, or 5 
• Schedule A only - PK sample collection as outlined in Section 6 and Appendix C 
10.2.4. 
Cycle 1, Day 8 and 15 
• Symptom-directed physical examination (Appendix A) 
• Clinical laboratory tests (Section 8.10, Appendix A and Appendix B):  
o Serum chemistry 
o Hematology 
• Pulse oximetry (Section 8.8) 
• PK sample collection as outlined in Section 6 and Appendix C 
• AEs and SAEs (Appendix A and Appendix B) 
• Concomitant medications (Appendix A and Appendix B)  
• Schedule B Only: 
o IMGN853 administration (Appendix A and Appendix B) 
10.2.5. 
Cycle 1, Day 16 (Schedule B only) 
• PK sample collection as outlined in Section 6 and Appendix C 
10.2.6. 
Cycle 1, Day 22 (Schedule B only) 
• PK sample collection as outlined in Section 6 and Appendix C 
10.3. 
Cycle 2 Assessments 
10.3.1. 
Cycle 2, Day 1 
• Confirm that the patient satisfies all retreatment criteria (Section 5.9.3) 
• Symptom-directed physical exam (Appendix A and Appendix B) 


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• Vital signs (Section 8.6, Appendix A and Appendix B)  
• Pulse oximetry (Section 8.8) 
• Weight (Appendix A and Appendix B) 
• ECOG performance status (Appendix A and Appendix B) 
• Clinical laboratory tests (Section 8.10, Appendix A and Appendix B) 
o Serum chemistry 
o Hematology 
o Coagulation profile 
o Urinalysis 
• Directed neurological examination will be performed, to include light touch, pinprick, 
proprioception, and deep tendon reflexes (DTRs) of the upper and lower extremities; 
and questioning for symptoms of paresthesia and numbness.  (Appendix A and 
Appendix B) 
o Neurotoxicity Questionnaire (FACT/GOG NTx), Version 4.0 (Appendix G) 
• IMGN853 administration (Appendix A and Appendix B) 
• AEs and SAEs (Appendix A and Appendix B) 
• Ocular symptom assessment (Section 5.8.8) 
• Concomitant medications 
• PK sample collection, as outlined in Section 6 and Appendix C 
• HAHA and HADA sample collection as outlined in Section 6 and Appendix C 
10.3.2. 
Cycle 2, Day 8±3 Days 
• Blood sample for measurement of homocysteine and methylmalonate as outlined in 
Section 7.2.3 and Appendix C 
• Fresh tumor biopsy – Expansion Cohort  #3 (Sections 7.1.1, 7.3.1 and Appendix C)  
o In addition, patients who relapse after showing clinical benefit will be asked to 
undergo an optional biopsy at the time of disease progression to help 
understand the mechanism of resistance to IMGN853 
10.3.3. 
Cycle 2, Day 8 and 15 
• Symptom-directed physical examination  
• Vital signs (Section 8.6, Appendix A and Appendix B)  
• Clinical laboratory tests (Section 8.10, Appendix A and Appendix B):  
o Serum chemistry 
o Hematology 


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• Pulse oximetry (Section 8.8) 
• AEs and SAEs (Appendix A and Appendix B) 
• Concomitant medications (Appendix A and Appendix B) 
• Schedule B Only: IMGN853 administration (Appendix A and Appendix B) Cycle 3 
Assessments 
10.4. 
Cycle 3 Assessments 
10.4.1. 
Cycle 3, Day 1 
• Confirm that the patient satisfies all retreatment criteria (Section 5.9.3) 
• Symptom-directed physical examination (Appendix A and Appendix B) 
• Vital signs as outlined in Section 8.6, Appendix A and Appendix B 
• Pulse oximetry (Section 8.8) 
• Weight (Appendix A and Appendix B) 
• ECOG performance status (Appendix A and Appendix B) 
• Clinical laboratory tests (Section 8.10, Appendix A and Appendix B):  
o Serum chemistry 
o Hematology 
o Coagulation profile 
o Urinalysis 
• ECG – performed in triplicate as outlined in Section 8.7.  
• Directed neurological examination will be performed, to include light touch, pinprick, 
proprioception, and deep tendon reflexes (DTRs) of the upper and lower 
extremities; and questioning for symptoms of paresthesia and numbness 
(Appendix A and Appendix B). 
o Neurotoxicity Questionnaire (FACT/GOG NTx), Version 4.0 (Appendix G) 
• IMGN853 administration 
• AEs and SAEs (Appendix A and Appendix B) 
• Ocular symptom assessment (Section 5.8.8) 
• Concomitant medications 
• PK sample collection as outlined in Section 6 and Appendix C  
• HAHA and HADA sample collection as outlined in Section 6  
10.4.2. 
Cycle 3, Day 2 
• PK sample collection as outlined in Section 6 and Appendix C  


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• ECG – performed in triplicate as outlined in Section 8.7 
• Vital signs as outlined in Section 8.6, Appendix A and Appendix B 
• Pulse oximetry (Section 8.8) 
• AEs and SAEs (Appendix A and Appendix B) 
• Concomitant medications 
10.4.3. 
Cycle 3, Day 3 and Day 4 or 5 (Schedule A Only) 
• PK sample collection as outlined in Section 6 and Appendix C  
10.4.4. 
Cycle 3, Day 8 and 15 
• Clinical laboratory tests:  
o Serum chemistry 
o Hematology 
• Pulse oximetry (Section 8.8) 
• AEs and SAEs (Appendix A and Appendix B) 
• Concomitant medications 
• Schedule B Only: 
o IMGN853 administration (Appendix A and Appendix B) 
o PK sample collection as outlined in Section 6 and Appendix C  
10.4.5. 
Cycle 3, Day 16 (Schedule B only) 
• PK sample collection as outlined in Section 6 and Appendix C 
10.4.6. 
Cycle 3, Day 22 (Schedule B only) 
• PK sample collection as outlined in Section 6 and Appendix C 
10.5. 
Even-Numbered Cycles (2, 4, 6, etc.), End of Cycle  
• Pregnancy test (may be performed more frequently in accordance to institutional 
requirements) (Appendix A and Appendix B) 
o Schedule A – Day 18±3 days 
o Schedule B – Day 21±3 days 
• For patients who experience ocular toxicity and those who experience blurred 
vision but have normal eye examinations: complete ophthalmic examination 
(Section 5.8.8); to be performed by a board-certified ophthalmologist prior to the 
start of every other cycle from the time it is first reported. 
• Tumor assessments by CT scan (Appendix A and Appendix B) 
o Schedule A – Every 6 weeks±1 week 


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o Schedule B – Every 8 weeks±1 week 
• CA125 - for patients with EOC, primary peritoneal cancer, fallopian tube cancer or 
uterine cancer (Appendix F) should be scheduled to coincide approximately with 
the radiographic tumor assessments 
NOTE: Patients experiencing CA125 response must have a confirmatory test 
performed 28 days after initial response is documented. 
10.6. 
Cycles ≥ 4 Assessments 
10.6.1. 
Cycles ≥4, Day 1 
Within 96 hours prior to Day 1: 
• Confirm patient meets retreatment criteria as outlined in Section 5.9.3. 
• Symptom-directed physical examination (Appendix A and Appendix B) 
• Vital signs (Section 8.6, Appendix A and Appendix B) 
• Pulse oximetry (Section 8.8) 
• Weight (Appendix A and Appendix B) 
• ECOG performance status (Appendix A and Appendix B) 
• Clinical laboratory tests (Appendix A and Appendix B): 
o Serum chemistry 
o Hematology 
o Coagulation profile 
o Urinalysis  
• Directed neurological examination will be performed, to include light touch, pinprick, 
proprioception, and deep tendon reflexes (DTRs) of the upper and lower 
extremities; and questioning for symptoms of paresthesia and numbness.  If 
abnormal, an NCI CTAE grade will be recorded and if warranted a neurologist will 
be consulted (Appendix A and Appendix B) 
o Neurotoxicity Questionnaire (FACT/GOG NTx), Version 4.0 (Appendix G) 
• IMGN853 administration (Appendix A and Appendix B) 
• AEs and SAEs (Appendix A and Appendix B) 
• Ocular symptom assessment (Section 5.8.8) 
• Concomitant medications (Appendix A and Appendix B) 
• Up to Cycle 6 - PK sample collection as outlined in Section 6 and Appendix C  
• HAHA and HADA sample collection as outlined in Section 6 and Appendix C  


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10.6.2. 
Cycles > 4, Day 8 and 15 (Schedule B) 
• Clinical laboratory tests (Section 8.10, Appendix A and Appendix B):  
o Serum chemistry 
o Hematology 
• Pulse oximetry (Section 8.8) 
• Concomitant medications (Appendix A and Appendix B) 
• IMGN853 administration (Appendix A and Appendix B) 
• AEs and SAEs (Appendix A and Appendix B)   
10.7. 
End of Treatment Visit 
Patients may voluntarily withdraw from the study treatment at any time for any reason, and 
without prejudice to further treatment.  In addition, patients may be withdrawn by the 
Investigator if they do not feel the patient is deriving clinical benefit or because the patient is 
experiencing unacceptable toxicity.  The reasons for which a patient may be prematurely 
discontinued are listed in Section 5.10.  
Patients who withdraw or are removed from the study treatment will have an end of treatment 
visit within 7 days of the decision to discontinue study treatment.  All study evaluations 
described below will be performed.  Additionally, these patients will undergo a 28-day follow-up 
safety visit.  The eCRF will capture reasons for withdrawal.  
The procedures listed below are to be undertaken at the end of treatment visit and documented in 
the eCRF: 
• Symptom-directed physical examination (Appendix A and Appendix B) 
• Vital signs as outlined in Section 8.6, Appendix A and Appendix B 
• Pulse oximetry (Section 8.8)Weight (Appendix A and Appendix B) 
• ECOG performance status (Appendix A and Appendix B) 
• Clinical laboratory tests (Section 8.10, Appendix A and Appendix B):  
o Serum chemistry 
o Hematology 
• Blood sample for measurement of homocysteine and methylmalonate as outlined in 
Section 7.2.3 and Appendix C 
• Ophthalmic examinations: visual acuity, fundoscopic exam, ocular symptom 
assessment (Section 5.8.8) 
• Single, 12-lead ECG (Section 8.7) 
• Radiologic imaging to monitor tumor response if PD has not been documented 
already (Appendix A and Appendix B) 


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• 
CA125 - for patients with EOC, primary peritoneal cancer, fallopian tube cancer or uterine 
cancer (Appendix F) 
NOTE: patients experiencing CA125 response must have a confirmatory test performed at 
least 28 days after initial response is documented. 
• AEs and SAEs (Appendix A and Appendix B) 
• Ocular symptom assessment (Section 5.8.8) 
• Concomitant medications (Appendix A) 
• HAHA and HADA sample collection as outlined in Section 6 and Appendix C  
10.8. 
Follow-up Assessments 
Safety Follow-up: A safety follow-up visit will occur 28 days (+ 14 days) after the last 
treatment.  During this visit, the following assessments will be performed. 
• Complete physical examination (Appendix A and Appendix B) 
• Vital signs (Section 8.6, Appendix A and Appendix B) 
• Pulse oximetry (Section 8.8) 
• Weight (Appendix A and Appendix B) 
• ECOG performance status (Appendix A and Appendix B) 
• 12-Lead ECG (if clinically indicated) 
• Pregnancy test for WCBP (Appendix A and Appendix B) 
• Clinical laboratory tests (Section 8.10, Appendix A and Appendix B):  
o Serum chemistry 
o Hematology 
o Coagulation profile 
o Urinalysis 
• Radiologic imaging to monitor tumor response if PD has not been documented 
already (Appendix A and Appendix B) 
• For patients with EOC, uterine cancer or NSCLC only: 
• CA125 - for patients with EOC, primary peritoneal cancer, fallopian tube cancer or uterine 
cancer (Appendix F) 
NOTE: patients experiencing CA125 response must have a confirmatory test 
performed at least 28 days after initial response is documented. 
• AEs and SAEs (Appendix A and Appendix B)  
• Ocular symptom assessment (Section 5.8.8) 


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• Complete ophthalmic examination for all patients; alternatively, the complete 
examination can be performed at the End of Study visit. 
o Patients experiencing an ocular treatment-emergent adverse event (Section 
5.8.8.2) will continue to have examinations every 2 weeks until the condition 
resolves or is deemed to be irreversible by the investigator. 
• Concomitant medications(Appendix A and Appendix B) 
• Directed neurological examination will be performed, to include light touch, pinprick, 
proprioception, and deep tendon reflexes (DTRs) of the upper and lower 
extremities; and questioning for symptoms of paresthesia and numbness.  If 
abnormal, an NCI CTAE grade will be recorded and if warranted a neurologist will 
be consulted (Appendix A and Appendix B) 
o Neurotoxicity Questionnaire (FACT/GOG NTx), Version 4.0 (Appendix G) 
• HAHA and HADA sample collection as outlined in Section 6 and Appendix C 
All serious adverse events, and those adverse events assessed by the Investigator as at least 
possibly related to study drug should continue to be followed until they resolve or stabilize, 
whichever comes first. 
Response Follow-up: Patients who have discontinued study treatment for reasons other than PD 
will be followed per Revised Response Criteria (RECIST 1.1, see Appendix E) every 12 weeks 
(+/- 3 weeks) until documentation of PD, or until the patient starts subsequent anti-cancer 
therapy, whichever comes first.  


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11. 
STATISTICAL METHODS 
All descriptive statistical analyses will be performed using the most recently released and 
available SAS statistical software, unless otherwise noted.  For categorical variables, the number 
and percent of each category within a parameter will be presented.  For continuous variables, the 
sample size (n), mean, median, and standard deviation, as well as the minimum and maximum 
values, will be presented.  Missing data will not be imputed unless otherwise stated.  There will 
be a detailed description of patient disposition, patient demographics, and baseline 
characteristics. 
No formal interim analysis is planned for this study.  However, a review of safety data and 
available preliminary PK data will be conducted by the CRC after the MTD or a RP2D for 
IMGN853 has been determined.  Results from this data review could enable selection of dose 
and dosing schedule for additional studies with IMGN853, before full completion of this study. 
A statistical analysis plan (SAP) will fully describe the planned analyses for this trial.  All 
analyses will be performed for any patient that received study drug.  All analyses for efficacy 
will use Cycle 1, Day 1 as the start time. 
11.1. 
Sample Size 
Ascending doses of IMGN853 are to be evaluated to identify the MTD for both dosing 
schedules.  The actual number of patients accrued during this phase will be determined largely 
by the findings observed during the course of their treatment.  
Following identification of the MTD for Schedule A (Q3W), there was an expansion phase which initially 
accrued two cohorts at the MTD: (1) Dose Expansion Cohort 1 – 40 patients with platinum resistant EOC. 
(2) Dose Expansion Cohort #2 - 20 patients with advanced or recurrent uterine cancer.  Once the 
Schedule B MTD (modified weekly) was established, the CRC convened to review safety, PK and efficacy 
results from the both schedules as well as  preliminary data from the Expansion Cohorts 1 and 2, with 
the Q3W schedule of administration.  The CRC recommended use of Schedule A for all future cohorts. 
Three additional MTD Expansion Cohorts will enroll the following patients:  (3) Dose Expansion 
Cohort 3 – 20 patients with relapsed ovarian cancer, which is amenable to biopsy (4) Dose Expansion 
Cohort 4 – 20 patients with relapsed/refractory NSCLC adenocarcinoma, and (5) 40 patients with 
platinum resistant EOC who will receive daily treatment with corticosteroid-containing eye drops.   
If the true DLT rate at the MTD is 10-20%, there is an 98.5-99.9% probability of observing at 
least one DLT in each 40 patient cohort.  If the true response rate at the MTD is 20%, there is a 
99.9% probability of observing at least one response in each 40 patient cohort.   
 
 
 


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Table 16: 
Probability of Observing ≥ x Events (Response or DLT) For a 40 patient 
Cohort 
x (Number 
Observed) 
True Event Rate 
10% 
20% 
30% 
1 
0.985  
0.999  
0.999  
2 
0.919  
0.998  
0.999   
3 
0.777 
0.992 
0.999 
4 
0.577 
0.972  
0.999  
5 
0.371 
0.924 
0.997 
6 
0.206 
0.838 
0.991 
 
Given a sample size of 40 patients, the power to detect a difference of 20% (rate of Blurry vision 
decrease from 50% to 30%) is 68% using one-sided alpha of 20% and Chi-Square test statistics. 
Safety will be evaluated continuously, separately, and in aggregate in the expansion cohorts.  If 
at any time ≥ 33% of patients treated in an expansion cohort experiences a Cycle 1 DLT, further 
enrollment to that cohort will stop and a CRC will be convened.  The CRC will review all 
available safety data and PK data to determine how further dosing should proceed.  If the CRC 
determines that the dose should be revised during the expansion phase for a given expansion 
cohort, that cohort will enroll additional patients at the revised dose to fulfill the enrollment goal.  
Approximately 209 patients will be enrolled in the study, allowing for dropouts and expansion of 
dose escalation cohorts as needed.   
11.2. 
Pharmacokinetic Analyses 
PK parameters (Cmax, Tmax, Terminal half-life (t1/2), volume of distribution at steady state (Vss), 
clearance (Cl), AUC0-24, AUC0-168, AUCinf) will be derived from plasma concentrations of 
IMGN853, total M9346A antibody and DM4 using the actual sampling times.  Concentration 
data and all PK parameters will be listed per patient and summarized descriptively per dose.  
Standard algorithms of the non-compartmental pharmacokinetic analysis program, WinNonlin 
software, will be used for these analyses. 
Individual plasma concentration vs. actual time profiles for each patient and treatment, as well as 
the mean (+/- STD) plasma concentration vs. scheduled time profiles for each dose level, will be 
presented graphically.   
11.3. 
Safety Analyses 
Adverse events, concomitant medication, and results from physical examination will be listed.   
Adverse events will also be coded with the Medical Dictionary for Regulatory Activities 
(MedDRA; version 17.0 or greater) and summarized per system organ class (SOC) and preferred 
term. 


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Concomitant medications will be coded using the World Health Organization Drug Dictionary (WHO-DD; 
June 1, 2012 or later version).  A dictionary listing of all unique concomitant medications used in the 
study will be provided. 
All hematology, blood chemistry, vital signs, and ECG results will be listed per patient for each 
assessment and descriptive statistics will be tabulated for select criteria.  Changes from baseline 
in hematology, blood chemistry, vital signs, and ECG results will be summarized by treatment.  
Shifts in hematology and blood chemistry from Baseline values will be summarized.  Plasma 
also will be evaluated for the presence of humoral responses against the M9346A antibody 
component (HAHA) or against the DM4 component (HADA).  
11.4. 
Efficacy 
Objective response rate (ORR) - The best OR will be determined by the Investigator for each 
patient as either CR, PR, SD or relapsed disease/PD. Objective responses for patients in the dose 
escalation phase will be summarized by dose cohort assigned as well as the dose at which the 
response occurred.  Responses will be tabulated separately for expansion cohorts 1-4.  For each 
expansion cohort, the response rate will be calculated as the number of CR or PR divided by the 
number of response evaluable patients.  To meet the definition of response-evaluable, patients 
must have undergone radiographic assessment at baseline, received at least one dose of 
IMGN853, and must have had at least one post-dose tumor assessment. 
Duration of Response (DOR) – DOR, defined as the time from initial response until progressive 
disease, will be estimated for all patients who achieve a confirmed objective response (PR or 
CR) using the method of Kaplan-Meier.  Results will be summarized by dose cohort assigned as 
well as the dose at which the response occurred. 
Progression Free Survival (PFS) – PFS, defined as the time from initiation of study drug until 
progressive disease or death whichever occurs first, will be estimated using the Kaplan-Meier 
method.  Results will be summarized by dose cohort. 
Time to Progression (TTP) - TTP defined as the time from initiation of study drug until 
progressive disease, will be estimated using the method of Kaplan-Meier.  Results will be 
summarized by dose cohort. 
For DOR, PFS, and TTP calculations, subjects not achieving the endpoint will be censored at the 
time of the last endpoint assessment.  Median response times and associated 95% CIs will be 
presented for descriptive summaries.   
 
 


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12. 
QUALITY CONTROL AND ASSURANCE 
Clinical sites will be monitored by ImmunoGen or its designee to ensure the accuracy of data 
against source documents.  Data will be captured using validated systems.  Adverse events will 
be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 17.0 or later.  
Training will occur at an Investigator meeting or at the site initiation visit or both, and instruction 
manuals (e.g., laboratory manuals and pharmacy manuals) will be provided to aid consistency in 
data collection and reporting across sites. 
All required data will be entered into the clinical and/or safety database in accordance with Code 
of Federal Regulations (CFR) 21 Part 11 compliance.  The database will include an audit trail to 
document any evidence of data processing or activity on each data field by each user.  Users will 
be given restricted access based on their role in the study through a password protected 
environment.  All missing data will be explained. 
Data entered in the system must be verifiable against source documents and will be reviewed 
manually for validity and completeness against the source documents by a clinical monitor from 
ImmunoGen or its designee.  If necessary, the study site will be contacted for corrections or 
clarifications. 
 


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13. 
ADMINISTRATIVE CONSIDERATIONS, STUDY MONITORING 
AND DATA MANAGEMENT 
13.1. 
Investigators and Study Administrative Structure 
Before initiation of the study, the Investigators must provide the Sponsor with a completed Form 
FDA 1572.  Study medications may be administered only under the supervision of the 
Investigators listed on this form.  Curriculum vitae must be provided for the Investigators and 
sub-investigators listed on Form FDA 1572. 
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, the study treatments, and their study related 
duties and functions.  The Investigator must maintain a list of sub-investigators and other 
appropriately qualified persons to whom he or she has delegated significant study related duties. 
13.2. 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval 
Before initiation of the study, the Investigator must provide the Sponsor with a copy of the 
written IRB/IEC approval of the protocol, the study ICF and the screening ICF (latter ICF is 
applicable for sites requesting permission to prescreen for FOLR1 positivity prior to performing 
any additional study related tests).  This approval must refer to the ICF(s) and to the study title, 
study number, and version and date of issue of the study protocol, as given by the Sponsor on the 
cover page of the protocol. 
Status reports must be submitted to the IRB/IEC at least once per year or as per institutional 
guidelines.  The IRB/IEC must be notified of completion of the study and a final report must be 
provided to the IRB/IEC.  A copy of these reports will be sent to the study clinical monitor or 
designee.  The Investigators must maintain an accurate and complete record of all submissions 
made to the IRB/IEC, including a list of all reports and documents submitted.  AEs which are 
subject to expedited reporting to the US Food and Drug Administration (FDA) or other 
regulatory agencies (SUSARs) must be submitted promptly to the IRB/IEC. 
13.3. 
Ethical Conduct of the Study 
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
Good Clinical Practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonisation (ICH) GCP Guidelines.  Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in the 
Declaration of Helsinki. 
13.4. 
Patient Information and Consent 
Before enrolling in the clinical study, the patient or the patient’s legally authorized 
representative(s) must consent to participate after the nature, scope, and possible consequences 
of the clinical study have been explained in a form understandable to him or her.  An ICF that 
includes information about the study will be prepared and given to the patient, or the patient’s 
legally authorized representative(s).  This document will contain all FDA and ICH-required 


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elements.  The ICF must be in a language understandable to the patient or the patient’s legally 
authorized representative(s) and must specify who informed the patient or the patient’s legally 
authorized representative. 
After reading the informed consent document, the patient or the patient’s legally authorized 
representative(s) must give consent in writing.  If the patient or the patient’s legally authorized 
representative(s) is unable to read, oral presentation and explanation of the written ICF and 
information to be supplied must take place in the presence of an impartial witness.  Consent must 
be confirmed at the time of consent orally and by the personally dated signature of the patient or 
by the patient’s legally authorized representative(s).  The witness and the person conducting the 
informed consent discussions must also sign and personally date the informed consent document.  
It should also be recorded and dated in the source document that consent was given. 
A copy of the signed and dated consent document(s) must be given to the patient or the patient’s 
legally authorized representative(s).  The original signed and dated consent document will be 
retained by the Investigator.  Patient confidentiality will be maintained as outlined in Section 13.5. 
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained. 
A model of the full study ICF will be provided to the sites separately from this protocol.  
A screening ICF may be used to confirm a patient’s consent to analyze archived or fresh tumor 
samples for FOLR1 expression.  If the IHC screening assay is positive for FOLR1, the patient 
will be provided the full study consent and only after signing the full study ICF will additional 
study-specific screening tests be performed.  A model of the screening ICF will be provided to 
the sites separately from this protocol. 
13.5. 
Patient Confidentiality 
Patient names will not be supplied to the Sponsor.  If the patient name appears on any 
documents, it must be redacted before a copy of the document is supplied to the Sponsor.  Study 
findings stored on a computer will be stored in accordance with local data protection laws.  
Patient blood and tissue samples sent to outside laboratories and/or CROs (e.g. IHC laboratory) 
are identified by study patient number only to ensure maintenance of confidentiality.  The patient 
consent form will state publications resulting from this study will not refer to patient name or 
include any other information that might disclose the identity of the subject.  The patients will be 
told that representatives of the Sponsor, a designated CRO, the IRB/IEC, or regulatory 
authorities may inspect their medical records to verify the information collected, and that all 
personal information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws.  The Investigator will maintain a personal patient 
identification list (patient numbers with the corresponding patient names) to enable records to be 
identified. 
13.6. 
Study Monitoring 
Monitoring procedures that comply with current GCP guidelines will be followed.  On-site 
review of the case report forms (CRFs) for completeness and clarity, cross-checking with source 
documents, and clarification of administrative matters will be performed. 


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The study will be monitored by the Sponsor or its designee.  On-site monitoring will be 
performed by a representative of the Sponsor (Clinical Study Monitor) who will review the CRFs 
and source documents.  The site monitor will ensure that the investigation is conducted 
according to protocol design and regulatory requirements by frequent site visits and 
communications (e-mail, letter, telephone, and facsimile). 
13.7. 
Case Report Forms and Study Reports 
Case report forms (paper or electronic) are provided for each patient.  All forms must be filled out 
by authorized study personnel.  All corrections to the original CRF entry must indicate the reason 
for change.  The Investigator is required to sign/e-sign the CRF after all data have been captured 
for each patient.  If corrections are made after review and signature by the Investigator, he or she 
must be made aware of the changes, and his or her awareness documented by re-signing the CRF. 
13.8. 
Critical Documents 
Before ImmunoGen initiates the trial (i.e., obtains informed consent from the first patient), it is 
the responsibility of the Investigator to ensure that the following documents are available to 
ImmunoGen or their designee: 
• Curricula vitae of Investigator and sub-investigator(s) (current, dated and signed or 
supported by an official regulatory document) 
• Signed and dated agreement of the final protocol 
• Signed and dated agreement of any amendment(s), if applicable 
• Approval/favorable opinion from the IRB/IEC clearly identifying the document and 
document revision reviewed, including but not limited to: the protocol, any protocol 
amendments, Investigator’s Brochure, Patient Information/Informed Consent Form, 
and any other written information to be provided regarding patients recruitment 
procedures 
• Copy of  IRB/IEC approved Patient Information/Informed Consent Form/any other 
written information/advertisement 
• List of IRB/IEC Committee members/constitution or equivalent compliance statement 
• Study and Financial agreement(s) 
• Completed Form FDA 1572 
• Completed Financial Disclosure Form 
Additional documents such as laboratory reference ranges and certifications will be collected 
during the study.  Ongoing regulatory approvals and notifications as required must also be 
available; these are the responsibility of ImmunoGen. 
13.9. 
Protocol Violations/Deviations 
The Investigator will conduct the study in compliance with the protocol.  The protocol will not 
be initiated until the IRB/IEC and the appropriate regulatory authorities have given 
approval/favorable opinion.  Modifications to the protocol will not be made without agreement 


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of the Sponsor.  Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients.  The IRB/IEC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC.  The Sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations. 
A record of patients screened, but not entered into the study, is also to be maintained.   
When immediate deviation from the protocol is required to eliminate an immediate hazard to 
patients, the Investigator will contact the Sponsor or its designee if circumstances permit, to 
discuss the planned course of action.  Any departures from the protocol must be fully documented 
as a protocol deviation.  Protocol deviations will need to be reviewed by the Medical Monitor and 
may be required to be submitted to the IRB/IEC as per institutional guidelines. 
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/IEC and submitted to the FDA or other applicable international regulatory authority before 
initiation. 
13.10. 
End of Study 
End of study is defined as the date when the last patient on study has withdrawn or been discontinued 
from the study and all necessary follow up visits have been completed in order to complete safety and 
efficacy assessments. 
13.11. 
Study termination 
13.11.1. 
Study Termination 
If the Sponsor, an Investigator, or Study Clinical Monitor discovers conditions arising during the 
study that indicate that the clinical investigation should be halted due to an unacceptable patient 
risk, the study must be terminated after appropriate consultation between ImmunoGen and the 
Investigators.  In addition, a decision on the part of ImmunoGen to suspend or discontinue 
development of the test material may be made at any time.  
Within 15 days of premature closure, ImmunoGen must notify the competent authorities and 
IECs of any member state where the study is being conducted, providing the reasons for study 
closure. 
13.11.2. 
Site Termination 
A specific site may be terminated separate from the general study for, but not limited to, the 
following conditions: 
• The discovery of an unexpected, significant, or unacceptable risk to the patients 
enrolled at the site 
• Failure of the Investigator to enter patients at an acceptable rate 
• Insufficient adherence by the Investigator to protocol requirements 
• Insufficient, incomplete, and/or unevaluable data 


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13.12. 
Access to Source Documentation 
Regulatory authorities, the IEC/IRB, or the Sponsor may request access to all source documents, 
CRFs, and other study documentation for on-site audit or inspection.  Direct access to these 
documents must be guaranteed by the Investigator, who must provide support at all times for 
these activities.  Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed.  On-site review of the CRFs for completeness and clarity, cross-checking with 
source documents, and clarification of administrative matters will be performed. 
13.13. 
Data Generation and Analysis 
The clinical database will be developed and maintained by a CRO or an electronic data capture 
technology provider as designated by ImmunoGen.  ImmunoGen or its designee will be 
responsible for performing study data management activities. 
13.14. 
Retention of Data 
Essential documents should be retained until the following requirements are met: 
• A minimum of 2 years has elapsed following the last approval of a marketing application 
and, 
• there are no pending or contemplated marketing applications, or 
• at least 2 years have elapsed since the formal discontinuation of clinical development of 
the investigational product, or   
• the record retention policies and guidelines for countries in which the study is being 
conducted are followed (whichever is longer) 
It is the responsibility of the Sponsor to inform the Investigator or institution as to when these 
documents no longer need to be retained. 
13.15. 
Financial Disclosure 
The Investigator should disclose any financial interests in the Sponsor as described in 21 CFR 
Part 54 prior to beginning this study and 12 months after the study has completed.  The 
appropriate form will be provided to the Investigator by the Sponsor, which will be signed and 
dated by the Investigator, prior to the start of the study.  
All financial details relating to the Investigator’s participation in this study are provided in the 
separate contract between the institution and ImmunoGen. 
13.16. 
Publication and Disclosure Policy 
The information obtained during the conduct of this clinical study is confidential, and disclosure 
to third parties other than those noted below is prohibited.  All information concerning the 
product as well as any matter concerning the operation of the Sponsor, such as clinical 
indications for the drug, its formula, methods of manufacture and other scientific data relating to 
it, that have been provided by the Sponsor and are unpublished, are confidential and must remain 
the sole property of the Sponsor.  The Investigator will agree to use the information only for the 


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purposes of carrying out this study and for no other purpose unless prior written permission from 
the Sponsor is obtained. 
Information obtained during the conduct of this study will be used by ImmunoGen in connection 
with the development of the study drug.  The study Investigator is obliged to provide 
ImmunoGen with complete test results and all data developed in this study.  The Sponsor has full 
ownership of the original case report forms completed as part of the study.  This information 
may be disclosed to other physicians who are conducting similar studies and to the FDA as 
deemed necessary by the Sponsor.  Patient-specific information may be provided to other 
appropriate medical personnel related to the care of that patient only with patient's prior consent.  
The Investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with 
ImmunoGen, provided ImmunoGen a copy of the draft document intended for publication, and 
obtained ImmunoGen’s written consent for such publication.  All information obtained during 
the conduct of this study will be regarded as confidential.  ImmunoGen will use the information 
for registration purposes and for the general development of the drug. 


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Younes A, Kim S, Romaguera J, et al. Phase I Multidose-Escalation Study of the Anti-CD19 
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Zander T, Scheffler M, Nogova, L, et al. Early prediction of nonprogression in advanced non-
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APPENDIX A.  SCHEDULE OF CLINICAL ASSESSMENTS –SCHEDULE A (Q3W) 
Activity 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles ≥4 
End of  
Treatment 
28-Day 
Follow-up 
(+14 Days) 
Day 
1 
Day 
2 
Day 
8&15 
Day 
1 
Day 
8&15 
Day 18±3 
Day 
1 
Day 
2 
Day 
8&15 
Day 1 
Informed consent 
●a  
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
●a  
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
●a  
 
 
 
 
 
 
 
 
 
 
 
 
Confirm Disease 
Diagnosis/Current Stage and 
Prognostic Index Evaluation 
●a  
 
 
 
 
 
 
 
 
 
 
 
 
Record Baseline Signs and 
Symptoms 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
Review and document 
IC/EC (Sections 3.1 and 
3.1.2) 
●c 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm patient continues to 
satisfy I/E Criteria (Sections 
3.1 and 3.1.2) 
 
● 
 
 
 
 
 
 
 
 
 
 
 
Confirm patient meets 
retreatment criteria (Section 
5.9.3) 
 
 
 
 
● 
 
 
● 
 
 
● 
 
 
Height 
●a 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationb 
●c 
● 
 
● 
● 
● 
 
● 
 
 
● 
● 
● 
Weight 
●c  
● 
 
 
● 
 
 
● 
 
 
● 
● 
● 
Vital signsd 
●c  
● 
● 
 
● 
 
 
● 
● 
 
● 
● 
● 
Pulse oximetry 
 
● 
● 
● 
● 
● 
 
● 
● 
● 
● 
● 
● 
Pulmonary Function Teste 
● 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS 
●c  
● 
 
 
● 
 
 
● 
 
 
● 
● 
● 


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Activity 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles ≥4 
End of  
Treatment 
28-Day 
Follow-up 
(+14 Days) 
Day 
1 
Day 
2 
Day 
8&15 
Day 
1 
Day 
8&15 
Day 18±3 
Day 
1 
Day 
2 
Day 
8&15 
Day 1 
Hematology and Chemistry  
●c  
●f 
 
● 
● 
● 
 
● 
 
● 
● 
● 
● 
Coagulation (PT/INR/ 
aPTT)  
●c  
● f  
 
 
● 
 
 
● 
 
 
● 
 
● 
Urinalysis  
●c  
●f 
 
 
● 
 
 
● 
 
 
● 
 
● 
Pregnancy Test (urine or 
Serum)g 
●c  
● 
 
 
 
 
Even-
numbered 
cycles (2, 
4, 6, etc.)g  
 
 
 
 
 
●g 
Ophthalmic examinationsh 
● 
 
 
 
 
 
Every 
other cycle 
(from 
point at 
which 
toxicity 
first 
reported)h 
 
 
 
 
● 
● 
Schirmer Testh 
● 
For patients who experience treatment-emergent eye disorders, the Schirmer Test will be 
repeated at the first on-study ophthalmic examination and at subsequently if clinically 
indicated 
 
 
Ocular Symptom 
Assessmenth 
 
● 
 
 
● 
 
 
● 
 
 
● 
● 
● 
Radiologic tumor 
assessments 
●a  
 
 
 
 
 
Every 6 
weeks ± 1 
week)i  
 
 
 
 
●j 
●j  
CA125 (Appendix F) 
●c  
 
 
 
 
 
Every 6 
weeks( ± 1 
week)i  
 
 
 
 
●j 
●j  
12-Lead ECG (Section 8.7)k 
●c  
● 
● 
 
 
 
 
● 
● 
 
 
● 
●l 


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Activity 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles ≥4 
End of  
Treatment 
28-Day 
Follow-up 
(+14 Days) 
Day 
1 
Day 
2 
Day 
8&15 
Day 
1 
Day 
8&15 
Day 18±3 
Day 
1 
Day 
2 
Day 
8&15 
Day 1 
Neuropathy assessment, 
including FACT/GOG-
Neurotoxicity Questionnaire 
●c  
● 
 
 
● 
 
 
● 
 
 
● 
 
● 
IMGN853 Infusion 
 
● 
 
 
● 
 
 
● 
 
 
● 
 
 
Corticosteroid Eye Drops 
 
Patients in Expansion Cohort 5 (only) will self-administer corticosteroid eye drops as 
described in Section 5.8.2  
 
 
Lubricating Eye Drops 
 
All patients will self-administer lubricating eye drops as described in Section 5.8.3  
 
 
AE and SAE assessments 
●n 
● 
 
● 
● 
● 
 
● 
● 
● 
● 
● 
● 
Record concomitant 
medications 
●c  
● 
 
● 
● 
● 
 
● 
● 
● 
● 
● 
● 
a. 
Within 28 days prior to the start of Cycle 1, Day 1 
b. Directed physical examination is acceptable while on study treatment.  Full examination is required at screening and the 28-Day Follow Up visit. 
c. 
Within 14 days prior to the start of Cycle 1, Day 1 
d. Vital signs (blood pressure, pulse, respiration rate, and temperature) will be measured as outlined in Section 8.6 and 8.7. 
e. 
Pulmonary Function Tests will be performed within 14 days of receiving the first dose of study treatment (Cycle 1 Day 1) and as clinically indicated. 
f. 
Day 1 laboratory assessments may be performed up to 4 days prior to study agent administration.  Laboratory results must be reviewed prior to each 
scheduled administration of IMGN853.  In the event of severe toxicity, repeat laboratory tests should be performed as necessary until the toxicity resolves or 
stabilizes.  For a complete list of laboratory assessments, refer to Section 8.10. 
g. For WCBP, a urine or serum pregnancy test will be performed at screening, prior to dosing on Day 1, every-other-cycle while on study and at the 28-day 
Follow-Up visit.  Additional testing may be performed in accordance with institutional requirements or local regulation. 
h. Baseline ophthalmic exams will be performed by a board-certified ophthalmologist and will include the following: indirect fundoscopy, slit lamp 
examination under dilatation, intraocular pressure measurement, and corneal photography.  A Schirmer test will be performed at baseline for all patients, and 
for patients who experience ocular symptoms, it will be repeated at the first on-study ophthalmic examination and at subsequently if clinically indicated.  
The baseline exam may be performed within 14 days of Cycle 1, Day 1.  Ocular symptom assessment will be performed prior to the start of each cycle by 
the treating physician or other qualified individual.  If the subject reports ocular symptoms then IMGN853 will be stopped and the subject will then be 
referred to an ophthalmologist for a complete examination (Section 5.8.8).Patients who experience ocular toxicity will have a complete ophthalmologic 
exam performed every other cycle, including patients with blurred vision but normal eye examinations.  All patients will have a complete ophthalmologic 
exam performed at the End of Treatment visit or 28-Day Follow Up. 
i. 
Radiographic tumor assessment by CT scan is to be performed every 6 weeks (± 1 week).  Additionally, patients with elevated CA125 at baseline will have 
CA125 measured at approximately the same time they undergo radiologic assessment.  Patients experiencing CA125 response must have a confirmatory test 
performed at least 28 days after initial response is documented. 


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j. 
If a patient discontinues prior to documentation of PD, a tumor assessment is to be performed at the End of Study visit or 28-Day Follow up visit, if not 
performed within the previous 6 weeks.  Tumor assessments will be performed every 12 weeks until progression is documented or the patient begins a new 
treatment regimen.  Patients who have discontinued study treatment for reasons other than PD will be followed per RECIST 1.1 (Appendix E) every 12 
weeks (±3 weeks) until documentation of PD, starting a subsequent anti-cancer therapy or for up to one year from Cycle 1, Day 1, whichever comes first. 
k. ECGs will be performed as outlined in Section 8.7. 
l. 
As clinically indicated. 
m. Only AEs and SAEs attributed to study procedures are recorded. 
 


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APPENDIX B.  SCHEDULE OF CLINICAL ASSESSMENTS – SCHEDULE B (MODIFIED WEEKLY) 
Activity 
Screening 
Cycle 1 
Cycle 2 and Cycles>4 
Cycle 3 
End of 
Treatment 
28-Day 
Follow-up 
(+14 Days) 
Day 
1 
Day 
2 
Day 
8&15 
Day 1 
Day 8&15 
Day 21±3 
Day 1 
Day 
Day 
8&15 
Informed consent 
●a  
 
 
 
 
 
 
 
 
 
 
 
Demography 
●a  
 
 
 
 
 
 
 
 
 
 
 
Medical History 
●a  
 
 
 
 
 
 
 
 
 
 
 
Confirm Disease 
Diagnosis/Current Stage and 
Prognostic Index Evaluation 
●a  
 
 
 
 
 
 
 
 
 
 
 
Record Baseline Signs and 
Symptoms 
● 
● 
 
 
 
 
 
 
 
 
 
 
Review and document 
IC/EC (Sections 3.1 and 
3.1.2) 
●c 
 
 
 
 
 
 
 
 
 
 
 
Confirm patient continues to 
satisfy I/E Criteria (Sections 
3.1 and 3.1.2) 
 
● 
 
 
 
 
 
 
 
 
 
 
Confirm patient meets 
retreatment criteria (Section 
5.9.3) 
 
 
 
 
● 
 
 
● 
 
 
 
 
Height 
●a 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationb 
●c 
● 
 
● 
● 
Cycles 1-3 
only 
 
● 
 
● 
● 
● 
Weight 
●c  
● 
 
 
● 
 
 
● 
 
 
● 
● 
Vital signsd 
●c  
● 
● 
 
● 
● 
 
● 
● 
 
● 
● 
Pulse oximetry 
 
● 
● 
● 
● 
● 
 
● 
● 
● 
● 
● 
ECOG PS 
●c  
● 
 
 
● 
 
 
● 
 
 
● 
● 


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Activity 
Screening 
Cycle 1 
Cycle 2 and Cycles>4 
Cycle 3 
End of 
Treatment 
28-Day 
Follow-up 
(+14 Days) 
Day 
1 
Day 
2 
Day 
8&15 
Day 1 
Day 8&15 
Day 21±3 
Day 1 
Day 
Day 
8&15 
Hematology and Chemistry  
●c  
●e 
 
● 
● 
● 
 
● 
 
● 
● 
● 
Coagulation (PT/INR/ 
aPTT)  
●c  
● e  
 
 
● 
 
 
● 
 
 
 
● 
Urinalysis  
●c  
● e  
 
 
● 
 
 
● 
 
 
 
● 
Pregnancy Test (urine or 
Serum)f 
●c  
● 
 
 
 
 
Even-
numbered 
cycles (2, 
4, 6, etc.)f  
 
 
 
 
●f 
Ophthalmic examinationsg 
● 
 
 
 
 
 
Every other 
cycle (from 
point at 
which 
toxicity 
first 
reported)g 
 
 
 
● 
● 
Schirmer Testg 
● 
For patients who experience treatment-emergent eye disorders, the Schirmer Test will 
be repeated at the first on-study ophthalmic examination and at subsequently if 
clinically indicated 
 
 
Ocular Symptom 
Assessmentg 
 
● 
 
 
● 
 
 
● 
 
 
● 
● 
Radiologic tumor 
assessments 
●a  
 
 
 
 
 
Every 8 
weeks ± 1 
week)h  
 
 
 
●i 
●i  
CA125 (Appendix F) 
●c  
 
 
 
 
 
Every 8 
weeks( ± 1 
week)h  
 
 
 
●i 
●i  
12-Lead ECG (Section 8.7)j 
●c  
● 
● 
 
 
 
 
● 
● 
 
● 
●k 
Neuropathy assessment, 
including FACT/GOG-
Neurotoxicity Questionnaire 
●c  
● 
 
 
● 
 
 
● 
 
 
 
● 


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Activity 
Screening 
Cycle 1 
Cycle 2 and Cycles>4 
Cycle 3 
End of 
Treatment 
28-Day 
Follow-up 
(+14 Days) 
Day 
1 
Day 
2 
Day 
8&15 
Day 1 
Day 8&15 
Day 21±3 
Day 1 
Day 
Day 
8&15 
IMGN853 Infusion 
 
● 
 
● 
● 
● 
 
● 
 
● 
 
 
AE and SAE assessments 
●l 
● 
 
● 
● 
● 
 
● 
● 
● 
● 
● 
Record concomitant 
medications 
●c  
● 
 
● 
● 
● 
 
● 
● 
● 
● 
● 
a. 
Within 28 days prior to the start of Cycle 1, Day 1 
b. Directed physical examination is acceptable while on study treatment.  Full examination is required at screening and the 28-Day Follow Up visit. 
c. 
Within 14 days prior to the start of Cycle 1, Day 1 
d. Vital signs (blood pressure, pulse, respiration rate, and temperature) will be measured as outlined in Section 8.6 and 8.7. 
e. 
Day 1 laboratory assessments may be performed up to 4 days prior to study agent administration.  Laboratory results must be reviewed prior to each 
scheduled administration of IMGN853.  In the event of severe toxicity, repeat laboratory tests should be performed as necessary until the toxicity 
resolves or stabilizes.  For a complete list of laboratory assessments, refer to Section 8.10. 
f. 
For WCBP, a urine or serum pregnancy test will be performed at screening, prior to dosing on Day 1, every-other-cycle while on study and at the 28-day 
Follow-Up visit.  Additional testing may be performed in accordance with institutional requirements or local regulation. 
g. Baseline ophthalmic exams will be performed by a board-certified ophthalmologist and will include the following: indirect fundoscopy, slit lamp 
examination under dilatation, intraocular pressure measurement, and corneal photography.  A Schirmer test will be performed at baseline for all patients, 
and for patients who experience ocular symptoms, it will be repeated at the first on-study ophthalmic examination and at subsequently if clinically 
indicated.  May be performed within 14 days of Cycle 1, Day 1.  Ocular symptom assessment will be performed prior to the start of each cycle by the 
treating physician or other qualified individual.  If the subject reports ocular symptoms then IMGN853 will be stopped and the subject will then be 
referred to an ophthalmologist for a complete examination (Section 5.8.8).  Patients who experience ocular toxicity will have a complete ophthalmologic 
exam performed every other cycle, including patients with blurred vision but normal eye examinations.  All patients will have a complete 
ophthalmologic exam performed at the End of Treatment visit or 28-Day Follow Up. 
h. Radiographic tumor assessment by CT scan is to be performed every 8 weeks (± 1 week).  Additionally, patients with elevated CA125 at baseline will 
have CA125 measured at approximately the same time they undergo radiologic assessment.  Patients experiencing CA125 response must have a 
confirmatory test performed at least 28 days after initial response is documented. 
i. 
If a patient discontinues prior to documentation of PD, a tumor assessment is to be performed at the End of Study visit or 28-Day Follow up visit, if not 
performed within the previous 8 weeks.  Tumor assessments will be performed every 12 weeks until progression is documented or the patient begins a 
new treatment regimen.  Patients who have discontinued study treatment for reasons other than PD will be followed per RECIST 1.1 (Appendix E) 
every 12 weeks (±3 weeks) until documentation of PD, starting a subsequent anti-cancer therapy or for up to one year from Cycle 1, Day 1, whichever 
comes first. 
j. 
ECGs will be performed as outlined in Section 8.7. 
k. As clinically indicated. 
l. 
Only AEs and SAEs attributed to study procedures are recorded. 
 


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APPENDIX C.  PHARMACODYNAMIC, PHARMACOKINETIC AND IMMUNOGENICITY 
ASSESSMENTS 
Activity 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles 
≥ 4 
End of 
Study/28-
Day Follow 
Up 
Study Day 
Study Day 
Study Day 
Day 1  
1 
2 
3 
4 or 5 
8 
15 
22 
1 
8±3 
1 
2 
3 
4 or 5 
8 
15 
22 
 
 
Fresh tumor biopsya 
(Section 7.1.1 and 
7.3.1) 
●a,b 
 
 
 
 
 
 
 
 
●a,d 
 
 
 
 
 
 
 
 
● 
 
IHC archived tumor 
tissue (Section 
7.1.1) 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood samples for 
measurement of 
homocysteine and 
methylmalonate 
(Section 7.2.3) 
 
●c  
 
 
 
 
 
 
 
● 
 
 
 
 
 
 
 
 
● 
 
Blood samples for 
FcγR 
polymorphisms 
(Section 7.2.1) 
 
●c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Molecular 
pathology (e.g. 
genomic data) 
documentation 
 
●c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood samples for 
PK (Cycles 1&3) 
and 
immunogenicity 
assessmentse 
(Section 6) 
 
● 
● 
● 
● 
● 
● 
● 
●  
 
●  
● 
● 
● 
● 
● 
● 
● 
● 
● 
 


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a. 
All patients in MTD Expansion Cohort 3 (relapsed EOC) will be required to undergo tumor biopsy during screening and in Cycle 2, on Day8 (±3 days).  
Additionally, patients enrolled to the dose escalation phase of the study who do not have serous or endometrioid ovarian cancer, serous or endometrioid 
endometrial cancer, NSCLC adenocarcinoma or BAC and who do not have archival tumor tissue to submit for FOLR1 expression, will be required to 
undergo tumor biopsy during the screening period in order to confirm eligibility.  In addition, patients in the MTD expansion Cohort 3 who relapsed 
after showing clinical benefit will be asked to undergo an optional biopsy at the time of progression to help understand the mechanism of resistance. 
b. Within 28 days prior to the start of Cycle 1, Day 1 
c. 
Predose  
d. Cycle 2 (Day 8±3 days) and at the end of the study. These samples will be collected for patients enrolled in Expansion Cohort 3 (relapsed ovarian cancer 
only). 
e. 
Blood samples for PK analysis will be taken in Cycles 1 and 3 at the following timepoints: Schedule A - Day 1-predose and within 10 minutes of 
infusion completion and 2, and 4 hours post infusion (±10 minutes).  Single samples will also be taken on Days 2 and 3 (24 and 48 hours post infusion; 
(±2 hours).  A single blood sample will be drawn on Days 4 or 5, 8 and 15 (±24 hours post dose).  Schedule B - Blood samples for PK analysis will be 
taken in Cycles 1 and 3 at the following timepoints: Days 1 & 15 -predose and within 10 minutes of infusion completion and 2 and 4 hours post infusion 
(±10 minutes).  A single sample will be taken on Day 2, 24 hours post infusion (±2 hours).  On Day 8, a sample will be taken predose and within 10 
minutes of infusion completion.  On Day 16, a single sample will be taken 24 hours post infusion (±2hours).  On Day 22, a single sample will be drawn 
(+24 hours).  A single pre-dose sample will be collected before the IMGN853 infusion and following completion of the infusion in Cycles 2, 4, 5 and 6.  
For both schedules - single, predose samples will be collected predose and following completion of the infusion in Cycles 2, 4, 5 and 6, and a single 
blood sample for immunogenicity, will be taken on Day 1 of Cycles 2, 4, and 5 and at the End of Treatment and Follow-up visits. 
 


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APPENDIX D.  EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS SCALE 
(Oken 1982) 
GRADE 
SCALE  
0 
Fully active, able to carry out all pre-disease performance without restriction.  
(Karnofsky 90-100) 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light housework, office work.  
(Karnofsky 70-80) 
2 
Ambulatory and capable of all self-care but unable to carry out work 
activities.  Up and about more than 50% of waking hours.  (Karnofsky 50-
60) 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.  (Karnofsky 30-40) 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair.  (Karnofsky 10-20) 
 
 
 
 


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APPENDIX E.  RESPONSE DEFINITION (RECIST 1.1) 
(Eisenhauer 2009) 
DEFINITIONS 
Baseline:Baseline is defined as the most recent assessment performed prior to the first dose of 
study treatment.  Baseline assessments must be performed within the period defined in the 
protocol eligibility criteria. 
Measurable Lesions: Except for lymph nodes (described below), measurable lesions are defined 
as those that can be accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥ 10 mm with CT scan (if CT scans have slice thickness greater than 5 mm, the 
minimum size of a measurable lesion is twice the slice thickness).  
• To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm).  At baseline and in follow-up, only the short axis will be measured and recorded. 
• MRI may be substituted for contrast-enhanced CT for lesions at some anatomical sites, but 
not for lesions in the lungs.  The minimum size for measurability is the same as for CT (10 
mm) as long as the scans are performed with slice thickness of 5 mm and no gap.  If MRI is 
performed with thicker slices, the size of a measurable lesion at baseline should be twice the 
slice thickness.  In the event there are inter-slice gaps, this also needs to be considered in 
determining the size of measurable lesions at baseline. 
Non-measurable lesion: all other lesions (or sites of disease) including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered 
non-measurable.  
• Lymph nodes that have a short axis < 10mm are considered non-pathological and are not 
to be recorded or followed.  
• Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, are to be identified as target lesions and measured 
and recorded at baseline.  
• Target lesions are to be selected on the basis of their size (lesions with the longest 
diameter) to represent all involved organs, and to be those that lend themselves to 
reproducible repeated measurements.  
• It may be the case that on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. 
• Target lesions will be measured at each assessment (longest axis for non-nodal lesions, 
shortest axis for measurable malignant nodal lesions). 


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Non-target lesions: All other lesions (or sites of disease) including all non-measurable lesions 
(including pathological lymph nodes with ≥ 10 to < 15 mm short axis) and all measurable lesions 
over and above the 5 target lesions are to be identified as non-target lesions and recorded at 
baseline.  
• Measurements of these lesions are not required, but the presence, absence, 
unequivocal progression of each is to be recorded throughout follow-up.  
• Lymph nodes that have a short axis < 10 mm are considered non-pathological and are 
not to be recorded or followed. 
Special Considerations 
Clinical Examination of Lesions: Superficial or visible lesions that cannot be assessed by CT 
scan or MRI will only be considered for response assessment if these lesions are biopsy-proven 
metastatic lesions and ≥ 10 mm in diameter.  These lesions will be considered non-measurable 
and thus non-target for response assessment. 
Cystic lesions: Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesion.  
Bone lesions: Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions.  However, these techniques can be used to confirm the 
presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• Blastic bone lesions are non-measurable. 
Lesions with prior local treatment:  Lesions situated in a previously irradiated area, or in an 
area subjected to other locoregional therapy, are usually not considered measurable; however, if 
they meet the following criteria, they may be considered for study: 
• there has been prior documented progression in the lesion by at least 2 sequential CT or 
MRI scans performed after the completion of radiation, or  
• histopathological evidence of progression 
Additionally, if such lesions meet the criteria for measurability, they may be considered target 
lesions. 
Imaging Methods 
The same method of assessment and the same technique used to characterize each identified and 
reported lesion at baseline should be used during each follow-up assessment.  Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed 


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cannot be imaged but are assessable by clinical exam (referring to biopsy-proven visible 
lesions(s) at the vaginal apex).  
Chest X-ray: Lesions that are identified on chest X-ray must be confirmed and followed by CT 
scan.  If there is/are pre-existing chest lesion(s) before the baseline tumor assessment, a chest X-
ray is not necessary to assess those lesions.  The pre-existing chest lesion(s) must be assessed at 
baseline and followed by CT scans. 
Conventional CT or MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion is twice the slice thickness.  MRI is 
also acceptable in certain situations (e.g., for body scan) except for lung.  
CA-125: Tumor marker CA125 alone cannot be used to assess response or determine 
progression; however, it will be followed.  CA125 measurements should be scheduled to 
approximately coincide with radiological assessment (every 6 weeks±1 week).  Patients whose 
CA125 is above the upper normal limit at baseline will need to have their values normalize to ≤ 
upper normal limit, in addition to complete disappearance of measurable or evaluable disease, in 
order to be considered in complete response. 
Other methods of assessment, PET-CT, ultrasound and FDG-PET should not be used for 
response assessment in this study. 
Time Point Assessments 
Patients will have tumor measurements performed within 28 days prior to baseline and every 6 
weeks thereafter (±1 week). 
At baseline, tumors and lymph nodes are classified and documented as target or non-target per 
the definitions provided above.  It is possible to record multiple non-target lesions involving the 
same organ as a single item (e.g., ‘multiple liver metastases’).  
At all post-baseline evaluations, the baseline classification (target, non-target) is to be maintained 
and lesions are to be documented and described in a consistent fashion over time (e.g., recorded 
in the same order on source documents and CRFs). 
For target lesions, measurements should be taken and recorded in metric notation.  All tumor 
measurements must be recorded in millimeters. 
At each assessment, a sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported.  The baseline sum of the diameters 
(SoD) will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease.  The lowest SoD (nadir) since, and including, the baseline 
value will be used as reference for evaluating progression. 
After baseline, the actual size of the target lesion should be documented, if possible, even if the 
lesions become very small.  If in the opinion of the radiologist, the lesion has likely disappeared, 0 
mm should be recorded.  If the lesion is present but too small to measure, an indicator of “too small 
to measure” will be provided on the CRF (a default value of 5 mm will be imputed during analysis).  


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Non-target lesions are to be assessed qualitatively (present, resolved, or unequivocal 
progression) and new lesion, if any, are to be documented separately. 
At each evaluation, a time point response is to be determined for target lesions, non-target 
lesions, new lesions and overall. 


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Time Point Response Criteria 
Target Lesion Time Point Response (TPR) 
Complete Response (CR) 
Disappearance of all target lesions.  All pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 
mm.  
Partial Response (PR) 
At least 30% decrease in the SoD of target lesions, taking as reference 
the baseline SoD 
Progressive Disease (PD) 
At least a 20% increase in the SoD of target lesion, taken as reference 
the smallest (nadir) SoD since and including baseline.  In addition to the 
relative increase of 20%, the SoD must also demonstrate an absolute 
increase of at least 5 mm. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD. 
Not Applicable (N/A) 
No target lesions identified at baseline 
Unable to Evaluate (UE) 
One or more target lesions are not imaged and the remainder of the SoD 
compared with the nadir SoD does not meet the criteria for PD 
If the target lesion for a patient meets the criteria for both PR and PD at a given time point, the target 
lesion response is PD. 
If the nadir SoD is 0 (i.e., the patient had a prior target lesion CR), the re-appearance of any prior target 
lesions to any degree constitutes PD. 
Non-Target Lesion TPR 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor 
marker level if tumor marker at baseline is above the upper normal 
limit.  All lymph nodes must be non-pathological in size (< 10 mm short 
axis)  
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance of 
CA125 above the normal limits if CA125 at baseline is above the upper 
normal limit 
Progressive Disease (PD) 
Unequivocal progression of non-target lesions.  Unequivocal 
progression should not normally trump target lesion status.  It must be 
representative of overall disease status change, not a single lesion 
increase. 
Not Applicable (N/A) 
No non-target lesions identified at baseline 
Unable to Evaluate (UE) 
One or more non-target lesions are not imaged and the remaining non-
target lesions do not meet the criteria for PD 


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If the target lesion for a patient meets the criteria for both PR and PD at a given time point, the target 
lesion response is PD. 
If the nadir SoD is 0 (i.e., the patient had a prior target lesion CR), the re-appearance of any prior target 
lesions to any degree constitutes PD. 
 
New Lesion TPR 
Yes 
Lesion present at follow-up visit either for the very first time or re-appearing 
(i.e., lesion was present at baseline, disappeared at a follow-up visit and re-
appeared later). 
No 
No new lesions present at follow up 
Unable to Evaluate (UE) 
Patient non assessed or incompletely assessed for new lesion 
Determining Overall TPR 
Target Lesion TPR 
Non-Target TPR 
New Lesions TPR 
Overall TPR 
CR 
CR or NA 
No 
CR* 
CR 
Non-CR/non-PD 
No 
PR* 
CR 
UE 
No 
PR* 
PR 
Non-PD or NA or UE 
No 
PR* 
SD 
Non-PD or NA or UE 
No 
SD 
UE 
Non-PD 
No 
UE 
PD 
Any 
No or Yes or UE 
PD 
Any 
PD 
No or Yes or UE 
PD 
Any 
Any 
Yes 
PD 
NA 
CR 
No 
CR* 
NA 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Non-PD 
Non-PD 
UE 
UE 
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; UE, unable 
to evaluate; NA, not applicable (no such lesions at screening); Any, CR, PR, SD, PD, NA or UE. 
The overall response at a given time point does not depend upon the overall response assigned at any 
prior time-point.   
 
Best Overall Response 


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Best overall response is determined once all the data for the patient is known. Best overall 
response is defined as the best response across all time-points.  


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APPENDIX F.  GYNECOLOGIC CANCER INTERGROUP (GCIG 
CRITERIA FOR EVALUATION OF CA-125 
(Rustin 2004) 
On the basis of the available data and extensive discussions among the cooperative groups within the 
GCIG, it is recommended that the following definition of response be used in ovarian cancer trials so 
that response can be measured by either RECIST or CA 125 criteria.  If the response is evaluable by both 
criteria, then the date of response will be the date of the earlier of the two events. 
Definition of response: 
≥ 50% reduction in CA 125 levels from baseline 
• the response must be confirmed and maintained for at least 28 days 
• the pretreatment sample must be ≥ 2.0 times the UNL and within 2 weeks prior to 
starting treatment 
• the date of response corresponds to the date when the CA 125 level is first reduced by 
50%  
To calculate CA 125 responses accurately, the following rules apply:  
1) Intervening samples and the 28-day confirmatory sample must be less than or equal to (within an 
assay variability of 10%) the previous sample 
2) Variations within the normal range of CA 125 levels will not interfere with the response definition.  
Timing of CA125 assessments: 
The Gynecologic Cancer Intergroup (GCIG) recommends that CA 125 measurements be taken at specific 
time intervals.  
• The first sample would be collected within 2 weeks before treatment is started 
• Later samples would be collected at intervals of 2–4 weeks during treatment and at 
intervals of every two or three months during follow-up.  
• For each patient, the same assay method must be used and the assay must be tested in 
a quality-control scheme.  Patients are not evaluable by CA 125 if they have received 
mouse antibodies or if there has been medical and/or surgical interference with their 
peritoneum or pleura during the previous 28 days.  
This CA 125 response definition has been produced to evaluate relapse therapy.  If assessing therapy 
that includes two treatment modalities for relapse (e.g., surgery and chemotherapy), any CA 125 
response results from both treatments.  CA 125 cannot distinguish between the effects of each 
treatment.  To calculate response rates in protocols, an intent-to-treat analysis should be used that 
includes all patients with an initial CA 125 level of at least twice the upper limit of normal as eligible and 
evaluable.  In addition to calculating response rates in protocols, it is advisable to record those patients 
who have both a CA 125 response and whose CA 125 level falls to within the normal range. 


IMGN853 
 
Dated  02 September 2015 
Protocol 0401 
 
ImmunoGen, Inc. 
Confidential 
Page 138 of 138 
 
APPENDIX G.  FACT/GOG-NEUROTOXICITY QUESTIONNAIRE, 
VERSION 4.0 
(Cella 1993) 
By circling one (1) number per line, please indicate how true each statement has been for you during the 
past 7 days. 
ADDITIONAL CONCERNS 
Not 
at all 
A little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
I have numbness or tingling in my hands……… 
0 
1 
2 
3 
4 
I have numbness or tingling in my feet………… 
0 
1 
2 
3 
4 
I feel discomfort in my hands………………. 
0 
1 
2 
3 
4 
I feel discomfort in my feet………………… 
0 
1 
2 
3 
4 
I have joint pain or muscle cramps…………… 
0 
1 
2 
3 
4 
I feel weak all over…………………………… 
0 
1 
2 
3 
4 
I have trouble hearing………………………… 
0 
1 
2 
3 
4 
I get a ringing or buzzing in my ears………… 
0 
1 
2 
3 
4 
I have trouble buttoning buttons……………… 
0 
1 
2 
3 
4 
I have trouble feeling the shape of small 
objects when they are in my hand…………… 
0 
1 
2 
3 
4 
I have trouble walking……………………… 
0 
1 
2 
3 
4 
 
 
 
 
 

SAP_001.pdf: 
ImmunoGen, Inc./ Protocol: lMGN 0401 
Novella Clinical (Confidential) Project #501 
5 
·-))·-
Novello 
Cl.lNICAL. 
• IMMUNOGEN, INC.
ImmunoGen, Inc. 
Protocol#: 0401 
A Phase l, First-in-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics oflMGN853 in Adults with Ovarian Cancer and other FOLRl­
Positive Solid Tumors 
Statistical Analysis Plan 
Version 5.0 
Document last saved: 1-February-2018
Prepared for: 
Prepared bv: 
 
ImmunoGen, Inc. 
Novella Clinical 
830 Winter Street 
1700 Perimeter Park Drive 
Waltham, MA 02451 
Morrisville, NC 27560 
Approvals 
Date 
munoGen, Inc. 
 lmmunoGen, Inc. 
 Novella Clinical 
lMGN853 0401 SAP V5_1Febl8_Final 
Date 
Date 
p. I 
NCT#: NCT01609556


ImmunoGen, Inc. / Protocol: IMGN 0401 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
INTRODUCTION ........................................................................................................7 
1.1. 
Background ...................................................................................................................7 
2. 
STUDY DESIGN .........................................................................................................8 
2.1. 
Protocol Objectives .......................................................................................................8 
2.1.1. 
Primary .........................................................................................................................8 
2.1.2. 
Secondary .....................................................................................................................9 
2.1.3. 
Exploratory ...................................................................................................................9 
2.2. 
Study Endpoints ............................................................................................................9 
2.2.1. 
Primary .........................................................................................................................9 
2.2.2. 
Secondary .....................................................................................................................9 
2.2.3. 
Exploratory .................................................................................................................10 
2.3. 
Study Overview ..........................................................................................................11 
2.3.1. 
Dose Escalation ..........................................................................................................11 
2.3.1.1. 
Schedule A ..................................................................................................................11 
2.3.1.2. 
Schedule B ..................................................................................................................12 
2.3.2. 
Study Population .........................................................................................................12 
2.3.2.1. 
Dose Escalation ..........................................................................................................12 
2.3.2.2. 
Dose Expansion ..........................................................................................................12 
2.3.2.3. 
Enrollment ..................................................................................................................13 
2.3.3. 
Sample Size ................................................................................................................13 
2.3.3.1. 
Dose Escalation ..........................................................................................................13 
2.3.3.2. 
Dose Expansion ..........................................................................................................13 
2.3.4. 
Treatment Randomization ..........................................................................................14 
2.3.5. 
Schedule of Assessments ............................................................................................14 
2.4. 
Interventions ...............................................................................................................14 
2.4.1. 
Clinical Trial Material ................................................................................................14 
2.4.1.1. 
Schedule A ..................................................................................................................14 
2.4.1.2. 
Schedule B ..................................................................................................................14 
2.5. 
Study Procedures ........................................................................................................14 
3. 
GENERAL ANALYTICAL CONSIDERATIONS ...................................................15 


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3.1. 
Data Sources ...............................................................................................................15 
3.2. 
Definition of Baseline .................................................................................................15 
3.3. 
Missing Data ...............................................................................................................15 
3.4. 
Outliers .......................................................................................................................16 
3.5. 
Multiple Study Centers ...............................................................................................16 
3.6. 
Interim Analyses or Timing of Analyses ....................................................................16 
3.7. 
Analysis Populations ..................................................................................................16 
3.7.1. 
Safety Population ........................................................................................................16 
3.7.2. 
Response-Evaluable Population .................................................................................16 
3.7.3. 
CA-125 Evaluable Population ....................................................................................17 
3.8. 
Data Display Characteristics .......................................................................................17 
4. 
PATIENT ACCOUNTABILITY ...............................................................................17 
4.1. 
Patient Characteristics ................................................................................................17 
4.1.1. 
Demography ...............................................................................................................18 
4.1.2. 
Height and Body Weight ............................................................................................18 
4.1.3. 
Cancer History ............................................................................................................18 
4.1.4. 
Medical History ..........................................................................................................18 
4.2. 
Patient Disposition ......................................................................................................18 
4.2.1. 
Protocol Deviations and Population Inclusions ..........................................................19 
5. 
EFFICACY ANALYSES ...........................................................................................19 
5.1. 
Efficacy Outcomes ......................................................................................................19 
5.1.1. 
Best Overall Response ................................................................................................19 
5.1.2. 
Objective Response Rate ............................................................................................20 
5.1.3. 
Progression Free Survival (PFS) ................................................................................20 
5.1.4. 
Duration of Response .................................................................................................20 
5.1.5. 
Time to Progression ....................................................................................................20 
5.1.6. 
Time to Response .......................................................................................................21 
5.1.7. 
CA-125 Response .......................................................................................................21 
5.1.8. 
Overall Survival ..........................................................................................................21 
5.2. 
Analysis of Efficacy Outcomes ..................................................................................21 
5.2.1. 
ORR ............................................................................................................................21 
5.2.2. 
PFS ..............................................................................................................................21 
5.2.3. 
DOR ............................................................................................................................22 


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5.2.4. 
TTP .............................................................................................................................22 
5.2.5. 
TTR .............................................................................................................................22 
5.2.6. 
OS ...............................................................................................................................22 
5.2.7. 
Subgroup Analysis of Efficacy Outcomes in EOC Expansion Cohorts .....................22 
5.2.8. 
Efficacy Data Listings ................................................................................................22 
6. 
SAFETY ANALYSES ...............................................................................................23 
6.1. 
Exposure .....................................................................................................................23 
6.2. 
Adverse Events ...........................................................................................................23 
6.3. 
Dose Limiting Toxicities (DLTs) ...............................................................................25 
6.4. 
Clinical Laboratory Results ........................................................................................26 
6.5. 
Immunogenicity ..........................................................................................................27 
6.6. 
Vital Signs and Pulse Oximetry ..................................................................................27 
6.7. 
Electrocardiograms .....................................................................................................27 
6.8. 
Concomitant Medications ...........................................................................................28 
6.9. 
Concomitant Procedures .............................................................................................28 
6.10. 
Ophthalmic Examinations ..........................................................................................29 
6.11. 
Ocular Symptom Assessments ...................................................................................29 
6.12. 
Transfusions ................................................................................................................29 
6.13. 
Physical Examination .................................................................................................29 
6.14. 
Pulmonary Function Tests ..........................................................................................29 
6.15. 
Eastern Cooperative Oncology Group Performance Status (ECOG PS) ....................29 
6.16. 
FACT/GOG Neurotoxicity Questionnaire ..................................................................29 
7. 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES ...................29 
8. 
EXPLORATORY BIOMARKER ANALYSES ........................................................29 
 
LIST OF TABLES 
Table 1: 
History of Protocol and Amendments to the Protocol ..................................................7 
Table 2: 
Initial Planned Dose Levels for Schedule A ...............................................................11 
Table 3: 
Initial Planned Dose Levels for Schedule B ...............................................................12 
Table 4: 
Probability of Observing ≥ X Events (Response or DLT) for a 40 Patient 
Cohort .........................................................................................................................14 
Table 5: 
Analysis Populations ..................................................................................................16 
 


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LIST OF ABBREVIATIONS 
Abbreviation or Specialist 
Term 
Explanation 
AE  
Adverse event  
ADA 
Anti-drug antibody 
AIBW 
Adjusted Ideal Body Weight 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase  
AUC  
Area under the time-concentration curve  
BAC 
Bronchioloalveolar carcinoma 
BOR 
Best Overall Response 
CA-125 
Cancer Antigen 125, a marker for certain cancers 
CM 
Concomitant medication 
Cmax  
Maximum plasma drug concentration  
CR  
Complete response/remission  
CRC  
Cohort Review Committee  
CTC 
Circulating Tumor Cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DLT  
Dose limiting toxicity  
DOR 
Duration of Response 
eCRF  
Electronic case report form  
ECG  
Electrocardiogram  
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EOC 
Epithelial Ovarian Cancer 
FACT/GOG 
Functional Assessment of Cancer Therapy, Gynecologic Oncology 
Group 
FIH 
First in Human 
FOLR1 
Folate receptor 1 
IHC 
Immunohistochemistry 
MedDRA 
Medical Dictionary for Regulatory Activities 


ImmunoGen, Inc. / Protocol: IMGN 0401 
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Abbreviation or Specialist 
Term 
Explanation 
MMA 
Methylmalonic acid 
MTD 
Maximum Tolerated Dose 
NE 
Not Evaluable 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Relapsed/progressive disease 
Pd 
Pharmacodynamic 
PFS 
Progression-Free Survival 
PgP 
P-glycoprotein 
PK 
Pharmacokinetics 
PR 
Partial Response/remission 
Q3W 
Administration every 3 weeks 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
t 1/2 
Terminal half life 
TBL 
Total Bilirubin 
TEAE 
Treatment-emergent adverse event 
Tmax  
Time at which Cmax occurs  
TTP 
Time-to-Progression 
TTR 
Time to Response 
ULN 
Upper Limit of Normal 
Vss 
Volume of distribution at steady state 
WHO Drug 
World Health Organization drug dictionary 
 


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1.
INTRODUCTION
1.1. 
Background
IMGN853 0401 is an open label, non-randomized, first-in-human (FIH), dose-escalation and 
dose-expansion Phase 1 study.  It is designed to identify the maximum tolerated dose (MTD) 
of IMGN853 when administered intravenously as a single agent in adult patients with 
relapsed or refractory epithelial ovarian cancer (EOC) and other FOLR1-positive solid 
tumors (dose escalation) and enable further evaluation of the recommended Phase 2 dose 
(RP2D).  The safety, tolerability, pharmacokinetics (PK), pharmacodynamics (Pd), 
immunogenicity, and preliminary anti-tumor activity of IMGN853 will be characterized.   
During dose escalation two dosing schedules were evaluated:  Schedule A (IMGN853 
administered on Day 1, with cycles repeating every 21 days (Q3W)) and Schedule B 
(IMGN853 administered on Days 1, 8, and 15, with cycles repeating every 28 days).  Dose 
expansion began once the Schedule A MTD was identified and a dose was selected for 
further exploration.  Schedule B evaluation was stopped prior to identifying the MTD 
The purpose of this Statistical Analysis Plan (SAP) is to outline the statistical principles 
which will be used to analyze and present the data from this study.  This SAP includes a 
description of the study endpoints, stopping rules, and analysis populations.  Table, Figure, 
and Listing shells will be supplied in a separate document.  The SAP may be modified until 
the time of data base lock.  Any deviations from the SAP, including any deviations after the 
time of database lock, will be documented in the study report.   
The protocol for IMGN853 0401 describes the general approach to analysis of data from the 
study.  This Statistical Analysis Plan is based on Amendment 10 of Clinical Study Protocol 
IMGN853 0401.  A brief history of the protocol amendments is presented in Table 1.   
Table 1: 
History of Protocol and Amendments to the Protocol 
Version 
Approval Date 
Changes Expected to Impact the SAP 
Protocol 
01Mar2012 
Amendment 1 
13Apr2012 
Lowered starting dose, added additional escalation cohort 
Amendment 2 
18Oct2012 
Endometrioid endometrial cancer was added to the list of 
tumors that could be enrolled without proof of FOLR1+. 
Amendment 3 
07Mar2013 
Secondary endpoints PFS, TTP, and DoR added. 
Amendment 4 
13May2013 
Assay for Circulating Tumor Cells (CTCs) and other Pd 
assessments added 
Amendment 5 
18Oct2013 
FLT-PET was removed from the protocol 
Additional expansion cohort added for patients with 
endometrial cancer.  Dosing procedure modified to 
employ adjusted ideal body weight.  Collection of CTCs 
in selected patients added. 


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Table 1: 
History of Protocol and Amendments to the Protocol (Continued) 
Version 
Approval Date 
Changes Expected to Impact the SAP 
Amendment 6 
27Nov2013 
Additional dosing schedule added (Schedule B).  
Pd/Biomarker studies revised.  Increased number of 
patients.  Data capture of Ocular symptom assessments 
separated from Ophthalmic exams. 
Amendment 7 
13Aug2014 
Estimated number of patients has been increased.  Size of 
MTD expansion cohorts was revised.  Circulating Tumor 
Cell analyses have been removed from the study. 
Assessment of objective response rate for expansion 
cohorts has been added to the protocol.  
Amendment 8 
26Aug2014 
None 
Amendment 9 
25Feb2015 
Updated exploratory objectives and endpoints. 
Updated the number of patients to be enrolled in Dose 
Expansion Cohort 1.  Estimated number of patients 
planned therefore has increased.   
Added language to allow for selection of a less frequent 
dosing regimen for Schedule B if dosing is deemed sub-
optimal. 
Removed requirement for confirmation of the objective 
responses. 
Use of lubricating eye drops made mandatory.  Increased 
requirements for eye exams. 
Amendment 10 
02Sep2015 
Schedule B dosing discontinued.  A total of five specific 
dose expansion cohorts were defined: 
Cohort 1:Platinum resistant EOC 
Cohort 2:Advanced or recurrent uterine cancer 
Cohort 3: Relapsed ovarian cancer amendable to biopsy 
Cohort 4: Relapsed/refractory NSCLC adenocarcinoma 
or BAC 
Cohort 5: Relapsed EOC, using corticosteroid eye drops 
2.
STUDY DESIGN
2.1. 
Protocol Objectives
All objectives apply to both dosing schedules and all cohorts unless otherwise noted. 
2.1.1. 
Primary 
•
Determine MTD and RP2D of IMGN853 when administered intravenously


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2.1.2. 
Secondary 
•
Evaluate the safety and tolerability of IMGN853
•
Evaluate the effectiveness of primary, prophylactic steroid eye drops in
preventing or lessening keratopathy and/or blurred vision
•
Characterize the PK of IMGN853 when administered intravenously
•
Describe any preliminary evidence of IMGN853 antitumor activity
•
Characterize the immunogenicity of IMGN853
2.1.3. 
Exploratory
•
Determine the predictive value of FOLR1 expression on tumor cells as a
biomarker for IMGN853 anti-tumor activity
•
Explore the association of molecular alterations in oncogenic genes and pathways,
and established molecular tumor subtypes (e.g. the four molecular subtypes of
high grade serous ovarian cancer) with FOLR1 expression and IMGN853
antitumor activity
•
Evaluate any additional tumor or blood based biomarkers that may be associated
with sensitivity or resistance to IMGN853 (e.g. MDR1 expression,
polymorphism)
•
MTD Expansion Cohort#3 only: Characterization of post-dose biopsy samples to
evaluate:
−
Presence of IMGN853 in tumor
−
Pd activity measured as changes in Ki67 from baseline, and/or other
biomarkers based on emerging data
−
Changes in FOLR1 expression post-treatment and disease progression
−
Changes in the numbers of tumor infiltrating immune cells after treatment
with IMGN853
−
Mechanism of relapse or treatment emerging resistance to IMGN853
2.2. 
Study Endpoints 
2.2.1. 
Primary 
The primary endpoints: 
•
MTD
•
RP2D.
2.2.2. 
Secondary 
Secondary endpoints include: 


ImmunoGen, Inc. / Protocol: IMGN 0401 
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•
Treatment-emergent adverse events (TEAEs) and clinically significant ≥ Grade 3
changes in laboratory test results, physical examination, ECGs or vital signs
•
Treatment-emergent ocular adverse events
•
PK parameters: Cmax, AUC, terminal half-life (t½), clearance (Cl), volume of
distribution at steady state (Vss), Tmax, AUC
•
Number of patients with RECIST 1.1 criteria (see Protocol Appendix E) clinical
responses and/or number of patients with GCIG Cancer Antigen 125 (CA-125)
criteria clinical responses (see Protocol Appendix F)
−
Objective response rate (ORR; MTD Expansion Cohorts # 1 and 2)
−
Duration of response (DOR)
−
Progression-free survival (PFS)
−
Time-to-progression (TTP)
•
Human Anti-Drug Antibody (HADA) and Human Anti-Human Antibody
(HAHA) levels
2.2.3. 
Exploratory 
Exploratory endpoints include: 
•
Evaluate FOLR1 expression by immunohistochemistry (IHC) (protein), qRT-PCR
(mRNA) or other quantitative methods
•
Establish mutational status, copy number alterations, and gene structure
rearrangements in known oncogenic genes and pathways (e.g. mutations in p53,
BRCA1/2 in ovarian cancer, PTEN/PIK3CA in endometrial cancer, EGFR,
KRAS in NSCLC)
•
Infer somatic/germline status of BRCA1/2 mutations using data generated from
tumor tissue
•
Analyze mRNA and/or protein expression of genes known to be over expressed or
silenced in cancer, as well as genes associated with molecular cancer subtypes
•
Evaluate expression and polymorphism of drug transporters such as MDR1 (i.e.
P-glycoprotein (PgP) )
•
Evaluate additional biomarkers identified in preclinical studies that may be
associated with IMGN853 sensitivity or resistance
•
MTD Expansion Cohort #3 Only:
−
Measure binding of IMGN853 to tumor cells in post-treatment biopsy by anti-
Maytansine IHC
−
Compare the number of Ki-67 positive cells in baseline biopsies with that of
post-treatment biopsies using IHC


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−
Compare FOLR1 expression in archival samples, baseline, and post-treatment
(Cycle 2 Day 8) biopsies by IHC
−
Compare the number of different types of immune cells in baseline biopsies
with that of post-treatment biopsies using IHC for cell-type specific markers
−
Compare FOLR1 expression and mutation status at baseline with those of
biopsies taken after relapse
2.3. 
Study Overview 
IMGN853 0401 is an open label, non-randomized, FIH, dose-escalation and dose-expansion 
Phase 1 study.  It is designed to identify the MTD of IMGN853 when administered 
intravenously as a single agent in adult patients with relapsed or refractory EOC and other 
FOLR1-positive solid tumors (dose escalation) and enable the selection and further 
evaluation of a RP2D (dose escalation and dose expansion).  The safety, tolerability, PK, Pd, 
immunogenicity, and preliminary anti-tumor activity of IMGN853 will be characterized.   
2.3.1. 
Dose Escalation 
During dose escalation, 2 dosing schedules (Schedule A and Schedule B) were evaluated.  
Initially patients received IMGN853 using Schedule A.  After the introduction of Schedule B 
(Protocol Amendment 6) patients received IMGN853 either using Schedule A or Schedule B.  
Following the enrollment of 4 of the Schedule B dose escalation cohorts, Schedule B 
escalation was closed (Protocol Amendment 10). 
2.3.1.1. 
Schedule A 
IMGN853 dosed on Day 1 of a 21-day cycle. 
The first 4 escalation cohorts were single patient cohorts.  Subsequent escalation cohorts used 
a standard 3+3 design, with each cohort consisting of 3 or 4 to 6 patients.  The initial planned 
doses for Schedule A dose escalation are shown in Table 2, exploration of intermediate doses 
was allowed following CRC review of all available data.  
Patients initially had their doses calculated based on their actual body weight, from Protocol 
Amendment 5 onwards patients have had their doses calculated based on their adjusted ideal 
body weight (AIBW).  When the MTD for Schedule A was identified and a RP2D selected 
for further evaluation, enrollment into the Expansion Cohorts began.   
Table 2: 
Initial Planned Dose Levels for Schedule A 
Dose Level 
Dose (mg/kg)a 
Percent Increase From Previous 
Dose Level 
Number of Patients 
(Planned) 
1 
0.15 
N/A1/20 HNSTD 
1 
2 
0.5 
233% 
1 
3 
1.0 
100% 
1 
4 
2.0 
100% 
1 
5 
3.3 
65% 
3 or 4-6 


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Table 2: 
Initial Planned Dose Levels for Schedule A  (Continued) 
Dose Level 
Dose (mg/kg)a 
Percent Increase From Previous 
Dose Level 
Number of Patients 
(Planned) 
6 
5.0 
52% 
3 or 4-6 
7 
7.0 
40% 
3 or 4-6 
8 
9.0 
28% 
3 or 4-6 
a Patients enrolled under Amendment 5 or later were dosed based on AIBW.  Patients enrolled prior to 
Amendment 5 were dosed based on actual body weight. 
2.3.1.2. 
Schedule B 
IMGN853 administered on Days 1, 8, and 15, with cycles repeating every 28 days. 
The starting dose of IMGN853 for Schedule B was 1.1 mg/kg, which was 1/3 the 3.3 mg/kg 
dose level deemed clinically safe in 9 patients dosed at that level in Schedule A.  All patient 
doses were calculated according to AIBW.  Patients were enrolled in cohorts of 3 to 6 
patients.   
The initial planned doses for Schedule B dose escalation are shown in Table 3.  If additional 
dose exploration was required to define the MTD then dose escalation could proceed at 
increments ≤ 25%.  The CRC determined the magnitude of the dose escalation increments 
following review of available clinical and PK data from patients treated in the current cohort. 
Table 3: 
Initial Planned Dose Levels for Schedule B 
Dose Level 
Dose 
(mg/kg)a 
Percent Increase From Previous 
Dose Level 
Number of Patients (Planned) 
1 
1.1 
N/A 
3 or 4-6 
2 
1.8 
65% 
3 or 4-6 
3 
2.5 
40% 
3 or 4-6 
4 
3.3 
32% 
3 or 4-6 
a Patients were dosed based on AIBW 
2.3.2. 
Study Population 
2.3.2.1. 
Dose Escalation 
Patients with a pathologically documented, definitively diagnosed, advanced solid tumor that 
is either refractory to standard treatment, or for which no standard treatment is available, or 
the patient refuses standard therapy.  
Enrollment without prior documentation of tumor FOLR1 expression was limited to a set of 
histologic subtypes which were likely to have a high incidence of FOLR1 positivity, as 
described in Section 3.1.A of the protocol. 
2.3.2.2. 
Dose Expansion 
Patients were enrolled into 1 of the following 5 expansion cohorts: 


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•
Cohort 1 -patients with platinum-resistant EOC
•
Cohort 2 - patients with advanced or recurrent uterine cancer
•
Cohort 3 - patients with relapsed or refractory EOC
•
Cohort 4 - patients with relapsed/refractory non-small cell lung cancer (NSCLC)
adenocarcinoma or bronchioloalveolar carcinoma (BAC)
•
Cohort 5 - patients with EOC which has relapsed following platinum-based
therapy and who will receive prophylactic corticosteroid eye drops
Further details for the Criteria for Selection of Patient Population are described in Section 3.1 
of the protocol. 
2.3.2.3. 
Enrollment 
Patients who received at least one dose of IMGN853 will be considered enrolled.  Patients 
who were issued a patient number, but who did not successfully complete the screening 
process and who did not receive a dose of IMGN853 will be considered screen failures.  
Patient numbers were not re-issued. 
2.3.3. 
Sample Size 
Approximately 209 patients were to be enrolled in the study, allowing for dropouts and 
expansion of dose escalation cohorts as needed.  
2.3.3.1. 
Dose Escalation 
Ascending doses of IMGN853 were evaluated to identify the MTD for both dosing 
schedules.  In Schedule A, single patient was enrolled into the first 4 cohorts and then 3 or 4 
to 6 patients into the following cohorts dependent on the incidence of DLTs and all other 
emerging data.  In Schedule B, 3, or 4 to 6 patients were enrolled into each of the cohorts 
dependent on the incidence of DLTs and all other emerging data.  The actual number of 
patients accrued during this phase was determined by the evaluation of all patient data.  
2.3.3.2. 
Dose Expansion 
Following identification of the MTD for Schedule A and the selection of a dose for further 
evaluation there was an expansion phase.  The number of patients to be enrolled into each of 
the expansion cohorts were:  
•
Cohort 1 - 40 patients
•
Cohort 2 - 20 patients
•
Cohort 3 - 20 patients
•
Cohort 4 - 20 patients
•
Cohort 5 - 40 patients
If the true DLT rate at the MTD is 10-20%, there is a 98.5-99.9% probability of observing at 
least one DLT in each 40 patient cohort.  If the true response rate at the MTD is 20%, there is 
a 99.9% probability of observing at least one response in each 40 patient cohort (Table 4).  


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Table 4: 
Probability of Observing ≥ X Events (Response or DLT) for a 40 Patient 
Cohort  
X (Number Observed) 
True Event Rate 
10% 
20% 
30% 
1 
0.985 
0.999 
0.999 
2 
0.919 
0.998 
0.999 
3 
0.777 
0.992 
0.999 
4 
0.577 
0.972 
0.999 
5 
0.371 
0.924 
0.997 
6 
0.206 
0.838 
0.991 
2.3.4. 
Treatment Randomization 
No randomization will be performed in this study. 
2.3.5. 
Schedule of Assessments 
See Protocol Appendix A and Appendix B. 
2.4. 
Interventions 
2.4.1. 
Clinical Trial Material 
2.4.1.1. 
Schedule A 
Patients will receive an infusion of IMGN853 as a single agent on Day 1 of a planned 21 day 
cycle.  For logistical reasons such as holidays, delays in the scheduled study treatment of up 
to 3 days may be allowed.  Additionally, shifts in the start of a new cycle by -1 or +3 days 
will be permitted in Cycles ≥3.    
2.4.1.2. 
Schedule B 
Patients received infusions of IMGN853 as a single agent on Days 1, 8, and 15 of each 
planned 28-day cycle.  A delay of 1 day in the doses received on Days 8 and 15 was 
permitted; if a delay occurred, each subsequent dose in that cycle was shifted by 1 day.  
Intervals of <7 days between each dose were not permitted.  The start of the next cycle 
remained the same. 
2.5. 
Study Procedures 
Secondary and exploratory objectives include characterization of PK, Pd, immunogenicity, 
FOLR1 levels, and other potential biomarkers in blood, tumor tissue, and biologic fluids that 
might predict response to IMGN853.  Full profiles of blood samples for PK measurements 
were taken in Cycles 1 and 3 for all patients.  Additionally, a single sample was collected 
pre-dose and following completion of the infusion in Cycles 2, 4, 5 and 6 for PK.  A single 
blood sample for analysis of HADA and HAHA was taken on Day 1 of Cycles 2, 4, and 5 


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and at EOT and 28 day follow up visits, and three hours and 1 week following the onset of an 
IMGN853 infusion-related reaction.  If PK sampling were performed concurrently, the 
HADA and HAHA samples were taken from the PK sample tube.  
Ki67 IHC staining was assessed as a marker of cell proliferation on fresh biopsy samples 
from patients in Expansion Cohort 3.  
All patients were genotyped for FcγR alleles via Peripheral Blood Mononuclear Cell (PBMC) 
analysis at screening.  
Samples for FcγR were taken at screening.  P-glycoprotein (PgP) IHC staining will be 
assessed in archived tumor tissues and on fresh biopsy samples obtained from patients in the 
expansion cohorts.   
FOLR1 expression via a homocysteine-dependent upregulation of FOLR1 mRNA translation 
and plasma total homocysteine levels will be assessed in all patients at baseline, during 
Cycle 2, and at the end of treatment visit.  Plasma methylmalonic acid (MMA) will be 
analyzed in parallel with plasma total homocysteine to differentiate folate and B12 status. 
Exploratory biomarkers were collected pre-dose on the first day of each cycle and at other 
noted time points.  Details can be found in Sections 6 and Section 7 of the study protocol. 
3. 
GENERAL ANALYTICAL CONSIDERATIONS 
3.1. 
Data Sources 
All data is to be collected via eCRFs through remote data entry, or through electronic 
transfers.  Section 13 of the study protocol provides additional details regarding data 
recording and handling. 
3.2. 
Definition of Baseline 
Cycle 1, Day 1 (Study Day 1) was designated as the first day a patient receives IMGN853.  
For most measurements, baseline labs were taken pre-dose on Day 1.  If pre-dose 
assessments on Day 1 are not available, the screening result closest to (prior to dosing on) 
Day 1 will be substituted.   
3.3. 
Missing Data 
TEAE onset dates will be reported in listings as collected.  Every effort will be made to query 
missing dates.  If exploratory analyses require imputed dates, the following procedure will be 
employed: 
• TEAE onset dates with missing year will be assumed to occur on Study Day 1. 
• TEAE dates with missing month will be assumed to occur on the first day of the 
non-missing year, except for TEAEs occurring in the first year of dosing, in 
which case the date will be the first day of dosing.   


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•
TEAE dates with non-missing month and missing day will be assumed to occur
on the first day of the non-missing month, except for TEAEs occurring in the first
month of dosing, in which case the date will be the first day of dosing.
All other data will be reported as they are collected.  No imputation methods will be used to 
replace missing data.   
3.4. 
Outliers 
No adjustments for outliers will be made.  
3.5. 
Multiple Study Centers 
No adjustment for stratification by the study centers is planned. 
3.6. 
Interim Analyses or Timing of Analyses 
No formal interim analysis is planned for this study.  However, a review of safety data and 
available preliminary PK data will be conducted by the CRC after the MTD or a RP2D for 
IMGN853 has been determined. 
3.7. 
Analysis Populations 
Three analysis populations will be defined for use with various analyses.  The following table 
illustrates the relationship between each population and the analyses for which the data from 
the population will be used (Table 5). 
Table 5: 
Analysis Populations 
Analysis Population 
Analysis 
Baseline 
Patient 
Disposition 
Efficacy 
Safety 
DLT 
Safety 
X 
X 
X 
X 
Response-Evaluable 
X 
CA-125-Evaluable 
CA-125 
only 
3.7.1. 
Safety Population 
The Safety Population will consist of all patients who received at least one dose of study 
drug.   
3.7.2. 
Response-Evaluable Population 
To meet the definition of response-evaluable, patients must have 
EITHER: 
•
received a radiographic assessment at baseline,
•
received at least one dose of IMGN853, and


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•
have had at least one post-dose tumor assessment;
OR 
•
have died within 105 days of receiving their first dose, or
•
have clinically progressed within 105 days of receiving their first dose.
3.7.3. 
CA-125 Evaluable Population
To meet the definition of CA-125 evaluable, patients must have a baseline CA-125 
value ≥2xULN, received at least one dose of IMGN853, and must have had at least one 
post-dose CA-125 assessment.  This population will be used in CA-125 response analysis 
only. 
3.8. 
Data Display Characteristics 
Data displays produced for this study will include data listings, summary tables, and figures.  
Unless stated otherwise, data listings will be produced for all recorded data.  Summary tables 
will be produced as specified in following sections.  Additional data listings will be produced 
for outcome measures that involve extensive procedures to derive the analyzed outcomes.  
Figures will be produced when specified in sections to follow.  Final delivery of tables, 
listings, and figures will have numbering in compliance with the ICH E3 guideline.  Prior to 
compilation of the clinical study report, Novella standard TREF, FREF, and LREF reference 
numbers will be used. 
Data listings will simply list the data recorded in the eCRF or derived for each patient.  They 
will be ordered by phase (escalation or expansion), cohort, patient number, and time of 
assessment.  When expedient, additional levels of ordering hierarchy may reflect subsets of 
assessments within patient.  Data listings will not display patient initials. 
Summary tables will display summary statistics calculated for each of the dose cohorts or 
treatment groups, unless described otherwise in following sections.  See shell tables for 
specific formats. 
The summary statistics displayed will be a function of the type of data associated with the 
summarized assessment.  For categorical variables, the number and percent of each category 
within a parameter will be calculated.  For continuous variables, the sample size (n), mean, 
median, and standard deviation, as well as the minimum and maximum values, will be 
presented.  Some continuous variables may also be grouped into categorical levels and 
evaluated in frequency tables.   
4.
PATIENT ACCOUNTABILITY
4.1. 
Patient Characteristics
Patient characteristics will be summarized and listed for the Safety population. 


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4.1.1. 
Demography 
Demography will include age, race, ethnicity, gender, ECOG performance status, and cancer 
stage at study entry. 
Age will be calculated as (First Dose Date – Birth Date + 1)/365.25, rounded down to the 
nearest whole number.  This corresponds to the typical calculation of age a person would use 
in conversation. 
4.1.2. 
Height and Body Weight 
Height, weight, and AIBW at baseline will be summarized. 
4.1.3. 
Cancer History 
Cancer history will summarize: stage of cancer at diagnosis; prior radiation therapy (yes/no); 
prior cancer systemic therapy (number of regimens), prior cancer-related surgery (yes/no). 
Cancer histories will be summarized for the Safety population as the numbers and 
percentages of patients with histories significant for each of the cancer history elements. 
4.1.4. 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) (version 18.1 or later), associating lower-level terms with preferred terms and 
system organ classes by the primary hierarchy.  All medical history information will be 
provided in listings. 
4.2. 
Patient Disposition 
A summary of patient disposition will show the total number of patients who were treated 
and the number of patients treated in each relevant treatment group.  The reasons for 
discontinuation will be summarized by categories included on the End of Study form as listed 
below, the summary will include the total number and percentage of patients per category 
and the number of patients and percentage of patients in each relevant treatment group.  
Percentages of patients will be calculated using all members of the relevant population in the 
relevant treatment group for the denominator.   
End of Study form categories for discontinuation are: 
•
One year post treatment without PD or subsequent therapy
•
Adverse Event
•
Disease progression
•
Clinical Progression
•
Began new anti-cancer therapy
•
Study Terminated by Sponsor
•
Withdrawal from Study
•
Investigator decision


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•
Lost to follow up
•
Death
•
Other
End of Treatment information, including reason for discontinuation of IMGN853, will also 
be summarized. 
4.2.1. 
Protocol Deviations and Population Inclusions 
Protocol deviations will be summarized by the categories used in the protocol deviation log 
as follows: 
•
Patients who were enrolled into the study even though they did not satisfy all of
the entry criteria
•
Patients who developed withdrawal criteria during the study but were not
withdrawn
•
Patients who received the wrong treatment or incorrect dose
•
Patients who received an excluded concomitant treatment
A listing of all deviations will also be presented. 
5.
EFFICACY ANALYSES
Efficacy analyses will use data from the Response-Evaluable population unless otherwise 
specified.  Unless stated otherwise, patients will be analyzed in the following groups: 
Escalation Schedule A, Escalation Schedule B, EOC Expansion Cohorts, Endometrial 
Expansion Cohort.   
5.1. 
Efficacy Outcomes 
5.1.1. 
Best Overall Response  
Best overall response (BOR) for a patient is the best response designation as assessed by the 
investigator, recorded between the date of the first dose of study treatment and the date of 
objectively documented progression per RECIST v1.1 or the date of treatment 
discontinuation, whichever occurs first.  The BOR will be categorized as a complete 
response/remission (CR), a partial response/remission (PR), a stable disease (SD), or a 
relapsed/progressive disease (PD).  Patients who cannot be evaluated for response will be 
categorized as Not Evaluable (NE).  Patients with an overall response of CR or PR must have 
a repeat tumor assessment performed no less than 4 weeks (28 days) after the criteria for 
response are first met.  Patients with an overall response of SD must have a minimum 
duration of 35 days (6 weeks – 1 week window = 35 days).  The confirmatory scan is valid 
following treatment discontinuation as long as the patient has not started a new anti-cancer 
therapy.  BOR will be reported in listings for all patients and summarized for each of the 
expansion cohorts. 


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5.1.2. 
Objective Response Rate 
The objective response rate (ORR) will be calculated as the number of subjects with a BOR 
of CR or PR divided by the number of subjects in the Response-Evaluable population.  
Subjects without at least one post-baseline RECIST assessment will be treated as non-
responders.  ORR with 95% confidence intervals will be reported for each group. 
5.1.3. 
Progression Free Survival (PFS) 
PFS is defined as the time from the date of the first dose of study drug until the date of 
progressive disease or death from any cause, whichever occurs first.  PFS is defined based on 
radiological assessments and determined by the investigator.  Clinical progression is not 
considered a progression endpoint.  PFS will be calculated using the following: 
•
Patients who did not die or have PD will be censored at the date of their last
radiological assessment.
•
Patients who had PD or death after missing two or more consecutive radiological
assessments (PD or death date – last radiological assessment date +1 >=105 days)
will be censored at the last adequate radiological assessment.
•
Patients who had no baseline or post-baseline radiological assessment(s) will be
censored on Day 1 unless the patient died within 105 days of Day 1; in that case,
the patient will be considered as having an event at the date of death.
•
Patients who started a new anti-cancer therapy prior to documented PD or death
will be censored at the last radiological assessment prior to initiation of new anti-
cancer therapy.
•
When an analysis cutoff date is implemented, only data (deaths and radiological
assessments) occurring on or prior to the cutoff date will be used for analysis.
5.1.4. 
Duration of Response
Duration of response (DOR) is defined as the time from the date of the first response (CR or 
PR), whichever is recorded first, to the date of progressive disease (PD).  Duration of 
response is only defined for patients who have a best overall response of CR or PR using the 
method of Kaplan-Meier.  Confirmation of the response must be performed no less than 
4 weeks (28 days) after the criteria for response are first met.  The first date at which a CR or 
PR response was noted will be used to calculate DOR, not the date of the confirmatory tumor 
assessment. 
5.1.5. 
Time to Progression  
Time to progression (TTP) is defined as the time from the date of the first dose of study drug 
until the date of progressive disease.  TTP is defined based on radiological assessments and 
determined by the investigator.  Clinical progression is not considered a progression 
endpoint.  TTP will be censored as follows: 
•
Patients who did not have PD will be censored at the date of their last radiological
assessment.


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•
Patients who had PD after missing two or more consecutive radiological
assessments (PD date – last radiological assessment date +1 >=105 days) will be
censored at the last adequate radiological assessment.
•
Patients who had no baseline or post-baseline radiological assessment(s) will be
censored on Day 1.
•
Patients who started a new anti-cancer therapy prior to documented PD will be
censored at the last radiological assessment prior to initiation of new anti-cancer
therapy.
•
When an analysis cutoff date is implemented, only radiological assessments
occurring on or prior to the cutoff date will be used for analysis.
•
Patients who died prior to PD will be censored at the last radiological assessment.
5.1.6. 
Time to Response
Time to response (TTR) is defined as the time from the date of the first dose of study 
treatment until the date of the first observed CR or PR.  TTR is only defined for subjects who 
have confirmed CR or PR.  TTR will be reported in listings for all patients and summarized 
for each of the expansion cohorts with medians and 95% confidence intervals for the medians 
will be presented for TTR for the expansion cohorts.    
5.1.7. 
CA-125 Response 
A CA-125 response is defined as a ≥ 50% reduction in CA-125 levels from baseline.  The 
response must be confirmed and maintained for at least 28 days.  The baseline sample must 
be ≥ 2.0 times the upper limit of normal (ULN) and within two weeks prior to starting 
treatment.  The date of response corresponds to the date when the CA-125 level is first 
reduced by 50%.  The summary table for CA-125 will be based on CA-125 evaluable 
population for the expansion cohorts only.   
5.1.8. 
Overall Survival  
Overall survival (OS) is defined as the time from the date of the first dose of study treatment 
until the date of death from any cause.  Patients who are still alive at the time of the analysis 
will be censored at the last known time alive. 
5.2. 
Analysis of Efficacy Outcomes 
5.2.1. 
ORR 
Responses will be tabulated separately for each group with medians and 95% confidence 
intervals.   
5.2.2. 
PFS 
The PFS will reported in listings and tabulated separately for each group with medians and 
95% confidence intervals.  


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5.2.3. 
DOR 
DOR will be reported in listings for all patients and will be tabulated separately for each 
group with medians and 95% confidence intervals.   
5.2.4. 
TTP 
TTP will be reported in listings for all patients and will be tabulated separately for each group 
with medians and 95% confidence intervals.   
5.2.5. 
TTR 
TTR will be reported in listings for all patients and will be tabulated separately for each 
group with medians and 95% confidence intervals.   
5.2.6. 
OS 
OS will be reported in listings for all patients and will be tabulated separately for each group 
with medians and 95% confidence intervals.   
5.2.7. 
Subgroup Analysis of Efficacy Outcomes in EOC Expansion Cohorts 
Efficacy outcomes will be analyzed for EOC expansion cohorts (1, 3, and 5) on the following 
patient subgroups: 
•
Patients who are platinum resistant in EOC expansion cohorts 1, 3, and 5.
•
Patients who are platinum resistant in EOC expansion cohorts 1, 3 and 5 by
number of prior regimens (1-3 vs >3).
•
Patients who are platinum resistant in EOC expansion cohorts 1, 3 and 5 by FRa
percent staining at intensity 2+ (PS2) (25-49%, 50-74%, 75-100%, and 50-100%).
•
Patients who are platinum resistant in EOC expansion cohorts 1, 3, and 5 by
number of prior regimens and FRα percent staining at intensity 2+ (1-3 priors and
PS2>=50%, 1-3 priors and PS2 is 25-49%, >3 priors and PS2>=50%, >3 priors and
PS is 25-49 %).
Kaplan-Meier plots for PFS will be generated for the above subgroup analyses. 
5.2.8. 
Efficacy Data Listings 
Efficacy data listings will include: 
•
All lesion assessments (target lesion, non-target lesion, new lesion)
•
Investigator’s RECIST assessments
•
CA-125 results
•
derived parameters for CA-125 response, BOR, PFS, TTP, DOR, TTR and OS
•
censoring for time-to-event variables


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6.
SAFETY ANALYSES
Safety analyses will use data from the Safety population.  Patients will be analyzed according 
to the actual study treatment received.  
6.1. 
Exposure 
Exposure to IMGN853 will be summarized with descriptive statistics for the number of doses 
received, the number of cycles received, duration of dosing (weeks, calculated as [date of last 
dose – date of first dose + 21]/7 for Schedule A, and [date of last dose – date of first dose + 
14]/7 for Schedule B), total cumulative dose (mg), dose intensity (mg/kg AIBW Q3W, 
calculated as [total cumulative dose (mg) / {baseline AIBW (kg) * duration of dosing 
(weeks)/3}]), and relative dose intensity (%, calculated as [dose intensity/ 6] *100). 
The number of infusions with dose decreased, infusions interrupted, and dose delayed will 
also be summarized by cohort.  The number of infusions with the rate of infusion decreased 
will also be summarized by cohort. 
Listings will be provided with the information from all of the study drug administration 
eCRFs.  A further listing reporting the exposure measures above will be provided. 
6.2. 
Adverse Events 
Adverse event (AE) data are available to ImmunoGen from two sources, the eCRFs and the 
serious adverse event (SAE) forms.  While SAE reconciliation will be performed, the 
production of data summaries and listings will be based on the data collected on the eCRF.  
Treatment-emergent adverse events (TEAEs) are defined as adverse events with an onset 
date on or after the first dose of study drug, and within 28 days of the last dose of study drug. 
The adverse events will be coded using MedDRA (version 18.1 or later), associating lower-
level terms with preferred terms and system organ classes by the primary hierarchy.  The 
tables will display the counts and percentages of patients who reported at least one TEAE in 
each system organ class represented in the AE data.  Within each system organ class, the 
tables will display the counts and percentages of patients reporting at least one TEAE as 
designated by the preferred terms. 
The following TEAEs are of special interest: 
•
Ocular TEAEs
−
This subset includes TEAEs meeting criteria for the following terms:
keratopathy and blurred vision.  A list of preferred terms for keratopathy will
be provided and finalized by the Sponsor before the final database lock.
•
Peripheral Neuropathy
−
A list of preferred terms for peripheral neuropathy will be provided and
finalized by the Sponsor before the final database lock.
•
Pneumonitis
The following AE tables will be produced: 


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•
An Overall Summary of Safety will summarize the numbers of patients with
TEAEs by cohort and CTCAE grade and the number of patients who died during
the study or within 28 days of last dose.
•
All TEAEs
•
TEAEs related to IMGN853.  This table will include TEAEs with a drug
relationship of “Possibly Related” or “Definitely Related.”  It will also include
TEAEs with missing drug relationships.  An AE reported by a patient more than
once will be included in this table if at least one of the drug association grades is
one of the grades listed here.
•
Serious TEAEs
•
Serious, Related TEAES.  This subset includes all serious TEAEs with a drug
relationship of “Possibly Related” or “Definitely Related.”  It will also include
serious TEAEs with missing drug relationships.  An AE reported by a patient
more than once will be included in this table if at least one of the drug association
grades is one of the grades listed here.
•
Grade 3 or above TEAEs
•
Treatment related ≥Grade 3 TEAEs
•
TEAEs leading to drug withdrawal.  This subset includes TEAEs with an Action
Taken of “Drug Permanently Discontinued.”
•
Related TEAEs leading to drug withdrawal.
•
TEAEs leading to dose delay.
•
TEAEs leading to dose reduction.
•
TEAEs leading to dose delay or dose reduction.
•
Related TEAEs leading to dose delay.
•
Related TEAEs leading to dose reduction.
•
Related TEAEs leading to dose delay or dose reduction.
•
All deaths as well as deaths on Study or within 28 Days of the Last Dose
•
Treatment  related TEAEs leading to death on study or within 28 days of Last
Dose
•
Ocular TEAEs
−
Incidence and CTCAE grade of ocular TEAEs
−
Time to first onset of ocular TEAEs
−
Action taken (none, interruption, dose reduction or delay, discontinuation) due
to ocular TEAEs
•
Peripheral Neuropathy


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Subgroup analyses of TEAEs for the patients in EOC expansion cohorts (cohorts 1, 3, and 5) 
will be performed on the following patient subgroups: 
•
Patients in EOC expansion cohorts 1, 3, and 5 by platinum resistant status
(platinum resistant vs platinum sensitive).
•
Patients who are platinum resistant in EOC expansion cohorts 1, 3, and 5 by
number of prior regimens (1-3 vs >3).
•
Patients who are platinum resistant in EOC expansion cohorts 1, 3, and 5 by FRα
percent staining at intensity 2+ (PS2) (25-49%, 50-74%, 75-100%, 50 – 100%).
In addition, TEAEs and related TEAEs will be summarized for patients in EOC expansion 
cohorts (1, 3, and 5) who are platinum resistant and who have received 1-3 prior lines of 
therapy and whose FRα percent staining at intensity 2+ (PS2) is 50-100%.   
The following AE listings will be produced: 
•
All pre-treatment AEs will be listed.
•
All AEs, sorted by cohort and chronologically within patient.  This listing
includes system organ class, preferred term, onset and end dates, and other
relevant information.
•
Serious TEAEs, sorted by cohort and chronologically within patient.
•
TEAEs leading to drug withdrawal.  This subset includes TEAEs with an Action
Taken of “Drug Permanently Discontinued.”
•
TEAEs related to study drug.  This listing will include TEAEs with a drug
relationship of “Possibly Related” or “Definitely Related.”  It will also include
TEAEs with missing drug relationships.
•
Serious TEAEs related to study drug.  This listing will include serious TEAEs
with a drug relationship of “Possibly Related” or “Definitely Related.”  It will
also include serious TEAEs with missing drug relationships.
•
TEAEs resulting in death.  This listing includes TEAEs with a Common
Terminology Criteria for Adverse Events (CTCAE) v4.03 Grade of “Grade 5
(Death)”.
•
Ocular TEAEs
•
Neuropathy TEAEs
•
Pneumonitis TEAEs
6.3. 
Dose Limiting Toxicities (DLTs)
DLTs will be defined as a TEAE or abnormal laboratory value related to study treatment 
(i.e., assessed as unrelated to disease, intercurrent illness, or concomitant medications), 
including those TEAEs and abnormal laboratory values that result in a failure to meet the 
criteria for retreatment.  DLTs will be considered related to the study treatment unless there 
is clear evidence of an alternative explanation and this attribution is agreed to by the CRC. 


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For the purposes of dose escalation and determination of the MTD, only DLTs that occur 
during the first cycle will be necessarily considered for decisions regarding dose escalation.  
Clinically significant toxicities or treatment-emergent adverse events that meet the definition 
of dose limiting but occurring after Cycle 1 (dose modifying events) may be considered when 
determining the RP2D. 
A listing of DLTs will be provided. 
6.4. 
Clinical Laboratory Results 
Laboratory test results (including hematology, coagulation, serum chemistry, and urinalysis) 
and abnormal laboratory values will be presented in data listings.  CTCAE v4.03 lab grades 
will also be presented for those tests which have associated grading criteria.  CTCAE grades 
will be derived based on laboratory results, and will not factor in clinical evaluations.   
Shift tables summarizing the changes from baseline in severity of lab grades will be provided 
for lab parameters that are graded according to the CTCAE v4.03.  Summaries of actual 
values and changes from baseline will be presented by treatment group for each assessment 
time point, beginning with the first post-baseline assessment.  Grade 3 or above lab values 
will also be summarized based on the worst grade observed on study.   
For the liver function tests, a summary of clinically significant values in liver function tests 
will be reported by the following categories using the maximum value while on treatment.  
The denominator for the summaries will be the number of patients who had at least one non-
missing value during treatment.  Note the categories for each test are not mutually exclusive: 
•
Aspartate Aminotransferase (AST)
−
>3xULN
−
>5xULN
−
>10xULN
−
>20xULN
•
Alanine Aminotransferase (ALT)
−
>3xULN
−
>5xULN
−
>10xULN
−
>20xULN
•
AST or ALT
−
>3xULN
−
>5xULN
−
>10xULN
−
>20xULN


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•
Total Bilirubin (TBL)
−
>1.5xULN
−
>2xULN
•
Alkaline Phosphatase (ALP)
−
>1.5xULN
•
(AST or ALT) and TBL
−
AST or ALT >3xULN and TBL >1.5xULN
−
AST or ALT >3xULN and TBL >2xULN
•
(AST or ALT) and ALP and TBL
−
AST or ALT >3xULN and ALP <2xULN and TBL ≥2xULN
Results from pregnancy tests will be provided in data listings.  
6.5. 
Immunogenicity 
The potential immunogenicity against IMGN853 or DM4 will be assessed at various time 
points in Cycles 1 through 6, as outlined in Protocol Section 6.3 and Protocol Appendix C.  
Exploratory analyses will be completed to evaluate the potential impact of immunogenicity 
on PK, safety, and efficacy. 
6.6. 
Vital Signs and Pulse Oximetry 
Vital signs (including temperature, pulse rate, systolic blood pressure, diastolic blood 
pressure, respiratory rate and weight, pulse oximetry) will be presented in data listings.  
Summaries of actual values and changes from C1D1 pre-dose baseline at each time point will 
be presented. 
6.7. 
Electrocardiograms 
Electrocardiograms (ECG) results (Rhythm, Heart Rate, PR Interval, RR Interval, QRS 
Interval, QT Interval, QTcF Interval, and classification of Within Normal Limits, Abnormal, 
Not Clinically Significant, and Abnormal, Clinically Significant will be presented in data 
listings.  If a different correction for QT is captured in the eCRF, that QTc will also be 
reported in the listing for that patient along with QTcF.   
The number and percent of patients in the following non-mutually exclusive categories will 
be summarized by visit: 
•
QTc >450 ms
•
QTc >480 ms
•
QTc >500 ms
•
QTc change from baseline >30 ms
•
QTc change from baseline >60 ms


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Note that dosing ECGs are collected in triplicate; analyses for replicated results will be based 
on the average of the replicate results.  The QTcB and QTcF collected on eCRF will not be 
used in this summary table.  Instead, for this summary table, QTcB and QTcF will be derived 
from QT and RR: 
Where QT and RR are both measured in seconds.  
For the overall ECG result (Within Normal Limits, Abnormal, Not Clinically Significant, and 
Abnormal, Clinically Significant) summaries will be provided for baseline and each post-
baseline assessment time point.  Note that dosing ECGs are collected in triplicate and 
analyses for the overall ECG result will be based on the worst-case result (i.e. if any one of 
the triplicate results is Abnormal, Clinically Significant then the value for the time point will 
be Abnormal, Clinically Significant).  The hierarchy for the worst-case assessment is: 
Abnormal, Clinically Significant will be considered the worst value, with Abnormal, Not 
Clinically Significant being considered worse than Within Normal Limits. 
6.8. 
Concomitant Medications 
All medications and supportive therapy taken within four weeks prior to Cycle 1, Day 1 and 
through 28 days after last study treatment must be recorded on the appropriate electronic case 
report form (eCRF).  The identity of all medications, dosage, and route of administration, 
frequency, duration of administration, and indication for use will be recorded in the 
appropriate sections of the eCRF.   
Prior and concomitant medications will be coded using the September 2015 or later version 
of World Health Organization drug dictionary (WHO Drug).  Separate summary tables will 
be provided for prior and concomitant medications.  Summary tables will be organized to 
display the anatomical main class of each coded medication (ATC level 1 term) and, within 
that, the pharmacological subgroup (ATC level 3 term) of the coded medication.  The 
summary table will display counts and percentages of patients who reported using at least 1 
medication in each represented pharmacological subgroup.  If a patient has more than one 
medication in the subgroup, they will be counted only once.  A complete listing will be 
generated as well.   
6.9. 
Concomitant Procedures 
All procedures within four weeks of Cycle 1, Day 1 and through 28 days after last study 
treatment must be recorded on the appropriate electronic case report form (eCRF).  
Concomitant procedures will be coded using MedDRA (version 18.1 or later), associating 
lower-level terms with preferred terms and system organ classes by the primary hierarchy. 
Complete listings of these data will be generated.   


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6.10. 
Ophthalmic Examinations 
Results of the Ophthalmic Examinations will be presented in data listings.  
6.11. 
Ocular Symptom Assessments 
Results of the Ocular Assessments will be presented in data listings.  
6.12. 
Transfusions 
All blood product transfusions recorded on the concomitant procedure or concomitant 
medication eCRF will be presented in data listings. 
6.13. 
Physical Examination 
Physical Examination results will be presented in data listings. 
6.14. 
Pulmonary Function Tests 
Pulmonary Function Test results will be presented in data listings. 
6.15. 
Eastern Cooperative Oncology Group Performance Status 
(ECOG PS) 
Eastern Cooperative Oncology Group performance status (ECOG PS) results will be 
presented in data listings. 
6.16. 
FACT/GOG Neurotoxicity Questionnaire 
Data from the Functional Assessment of Cancer Therapy, Gynecologic Oncology Group 
(FACT/GOG) Questionnaire will be reported in data listings. 
7.
PHARMACOKINETIC AND PHARMACODYNAMIC
ANALYSES
The PK analyses for this study will be covered by a separate, independent analysis plan 
prepared by the PK analysis vendor in collaboration with ImmunoGen. 
8.
EXPLORATORY BIOMARKER ANALYSES
The exploratory biomarker analyses will be covered by a separate, independent Exploratory 
Biomarker analyses plan. 


 
 
 
 
 
 
IMGN853 0401 
 
Pharmacokinetic and Immunogenicity Analysis Plan 
A Phase 1, First-in-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of IMGN853 in Adults with Ovarian Cancer and other FOLR1-Positive Solid Tumors 
 
Report Number  
QPK28-001 
Facility 
qPharmetra 
9 Nollet Drive 
Andover, MA 01810 
Report Date 
07 December 2017 
Report Author 
Name: 
 
Title: 
 
Department: 
 


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TABLE OF CONTENTS 
LIST OF TABLES ...........................................................................................................................3 
LIST OF FIGURES .........................................................................................................................4 
ABBREVIATIONS .........................................................................................................................5 
1. 
OVERVIEW AND INVESTIGATIONAL PLAN/PURPOSE ....................................6 
1.1. 
Study Design.................................................................................................................6 
1.2. 
Pharmacokinetic and Immunogenicity Analysis Objectives ........................................6 
1.3. 
PK Sampling Schedule .................................................................................................7 
1.3.1. 
Schedule A ....................................................................................................................7 
1.3.2. 
Schedule B ....................................................................................................................7 
1.3.3. 
Additional Samples.......................................................................................................8 
1.3.4. 
Bioanalysis of PK Samples...........................................................................................8 
1.4. 
Immunogenicity Assessments ......................................................................................8 
1.4.1. 
Bioanalysis of Immunogenicity Samples .....................................................................8 
2. 
METHODS ...................................................................................................................9 
2.1. 
PK Analysis ..................................................................................................................9 
2.1.1. 
PK Population ...............................................................................................................9 
2.1.2. 
Data Handling ...............................................................................................................9 
2.1.3. 
Data Presentation ..........................................................................................................9 
2.1.4. 
Analysis of PK Data .....................................................................................................9 
2.1.5. 
Statistical Analysis......................................................................................................10 
2.1.6. 
Additional Analyses....................................................................................................10 
2.2. 
Immunogenicity Analysis ...........................................................................................10 
2.2.1. 
Immunogenicity Population........................................................................................10 
2.2.2. 
Analysis of Immunogenicity Data ..............................................................................10 
2.2.3. 
Exploratory Analyses..................................................................................................11 
3. 
REFERENCES ...........................................................................................................12 
4. 
APPENDIX LISTING ................................................................................................13 
 


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LIST OF TABLES 
Table 1: 
PK Parameters to be Calculated from Data Collected in Cycles 1 and 3 ...................10 
 


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LIST OF FIGURES 
N/A 
 


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ABBREVIATIONS 
ADA 
Anti-Drug Antibody 
ASCII 
American Standard Code for Information Interchange 
AUC 
Area Under the Time-Concentration Curve 
BQL 
Below the Quantifiable Limit 
CI 
Confidence Interval 
Cmax 
Maximum Plasma Drug Concentration 
CRC 
Cohort Review Committee 
CRO 
Clinical Research Organization 
CV 
Coefficient of Variance 
DM4 
N2’-[4-[(3-carboxypropyl)dithio]-4-methyl-1-oxo-2-sulfopentyl]-N2’-deacetylmaytansine 
ELISA 
Enzyme Linked Immunosorbent Assay 
EOC 
Epithelial Ovarian Cancer 
FIH 
First in Human 
FOLR1 
Folate Receptor 1 
K2EDTA 
Potassium Ethylenediaminetetraacetic Acid 
LC-MS 
Liquid Chromatography – Mass Spectrometry 
LLOQ 
Lower Limit of Quantification 
Max 
Maximum 
Min 
Minimum 
MTD 
Maximum Tolerated Dose 
N 
Number of Observations 
NC 
Not Calculated 
NSCLC 
Non-Small Cell Lung Cancer 
PK 
Pharmacokinetics 
Q3W 
Administration Every 3 Weeks 
SAE 
Severe Adverse Event 
SD 
Standard Deviation 
t1/2 
Terminal Half-Life 
TAB 
Total Antibody 
Tmax 
Time at Which Cmax Occurs 
Vss 
Volume of Distribution at Steady State 
Wx3Q4W 
Dosing on Day 1, 8, 15, with Cycles Repeating Every 28 Days 


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1. 
OVERVIEW AND INVESTIGATIONAL PLAN/PURPOSE 
This analysis plan provides a description of the strategy and techniques to be used to analyze 
pharmacokinetic (PK) and immunogenicity data for the mirvetuximab soravtansine (IMGN853) 
0401 study. 
1.1. 
Study Design 
This was an open label, Phase 1, non-randomized, first in human (FIH) study of IMGN853 in 
adult patients with FOLR1-positive solid tumors that have relapsed, or are refractory to standard 
therapies.  Two dosing schedules were evaluated in this study:  
Schedule A: IMGN853 administered on Day 1, with cycles repeating every three weeks (Q3W) 
The dose escalation phase initially enrolled 1 patient each at the first four dose levels.  Patients 
were enrolled in subsequent cohorts using a standard 3+3 design, with each cohort consisting of 
3 or 4 up to 6 patients.   
Schedule B: IMGN853 administered on Days 1, 8, and 15, with cycles repeating every 28 days 
(modified weekly) 
 
 
 
 
1.2. 
Pharmacokinetic and Immunogenicity Analysis Objectives 
The objective of this analysis is to characterize the PK and immunogenicity of IMGN853. 
 
 


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1.3. 
PK Sampling Schedule 
1.3.1. 
Schedule A 
Blood samples for PK measurements were taken at the following time points: 
Cycles 1 and 3: 
Day 1 – Pre-dose, immediately following completion of infusion (+10 minutes), 2 hours (±10 
minutes) following the completion of infusion, 4 hours (±10 minutes) following the completion 
of infusion, 6 hours (±10 minutes) following the completion of infusion and 8 hours (±10 
minutes) following the completion of infusion 
NOTE: 8 hours and 6 hours following the completion of infusion were not required for all 
patients 
Day 2 – 24 hours after completion of infusion (±2 hours) 
Day 3 – 48 hours after completion of infusion (±2 hours) 
Day 4 or 5 – a single blood sample for PK (±24 hours) 
Day 8– a single blood sample for PK (±24 hours) 
Day 15 – a single blood sample for PK (±24 hours) 
Cycles 2 and 4 through 6: 
Day 1 – Pre-dose and immediately following completion of infusion (+10 minutes) 
End of Treatment 
28 Day Follow Up 
1.3.2. 
Schedule B 
Blood samples for PK measurements were taken in at the following time points: 
Cycles 1 and 3: 
Day 1 – Pre-dose, immediately following completion of infusion (+10 minutes), 2 hours (±10 
minutes) following the completion of infusion, and 4 hours (±10 minutes) following the 
completion of infusion 
Day 2 – 24 hours after completion of infusion (±2 hours) 
Day 8 – Pre-dose and immediately following completion of infusion (+10 minutes) 
Day 15 – Pre-dose, immediately following completion of infusion (+10 minutes), 2 hours (±10 
minutes) following the completion of infusion, and 4 hours (±10 minutes) following the 
completion of infusion 
Day 16 – 24 hours after completion of infusion (±2 hours) 
Day 22 – a single blood sample for PK (±24 hours) 
Cycles 2 and 4 through 6: 
Day 1 – Pre-dose and immediately following completion of infusion (+10 minutes) 


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End of Treatment 
28 Day Follow Up 
 
1.3.3. 
Additional Samples  
Per study protocol, any patient who experienced a Grade 2 or greater infusion reaction during the 
administration of IMGN853 had blood drawn within 3 hours of the onset of the reaction and one 
week later for determination of drug concentration and antibodies to IMGN853.  
PK samples were also obtained, as feasible, any time during the treatment period for assessment 
of study drug related SAEs if deemed appropriate by the Investigator and Sponsor. 
1.3.4. 
Bioanalysis of PK Samples 
The following table summarizes the bioanalytical methodology used to quantitate IMGN853, 
total antibody, and free payload (DM4 and s-methyl DM4). 
Analyte 
Method 
Lower Limit of 
Quantitation 
CRO Validation 
Report Number 
IMGN853 
ELISA 
75.0 ng/mL 
REYB2, REGD2 
Total Antibody 
ELISA 
500 ng/mL 
REYN2, REGE2 
DM4, S-methyl-DM4 
LC-MS 
0.100 ng/mL 
REGC2 
ELISA, enzyme linked immunosorbent assay; LC-MS, liquid chromatography-mass spectrometry.  
 
1.4. 
Immunogenicity Assessments 
Assessments for immunogenicity against IMGN853 were performed on plasma samples 
collected for PK assessments.  This included samples collected prior to infusion on Day 1 of 
Cycles 1, 2, 4, and 5, at the End of Treatment and at Follow-up visits.  The current analysis will 
evaluate the potential impact of immunogenicity on PK of IMGN853 and total M9346A 
antibody, specifically comparing IMGN853 and total antibody exposure between the immune 
positive and immune negative populations.  
1.4.1. 
Bioanalysis of Immunogenicity Samples 
An electrochemiluminescent method was used for the detection of anti-IMGN853 antibodies in 
plasma from samples collected into either sodium heparin or K2EDTA tubes (respective 
validation reports: REYO2 and REGG2).  The qualitative assay was designed to detect anti-
IMGN853 antibodies in human plasma.  Samples with a signal response above the fixed cut 
point were classified as potentially positive, while those below the cut point were classified as 
negative.  Potentially positive samples were confirmed in the Tier 2 screening assay, where 
conjugate was added as an inhibition solution.  Samples were confirmed positive if the percent 
inhibition was ≥ 29.1% for sodium heparin samples and 30.2% for K2EDTA samples.  In Tier 3, 
the confirmed positive samples were titered until a negative response was obtained and the 
sample titer was reported as the reciprocal of the last dilution that produced a response above the 
cut point.  


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2.
METHODS
2.1. 
PK Analysis
2.1.1. 
PK Population
The PK population includes all patients who received at least one infusion of IMGN853 and 
have evaluable PK data.  All patients who received IMGN853 and had samples collected with no 
major deviations related to administration of study drug will be included in the PK population.  
2.1.2. 
Data Handling 
Analysis-ready PK datasets will be constructed from audited and locked clinical databases.  The 
data and dosing information will be formatted for PK analysis and saved in ASCII format using 
R software, Version 3 or higher (R Core Team  2015).  All data manipulation programs will be 
documented and archived to maintain an audit trail, and will be subject to quality review. 
Individual data for all PK subjects will be tabulated by patient and summarized by time point, 
dose level, and cycle, unless stated otherwise. 
2.1.3. 
Data Presentation 
The number of significant digits displayed for the individual values of plasma concentrations 
will be based on the number of significant figures in the source data.  The following descriptive 
statistics will be reported for each nominal sampling point and PK parameter: number of 
observations (N), mean, geometric mean, standard deviation (SD), minimum (min), median, 
maximum (max), coefficient of variation (CV) (CV = SD/mean, expressed as %), and 95% 
confidence interval (CI) of the mean.  The number of significant digits given for the descriptive 
statistics will generally exceed that of the source data by one.  The min and max will have the 
same number of significant digits as the source data, and CV% will be quoted to one decimal 
place.  If the mean, geometric mean, or median are below the lower limit of quantification 
(LLOQ), these statistics will be reported as below the quantifiable limit (BQL) and ignored in the 
calculation of geometric mean.  The SD, CV%, and 95% CI will not be calculated (NC) when 
less than three individual values are available.  The other descriptive statistics will be determined 
when at least one value is reported.  Descriptive statistics will be calculated using R software. 
2.1.4. 
Analysis of PK Data 
All the PK analyses will be performed using the PK population, and will be conducted similarly 
for the Schedule A, Schedule B, and Dose Expansion cohorts.  Initially, individual and mean 
concentrations for IMGN853, total antibody (TAb), DM4, and s-methyl-DM4 will be plotted vs. 
time by dose level for data collected in Cycles 1 and 3.  The PK parameters listed in Table 1 will 
be calculated from these data via standard non-compartmental methods (Gabrielsso 2016), and 
the results will be tabulated and summarized by Cycle and dose level.  The PK data will be 
evaluated for dose proportionality and accumulation of each analyte will be assessed.  
The observed concentrations for end of infusion in Cycles 2, 4, 5, and 6, as well as end of 
treatment and follow-up will be summarized and tabulated, but will not be analyzed further. 


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Table 1: PK Parameters to be Calculated from Data Collected in Cycles 1 and 3 
PK Parameter 
Definition 
Cmax Maximum plasma concentration observed 
Clast Final observed plasma concentration above LLOQ 
AUC Area under the plasma concentration versus time curve extrapolated to infinite time 
AUClast Areas under the plasma concentration versus time curve from time of dose until Tlast 
Tmax Observed first time to reach Cmax 
Tlast Time corresponding to the last concentration above the limit of quantification 
t1/2 Terminal half-life  
CL Clearance, i.e. volume of plasma that is completely cleared of the drug per unit time 
Vss Volume of distribution at steady-state 
 
2.1.5. 
Statistical Analysis 
PK parameters will be summarized using descriptive statistics by Cycle and dose level.  No 
hypothesis testing between dose-levels will be performed.  Examinations of dose proportionality 
will be conducted according to the method of Smith (2000).  
2.1.6. 
Additional Analyses 
Additional analyses may be performed to determine the effect of CYP3A inhibitors or inducers 
on PK as well as the effect of FRα levels on PK. 
2.2. 
Immunogenicity Analysis 
2.2.1. 
Immunogenicity Population 
The immunogenicity population includes all patients who received at least one infusion of 
IMGN853 and have evaluable immunogenicity data. 
2.2.2. 
Analysis of Immunogenicity Data 
Anti-IMGN853 seroconversion refers to the development of detectable antibodies which bind to 
IMGN853 and is based upon positive results in both screening and confirmatory assays.  If a 
patient tests negative at all visits (no seroconversion), then the patient will be classified as 
seronegative.  If the patient is positive at one or more visits (seroconversion), then the patient 
will be classified as seropositive.  Percentage of patients who screen positive for anti-drug 
antibodies (ADA), percentage of patients who confirm positive, and antibody titer data will be 
summarized by time point using descriptive statistics.  All data will be presented in listings for 
each patient.  
Time to seroconversion will be calculated for the patients who have confirmed positive ADAs 
during the study.  A table of time to seroconversion will be provided.  Additionally, a table of 
ADA titer over time, and a table for last titer will be provided, as well as the supporting listing. 


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Peak titer value is defined as the maximum titer value experienced by a patient during the study.  
A table of peak titer and time to peak titer will be provided, including summary statistics, 
specifically, median, mean peak tiers and minimum, maximum titers by dose level. 
2.2.3. 
Exploratory Analyses 
Exploratory analyses may be performed to elucidate the relationship between IMGN853 PK and 
ADA titers.  Analyses and presentation of data may be done using pooled data and/or by dose 
cohort, dosing schedule or tumor type as appropriate.  For each assessment, raw observed 
measures and change and percentage change from baseline data will be tabulated and 
summarized. 


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3. 
REFERENCES 
R Core Team (2015). R: A language and environment for statistical computing. R Foundation for 
Statistical Computing, Vienna, Austria. URL https://www.R-project.org/. 
Gabrielsson J, and Weiner D, Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts 
and Applications, 5th ed. Stockholm: Apotekarsocieten, 2016.  
Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, and Forgue ST 
(2000).  Confidence interval criteria for assessment of dose proportionality. Pharm Res; 
17(10):1278-1283. 
 


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4. 
APPENDIX LISTING 
N/A