Conditions: Epithelial Ovarian Cancer Primary Peritoneal Carcinoma Fallopian Tube Cancer Ovarian Cancer
Keywords: Epithelial ovarian cancer Fallopian tube cancer Primary peritoneal cancer IMGN853 ADC Antibody drug conjugate ImmunoGen Antibody Folate receptor alpha mirvetuximab soravtansine Phase 3 platinum-resistant MIRV
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 366
Healthy volunteers: no

Brief summary:
This is a Phase 3, open label, randomized study designed to compare the safety and efficacy of mirvetuximab soravtansine to that of selected single-agent chemotherapy (Investigator's choice) in women with platinum-resistant FR-alpha positive advanced EOC, primary peritoneal cancer and/or fallopian tube cancer.

Detailed description:
Participants will be randomized to either mirvetuximab soravtansine or investigator's choice chemotherapy.

Arms:
arm 1: Participants will receive mirvetuximab soravtansine at 6 milligrams/kilogram (mg/kg) adjusted ideal body weight (AIBW) administered intravenously (IV) on Day 1 of a 3 week cycle. Participants will continue to receive study drug until they experience progressive disease (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (as assessed by the blinded independent review committee \[BIRC\]), experience unacceptable toxicity, or withdraw consent, whichever comes first, or until the sponsor terminate the study. (Maximum exposure: 86.9 weeks) arm 2: Participants will receive a dose of IC chemotherapeutic agent calculated using body surface area (BSA). Paclitaxel will be administered at 80 milligrams/square meter (mg/m\^2) as a 1-hour IV infusion on Days 1, 8, 15, and 22 of a 4-week cycle; or topotecan will be administered at 4 mg/m\^2 over 30 minutes on Days 1, 8, and 15 of a 4-week cycle. Alternatively, topotecan could be administered at 1.25 mg/m\^2 over 30 minutes on Days 1 to 5 of a 3-week cycle; or pegylated liposomal doxorubicin will be administered at 40 mg/m\^2 as a 1 mg/minute IV infusion on Day 1 of a 4-week cycle. After Cycle 1, if tolerated, pegylated liposomal doxorubicin could be administered as a 1-hour infusion. Participants will continue to receive study drug until they experience PD per RECIST version 1.1 (as assessed by BIRC), experience unacceptable toxicity, or withdraw consent, whichever comes first, or until the sponsor terminate the study. (Maximum exposure: 62.9 weeks)

Interventions: intervention 1: Mirvetuximab soravtansine intervention 2: Paclitaxel intervention 3: Pegylated liposomal doxorubicin intervention 4: Topotecan
Intervention descriptions: intervention 1: Mirvetuximab Soravtansine will be administered per dose and schedule specified in the arm. intervention 2: Paclitaxel will be administered per dose and schedule specified in the arm. intervention 3: Pegylated liposomal doxorubicin will be administered per dose and schedule specified in the arm. intervention 4: Topotecan will be administered per dose and schedule specified in the arm.

Protocol document:
Prot_001.pdf: 
Study Title: 
FORWARD 1:  A Randomized, Open Label Phase 3 Study to 
Evaluate the Safety and Efficacy of Mirvetuximab 
Soravtansine (IMGN853) Versus Investigator’s Choice of 
Chemotherapy in Women with Folate Receptor α−positive 
Advanced Epithelial Ovarian Cancer, Primary Peritoneal 
Cancer or Fallopian Tube Cancer 
Study Number 
0403 
Study Phase: 
3
Product Name: 
Mirvetuximab soravtansine (IMGN853) 
IND Number: 
111915 
Indication: 
Folate Receptor α−positive Advanced Epithelial Ovarian 
Cancer, Primary Peritoneal Cancer or Fallopian Tube Cancer 
Investigator/Trial 
Location: 
Multinational, Multicenter trial 
Sponsor: 
ImmunoGen, Inc. 
830 Winter Street 
Waltham, MA 02451 USA 
Sponsor Contact: 
  
 
Phone: 
  
Email: 
 
Original Protocol Date: 
18 August 2015 
Amendment No. and Date: Amendment 1:  01 September 2015 
Amendment 2:  23 September 2015 
Amendment 3:  20 October 2015 
Amendment 4:  01 February 2016 
Amendment 4A (Spain):  05 April 2016 
Amendment 5:  17 August 2016 
Amendment 6:  19 September 2016 
Amendment 7:  04 November 2016 
Amendment 8:  08 May 2017 
Amendment 8A (North America):  25 September 2017 
Amendment 9 (US, Ireland, Italy):  05 December 2019 
Confidential Statement 
This document is the proprietary and confidential property of ImmunoGen, Inc. 
NCT02631876
CLINICAL STUDY PROTOCOL 


Mirvetuximab Soravtansine (IMGN853) 
 
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Protocol Number IMGN853-0403 
 
 
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Sponsor Contact List 
 
PRIMARY CONTACTS 
Primary Medical Monitor 
 
 
 
Phone: 
  
Email: 
 
Clinical Scientists 
 
Phone: 
 
Email: 
 
Trial Management  
 
Phone: 
 
Email: 
 
 
 


Mirvetuximab Soravtansine (IMGN853) 
 
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SPONSOR SIGNATURE PAGE  
 
 
 
 
 
 
 
 
830 Winter Street 
Waltham, MA 02451 
United States of America 
Tel: 
  
Email: 
 
 
Date 
 
 
 
 


Mirvetuximab Soravtansine (IMGN853) 
 
05 December 2019 
Protocol Number IMGN853-0403 
 
 
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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator Brochure for mirvetuximab soravtansine. I have 
read the ImmunoGen Protocol #0403 and agree to conduct the study as outlined and in 
conformance with Good Clinical Practice (GCP) 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 


Mirvetuximab Soravtansine (IMGN853) 
 
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Protocol Number IMGN853-0403 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
or Specialist 
Term 
Explanation 
ADA 
Anti-drug antibodies 
ADC 
Antibody drug conjugate 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
AE 
Adverse event 
AIBW 
Adjusted ideal body weight 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase (SGPT) 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase (SGOT) 
AUC0-24 
Area under the time-concentration curve from time 0 to 24 hours 
BIRC 
Blinded independent review committee 
BRCA 
Breast cancer susceptibility gene 
BSA 
Body Surface Area 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
CNS 
Central nervous system 
CR 
Complete response/remission 
CRF 
Case report form 
CT 
Computed Tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
DM4 
N2’-[4-[(3-carboxypropyl)dithio]-4-methyl-1-oxo-2-sulfopentyl]-N2’-
deacetylmaytansine 
DM4-Me 
Methylated N2’-[4-[(3-carboxypropyl)dithio]-4-methyl-1-oxo-2-
sulfopentyl]-N2’-deacetylmaytansine 
DNA 
Deoxyribonucleic acid 


Mirvetuximab Soravtansine (IMGN853) 
 
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Abbreviation 
or Specialist 
Term 
Explanation 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECHO 
Echocardiography 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EOC 
Epithelial Ovarian Cancer 
EORTC 
European organization for research and treatment of cancer 
EOS 
End of Study 
EOT 
End of Treatment 
EPO 
Erythropoietin 
FcγR 
Fc gamma receptor 
FDA 
Food and Drug Administration 
FFPE 
Formalin Fixed Paraffin Embedded 
FIH 
First-In-Human 
FOLR1, FRα 
Folate receptor 1/Folate receptor alpha 
FOSI 
Fact-ovarian symptom index 
GCIG 
Gynecologic Cancer Intergroup  
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
HFS 
Hand-Foot Syndrome 
HIV 
Human Immunodeficiency Virus 
IA 
Interim analysis 
IC 
Investigator’s choice 
IC50 
Half maximal (50%) inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation  
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 


Mirvetuximab Soravtansine (IMGN853) 
 
05 December 2019 
Protocol Number IMGN853-0403 
 
 
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Abbreviation 
or Specialist 
Term 
Explanation 
ILD 
Interstitial lung disease 
IMGN 
ImmunoGen 
IND 
Investigational New Drug  
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
MUGA scan 
Multigated Acquisition scan 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NGS 
Next Generation Sequencing 
nM 
Nanomolar 
NSCLC 
Non-Small Cell Lung Carcinoma 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Progressive Disease 
PET 
Positron Emission Testing 
PFS 
Progression-free Survival 
PFS2 
Time to Second Disease Progression  
PFT 
Pulmonary Function Tests 
PgP 
P-Glycoprotein 
PK 
Pharmacokinetics 
PLD 
Pegylated Liposomal Doxorubicin 
PR 
Partial Response/remission 


Mirvetuximab Soravtansine (IMGN853) 
 
05 December 2019 
Protocol Number IMGN853-0403 
 
 
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Abbreviation 
or Specialist 
Term 
Explanation 
PRO 
Patient-reported Outcomes 
PS 
Performance Status 
PT 
Prothrombin Time 
Q3W 
Every 3 weeks 
Q4W 
Every 4 weeks 
QoL 
Quality of Life 
QTc  
Corrected QT interval 
RBC 
Red Blood Cell (count) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic Acid 
RP2D 
Recommended Phase 2 Dose 
RR 
Response Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase (AST) 
SGPT 
Serum Glutamic Pyruvic Transaminase (ALT) 
SoD 
Sum of Diameters 
SOC 
Standard of Care 
SOP 
Standard Operating Procedure 
SSC 
Schedule Selection Committee 
SC 
Steering Committee 
STD 
Severely Toxic Dose 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Events 
TPR 
Time Point Response 
ULN 
Upper Limit of Normal 
US 
United States 


Mirvetuximab Soravtansine (IMGN853) 
 
05 December 2019 
Protocol Number IMGN853-0403 
 
 
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Abbreviation 
or Specialist 
Term 
Explanation 
WBC 
White Blood Cell (count) 
WCBP 
Woman of Child Bearing Potential 
WHO 
World Health Organization 
WHO-DD 
World Health Organization –Drug Dictionary 
 
 


Mirvetuximab Soravtansine (IMGN853) 
 
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Protocol Number IMGN853-0403 
 
 
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PROTOCOL SYNOPSIS 
Title of Study: FORWARD1: A Randomized, Open Label Phase 3 Study to Evaluate the 
Safety and Efficacy of Mirvetuximab Soravtansine (IMGN853) Versus Investigator’s Choice 
of Chemotherapy in Women with Folate Receptor α−positive Advanced Epithelial Ovarian 
Cancer, Primary Peritoneal Cancer or Fallopian Tube Cancer 
Number of Patients (planned): Approximately 333 patients 
Study Center(s): approximately 130 centers globally 
Studied Period (months): Approximately 72 months 
(including follow up):  
First patient enrolled: 02-Mar-2016 (amendment 4) 
First patient dosed: 03-Mar-2016 
First patient enrolled in Phase 3: 24-Jan-2017 
Phase of Development: 3 
Purpose/Rationale:  
Mirvetuximab soravtansine (IMGN853) is a specific, targeted antibody drug (maytansinoid) 
conjugate (ADC) that binds with high affinity to folate receptor alpha (FRα), a 
glycosylphosphatidylinositol-linked protein, which is highly expressed on the surface of solid 
tumors, particularly epithelial ovarian cancer (EOC), endometrial cancer, and non-small cell 
lung carcinoma (NSCLC). IMGN853 consists of a humanized anti-FRα monoclonal antibody 
attached via a disulfide containing linker to the cytotoxic maytansinoid, N2’-[4-[(3-
carboxypropyl) dithio]-4-methyl-1-oxo-2-sulfopentyl]-N2’-deacetylmaytansine (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 FRα with high apparent affinity (≤ 0.1 nM) and shows 
potent (IC50 ≤ 1 nM) and selective cytotoxicity against tumor cells expressing folate receptor 
1 (FOLR1). IMGN853 additionally demonstrates significant activity against FRα-positive 
xenografts, with partial and complete remissions observed in ovarian cancer and NSCLC 
models. Together with the selective upregulation of FRα in solid tumors, these results provide 
the rationale for exploring the clinical utility of IMGN853. 
EOC patients often present with advanced disease, and have limited prognosis. Despite 
considerable improvements in primary therapy, 80% of the patients with advanced EOC are 
expected to relapse during or after treatment with platinum-containing regimens (Ledermann 
2010). Treatment of patients with recurrent EOC is less standardized than treatment of newly 
diagnosed patients.  
A recent retrospective study demonstrated that progression-free survival (PFS) and overall 
survival (OS) decrease by more than 50% as patients move from the first to the fifth relapse 
(Hanker 2012). Therefore, there is a clear need for new therapies that can improve the 
outcomes of this patient population, even though several agents are approved for platinum-
resistant EOC, including pegylated liposomal doxorubicin (PLD), topotecan, paclitaxel, and 
more recently bevacizumab in combination with chemotherapy 


Mirvetuximab Soravtansine (IMGN853) 
 
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IMGN853 has a 44% confirmed overall response rate [95% confidence interval (CI): 20% to 
70%] and median PFS of 6.7 months (95% CI: 3.9 to 11 months) in the subset of 16 patients 
with FRα−positive (medium/high expression) platinum-resistant EOC with one to three prior 
regimens treated as part of a 46 patient expansion cohort in the Phase 1 study (IMGN853 
study 401) (Moore 2016). Adverse events occurring in > 20% of patients in this cohort 
included diarrhea, blurred vision, fatigue, nausea, vomiting, and peripheral neuropathy, and 
were mostly low grade. Blurred vision is likely related to corneal keratopathy, transient 
microcysts that form on the cornea, causing temporary astigmatism. In the initial part of the 
expansion cohort, blurred vision occurred in 54.5% of patients and was mostly Grade 2, data 
presented at ASCO 2015 (Moore 2015). The latter half expansion cohort was associated with 
lower frequency (38.5%) and grade of blurred vision, mostly Grade 1. This improvement may 
be explained by the use of more effective management procedures, and implementation of 
concomitant use of preservative-free lubricating eye drops that was first recommended in 
September 2014 then mandated in April 2015 (Section 1.7.1). Following the implementation 
of these improved management procedures, the rate of blurred vision in the platinum-resistant 
EOC expansion cohort is now near the 35% that was targeted by the primary objective of 
exploring an every four-week dosing schedule in the Phase 2 trial (Section 1.7.1 and 
Appendix L). Based on these findings the every four-week dosing schedule was not explored 
further.  
Objectives: 
Primary Objective: 
• To compare the progression free survival (PFS) of patients randomized to 
IMGN853 versus selected standard of care chemotherapy, as assessed by the 
blinded independent review committee (BIRC), in the intent to treat (ITT) 
population (defined as all randomized patients) and in the high FRα subgroup 
(≥ 75% of tumor staining at ≥ 2+ intensity)  
Key Secondary Objectives: 
• To compare the ORR of patients randomized to IMGN853 versus selected 
standard of care chemotherapy 
− Primary analysis of ORR will be based on BIRC assessments. ORR based on 
investigator’s assessment will be analyzed as sensitivity analysis 
• To compare the primary patient-reported outcome (PRO) endpoint using QLQ-
OV28 assessments from patients randomized to IMGN853 versus selected 
standard of care chemotherapy as described in Section 11.7  
• To compare the OS of patients randomized to IMGN853 versus selected standard 
of care chemotherapy 
Other Secondary Objectives: 
• To compare the safety and tolerability of IMGN853 with that of selected standard 
of care chemotherapy  


Mirvetuximab Soravtansine (IMGN853) 
 
05 December 2019 
Protocol Number IMGN853-0403 
 
 
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• To compare the duration of response (DOR) of patients randomized to IMGN853 
versus selected standard of care chemotherapy 
− Primary analysis of DOR will be based on BIRC assessments. DOR based on 
investigator’s assessment will be analyzed as sensitivity analysis 
• To compare the CA-125 response rate per Gynecologic Cancer Intergroup (GCIG) 
CA-125 criteria of patients randomized to IMGN853 versus selected standard of 
care chemotherapy (IC) 
• To compare the PFS of patients randomized to IMGN853 versus selected standard 
of care chemotherapy, as assessed by the investigator 
• To evaluate the pharmacokinetics (PK) of IMGN853 
• To assess the immunogenicity of IMGN853 (Anti-drug antibodies, ADA) 
• To assess PRO using the EORTC QLQ-C30, EORTC QLQ-OV28, EQ-5D-5L, 
and eight-item FACT-ovarian symptom index (FOSI) questionnaires  
Exploratory Objectives: 
• To evaluate potential biomarkers in blood and tumor tissue that might predict 
response to IMGN853  
• To compare the time to second disease progression (PFS2) of patients randomized 
to IMGN853 versus selected standard of care chemotherapy (IC) 
• To identify DM4 metabolites in urine  
Study Design Overview and Schema: 
This Phase 3, open label, randomized study is designed to compare the efficacy of IMGN853 
to that of selected standard of care chemotherapy (Investigator’s choice) in patients with 
FRα−positive advanced EOC, primary peritoneal cancer or fallopian tube cancer.  
In this study, patients are randomized 2:1 to Arm 1: IMGN853 6 mg/kg AIBW Q3W; or 
Arm 2: Investigator’s choice (IC) chemotherapy: weekly paclitaxel every four weeks, PLD 
administered once every four weeks; or topotecan administered either on Days 1, 8, and 15 
every four weeks or for five consecutive days every three weeks. Patients are stratified 
according to the number of prior lines of therapy (1 or 2 vs. 3), FRα levels (high, defined as 
≥ 75% of tumor staining at ≥ 2+ intensity, vs. medium, defined as ≥ 50% and < 75% at > 2+ 
intensity), and IC chemotherapy (Paclitaxel, PLD, or Topotecan).  
Study Schema: 




Mirvetuximab Soravtansine (IMGN853) 
 
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administered dose of platinum therapy to the date of the radiographic imaging 
showing progression.  
• Patients must have at least one lesion that meets the definition of measurable 
disease by RECIST v1.1.  
• Patients must have received at least one but no more than three prior systemic 
lines of anti-cancer therapy and for whom single agent chemotherapy is 
appropriate as the next line of treatment. 
− Adjuvant ± Neoadjuvant will be considered as one line of therapy 
− Maintenance therapy (example: bevacizumab, PARP inhibitors) will be 
considered as part of the preceding line of therapy (ie, not counted 
independently) 
• Patients must be willing to provide an archival tumor tissue block or slides, or 
fresh biopsy collected using a non-significant risk procedure.  
• Patients must meet threshold of FRα positivity criteria by the Ventana IHC test. 
• Female patients ≥ 18 years of age with Eastern Cooperative Oncology Group 
(ECOG) performance status (PS) 0 or 1. 
• Patients must have adequate hematologic, liver, cardiac, and kidney function. 
Key Exclusion Criteria:  
• Patients with clear cell, mucinous or sarcomatous histology, or low grade ovarian 
cancer 
• Patients with primary platinum-refractory disease as defined by those who 
progressed during or within four weeks of completion of first platinum-based 
chemotherapy (Friedlander 2011)  
•  Patients with prior wide-field radiotherapy affecting at least 20% of the bone 
marrow 
• Patients with uncontrolled bleeding disorders or inadequate coagulation 
parameters  
• Patients with > Grade 1 peripheral neuropathy  
• Patients with active or chronic ocular disorders 
• History of neurological conditions, or concurrent neurological condition that 
would confound assessment of treatment-emergent neuropathy 
• History of hemorrhagic or ischemic stroke within the prior six months 
• Women who are pregnant or lactating or women of childbearing potential 
(WCBP) not protected by highly-effective contraceptive methods 
Investigational Product, Dosage and Mode of Administration:  


Mirvetuximab Soravtansine (IMGN853) 
 
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Patients randomized to IMGN853 receive a dose of 6 mg/kg AIBW on Day 1, with cycles 
repeating every three weeks. IMGN853 doses are calculated according to AIBW.  
Duration of Study Participation:  
The duration of study participation extends from the time the patient signs study consent until 
the final follow-up study visit. Patients continue to receive study treatment until they present 
with PD per RECIST 1.1, as assessed by the BIRC, develop unacceptable toxicity or 
withdraw consent, whichever comes first, or until the Sponsor terminates the study. Patients 
who discontinue study drug for reasons other than PD continue with tumor assessments until 
documentation of PD or start of new anti-cancer therapy. All patients are followed for PFS2 
and survival until one year after final analysis for the primary endpoint of PFS.  
Patients still receiving clinical benefit from IMGN853 at the time the study is completed by 
the Sponsor may continue to receive IMGN853. Patients who choose to continue to receive 
IMGN853 after the study is completed by the Sponsor will continue to be followed by their 
treating physician as per standard of care for their disease (including radiological 
assessments). These patients may remain on IMGN853 until disease progression as assessed 
by the Investigator, development of unacceptable toxicity, withdrawal of consent, initiation of 
a new anticancer therapy, or death, whichever comes first (refer to Appendix D for Schedule 
of Assessments). 
Statistical Methods: 
This is a Phase 3 study designed to evaluate the efficacy of IMGN853 compared with that of 
standard of care chemotherapy in women with epithelial ovarian cancer (EOC), primary 
peritoneal cancer or fallopian tube cancer.  
Sample Size Estimation:  
Primary endpoint for the study is PFS as assessed by BIRC in all randomized patients and 
PFS as assessed by BIRC in the FRα high expression subgroup. The study is designed to test 
the null hypothesis that the survival function for PFS is the same between IMGN853 arm and 
the IC chemotherapy arm versus the alternative hypothesis that the survival function for PFS 
is different between IMGN853 and IC chemotherapy arm. The Hochberg procedure will be 
used to control the study-wise type I error (Appendix J). Approximately 333 patients will be 
randomized 2:1 (222 in IMGN853 arm: 111 in IC arm) over a period of approximately 21 
months. The final analysis will be conducted when at least 236 PFS events are observed. An 
interim futility analysis will be conducted when at least 80 PFS events have occurred. The 
study will be terminated for futility at interim analysis (IA) if the observed hazard ratio is 
greater than 1 in both, all randomized patients as well as in the FRα high expression 
subgroup. The study will have 91% power to detect a hazard ratio of 0.583 in the FRα high 
expression subgroup and 96% power in all randomized patients at a study-wise alpha level of 
5% and the study will have a 39% probability of stopping for futility at interim analysis under 
the null hypothesis. Sample size and power was determined by simulations using SAS® 
software with the following assumptions:  
• median PFS for the IC arm is 3.5 months 
• median PFS for the IMGN853 arm is 6 months 


Mirvetuximab Soravtansine (IMGN853) 
 
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• exponential distribution for both event and censoring processes 
• ratio of FRα high to FRα medium is 2:1  
• annual censoring rate is 20% in both arms 
Statistical Analyses: Sample size calculations were based on efficacy assumptions.  
An interim futility analysis will be conducted when at least 80 PFS events, as assessed by the 
BIRC, have been observed. If the observed hazard ratio is greater than 1 in all randomized 
patients as well as in the FRα high expression subgroup, the study will be terminated for 
futility. 
If the study continues to full enrollment of 333 patients, the final analysis will be conducted 
when at least 236 PFS events have been observed. The Hochberg procedure will be used to 
control the study-wise type I error. 
Demographics and baseline characteristics will be summarized using descriptive statistics (n, 
mean, standard deviation, median, and range) for continuous variables and n (%) for discrete 
variables. 
Efficacy Analyses: 
Endpoints 
Statistical Analysis Methods 
Primary 
PFS as 
assessed by 
BIRC 
Kaplan-Meier method for survival function estimate 
Stratified Cox proportional hazard regression for hazard ratio 
estimate 
Stratified log-rank test for hypothesis testing 
Stratification factors:  
FRα expression level (medium vs. high),  
IC chemotherapy (paclitaxel vs. PLD vs. topotecan), and  
Number of prior lines of therapy (1 or 2 vs. 3) 
Unstratified analysis will be conducted as sensitivity analysis 
Key 
secondary 
ORR as 
assessed by 
BIRC and by 
investigator 
Stratified Cochran-Mantel-Haenszel (CMH) test for treatment 
comparison 
Clopper-Pearson method for 95% CI estimation 
Primary PRO 
endpoint  
As described in Section 11.7  
OS 
Same as primary analysis 
Safety data such as treatment-emergent adverse events (TEAEs), laboratory parameters, vital 
signs, etc., will be summarized and presented in tables. TEAEs will be coded using the latest 


Mirvetuximab Soravtansine (IMGN853) 
 
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version of Medical Dictionary for Regulatory Activities (MedDRA) and concomitant 
medications will be coded using the latest version of WHO-DRUG. 
PK parameters will not be calculated due to the sparse sampling scheme in this study. 
Summary statistics of the concentration at each time point (nominal time) will be presented. 
Graphical presentation of the data may also be completed using nominal time. 
All analyses will be carried out using SAS and/or WinNonlin software. 
A Statistical Analysis Plan (SAP) will fully describe the planned analyses for this study. 
Study Committees: 
• Steering Committee (SC) 
• Independent Data Monitoring Committee (IDMC) 
• Blinded Independent Review Committee (BIRC) 


Mirvetuximab Soravtansine (IMGN853) 
 
05 December 2019 
Protocol Number IMGN853-0403 
 
 
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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ................................................................................. 3 
INVESTIGATOR’S AGREEMENT ............................................................................ 4 
LIST OF ABBREVIATIONS ....................................................................................... 5 
PROTOCOL SYNOPSIS ........................................................................................... 10 
TABLE OF CONTENTS ............................................................................................ 18 
LIST OF TABLES ...................................................................................................... 26 
LIST OF FIGURES .................................................................................................... 26 
1. 
INTRODUCTION ................................................................................... 27 
1.1. 
Target Background .................................................................................. 27 
1.2. 
IMGN853 ................................................................................................. 27 
1.3. 
Epithelial Ovarian Cancer (EOC) ............................................................ 28 
1.4. 
Current Therapies .................................................................................... 29 
1.4.1. 
Paclitaxel .................................................................................................. 29 
1.4.2. 
Topotecan ................................................................................................ 30 
1.4.3. 
Pegylated Liposomal Doxorubicin (PLD) ............................................... 30 
1.5. 
Non-Clinical Studies of IMGN853 .......................................................... 30 
1.5.1. 
Impact of FRα Expression ....................................................................... 30 
1.5.2. 
Pharmacology .......................................................................................... 31 
1.5.3. 
Pharmacokinetics ..................................................................................... 31 
1.5.4. 
Toxicology ............................................................................................... 31 
1.6. 
Clinical Studies of IMGN853 .................................................................. 32 
1.6.1. 
First-in-Human Phase 1 Clinical Trial: Study 0401 ................................ 32 
1.6.2. 
Phase 1b Combination Trial: Study 0402 ................................................ 32 
1.7. 
Rationale for the Selection of Drug Dose Levels and Dosing Schedules 32 
1.7.1. 
IMGN853: Rationale for 6 mg/kg AIBW Q3W Dosing Schedule .......... 32 
1.7.2. 
Chemotherapeutic Agents in the Investigator’s Choice (IC) Arm .......... 33 
1.7.2.1. 
Paclitaxel .................................................................................................. 33 
1.7.2.2. 
Topotecan ................................................................................................ 34 
1.7.2.3. 
Pegylated Liposomal Doxorubicin (PLD) ............................................... 34 
1.8. 
Rationale for the Study Plan .................................................................... 34 
1.8.1. 
Rationale for the Study Population .......................................................... 35 


Mirvetuximab Soravtansine (IMGN853) 
 
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1.8.2. 
Crossover to IMGN853 after Progressive Disease as Assessed by BIRC 
(Patients Enrolled Under Amendment 6 Only) ....................................... 35 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................... 35 
2.1. 
Objectives ................................................................................................ 35 
2.1.1. 
Primary Objective .................................................................................... 35 
2.1.2. 
Secondary Objectives .............................................................................. 36 
2.1.2.1. 
Key Secondary Objectives ....................................................................... 36 
2.1.2.2. 
Other Secondary Objectives .................................................................... 36 
2.1.3. 
Exploratory Objectives ............................................................................ 36 
2.2. 
Endpoints ................................................................................................. 37 
2.2.1. 
Primary Endpoints ................................................................................... 37 
2.2.2. 
Secondary Endpoints ............................................................................... 37 
2.2.2.1. 
Key Secondary Endpoints ........................................................................ 37 
2.2.2.2. 
Other Secondary Endpoints ..................................................................... 37 
2.2.3. 
Exploratory Endpoints ............................................................................. 37 
3. 
STUDY POPULATION .......................................................................... 38 
3.1. 
Criteria for Selection of Patient Population ............................................. 38 
3.1.1. 
Inclusion Criteria ..................................................................................... 38 
3.1.2. 
Exclusion Criteria .................................................................................... 39 
4. 
INVESTIGATIONAL PLAN .................................................................. 41 
4.1. 
Study Design ............................................................................................ 41 
4.1.1. 
Overview and Schema ............................................................................. 41 
4.1.2. 
Dosing and Dosing Schedules for IMGN853 and Chemotherapeutic 
Agents ...................................................................................................... 42 
4.1.3. 
Continuation of Treatment Beyond Study Closure ................................. 43 
5. 
STUDY TREATMENT ........................................................................... 44 
5.1. 
IMGN853 ................................................................................................. 44 
5.1.1. 
IMGN853 Packaging ............................................................................... 44 
5.1.1.1. 
IMGN853 Storage, Handling and Accountability ................................... 44 
5.2. 
Investigator’s Choice Chemotherapeutic Agents .................................... 45 
5.3. 
Assignment of Patient Number ................................................................ 45 
5.3.1. 
Enrolled Patient Definition ...................................................................... 45 
5.3.2. 
Patient Assignment to Dosing Regimens ................................................ 45 


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5.4. 
Blinding Methods .................................................................................... 46 
5.5. 
Study Treatment Administration ............................................................. 46 
5.5.1. 
Premedication for Study Treatment ......................................................... 46 
5.5.1.1. 
IMGN853 ................................................................................................. 46 
5.5.1.2. 
IC Chemotherapy ..................................................................................... 46 
5.5.2. 
Preparation and Administration of IMGN853 ......................................... 46 
5.5.2.1. 
Calculation for Adjusted Ideal Body Weight .......................................... 46 
5.5.3. 
Preparation and Administration of IC Chemotherapy ............................. 48 
5.5.3.1. 
Preparation and Administration of Paclitaxel .......................................... 48 
5.5.3.2. 
Preparation and Administration of Pegylated Liposomal Doxorubicin .. 48 
5.5.3.3. 
Preparation and Administration of Topotecan ......................................... 48 
5.6. 
Dose Modification Guidelines ................................................................. 48 
5.6.1. 
IMGN853 ................................................................................................. 48 
5.6.1.1. 
Treatment Criteria .................................................................................... 48 
5.6.1.2. 
IMGN853-Related Adverse Events ......................................................... 48 
5.6.1.3. 
IMGN853 Dose Reduction Dose Levels ................................................. 50 
5.6.1.4. 
Monitoring and Management of Nausea and Vomiting .......................... 50 
5.6.1.5. 
Monitoring and Management of Diarrhea ............................................... 51 
5.6.1.6. 
Ocular Disorders ...................................................................................... 51 
5.6.1.7. 
Monitoring of Non-Infectious Pneumonitis............................................. 53 
5.6.1.8. 
Management of Electrolytes Imbalance .................................................. 57 
5.6.1.9. 
Potential Infusion-Related Reactions ...................................................... 57 
5.6.1.10. 
Discontinuation of IMGN853 Due to Toxicity ....................................... 60 
5.6.2. 
Paclitaxel .................................................................................................. 60 
5.6.2.1. 
Dose Reduction Dose Levels ................................................................... 61 
5.6.2.2. 
Criteria for Permanent Discontinuation of Paclitaxel .............................. 61 
5.6.3. 
Topotecan ................................................................................................ 61 
5.6.3.1. 
Dose Reduction Dose Levels ................................................................... 62 
5.6.3.2. 
Criteria for Permanent Discontinuation of Topotecan ............................. 62 
5.6.4. 
Pegylated Liposomal Doxorubicin (PLD) ............................................... 63 
5.6.4.1. 
Hematological Toxicities ......................................................................... 63 
5.6.4.2. 
Non-hematological Toxicities ................................................................. 64 
5.6.4.3. 
Criteria for Permanent Discontinuation of PLD ...................................... 66 


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5.6.4.4. 
Dose Reduction Dose Levels ................................................................... 66 
5.7. 
Discontinuation of the Patients from the Study or Study Treatment ....... 66 
5.7.1. 
End of Treatment (EOT) .......................................................................... 66 
5.7.2. 
End of Study (EOS) ................................................................................. 66 
5.7.3. 
Study Closure........................................................................................... 66 
5.7.4. 
Withdrawal of Consent ............................................................................ 67 
5.7.5. 
Lost to Follow up ..................................................................................... 67 
5.8. 
Period of Observation .............................................................................. 68 
5.9. 
Concomitant Medications and Procedures .............................................. 68 
5.9.1. 
Antiemetic and Antidiarrheal Medications .............................................. 68 
5.9.2. 
Folate-Containing Supplements ............................................................... 68 
5.9.3. 
Antineoplastic Therapy ............................................................................ 68 
5.9.4. 
Hematopoietic Growth Factors ................................................................ 68 
5.9.5. 
Anticoagulants ......................................................................................... 69 
5.9.6. 
Contraception ........................................................................................... 69 
5.9.6.1. 
Acceptable Methods of Contraception .................................................... 69 
5.9.7. 
Other Concomitant Medications .............................................................. 70 
5.9.8. 
Medications that are CYP3A Substrates or CYP3A Substrates with 
Narrow Therapeutic Index ....................................................................... 70 
5.10. 
Overdose and Medication Error ............................................................... 70 
5.10.1. 
Overdose .................................................................................................. 70 
5.10.2. 
Medication Error ...................................................................................... 70 
6. 
PHARMACOKINETIC (PK) AND IMMUNOGENICITY 
ASSESSMENTS...................................................................................... 70 
6.1. 
PK Assessments – IMGN853 .................................................................. 70 
6.1.1. 
Blood Samples for PK Measurements ..................................................... 71 
6.1.2. 
Urine Samples for Identification of DM4 Metabolites Collection .......... 71 
6.2. 
Immunogenicity Assessments – IMGN853 ............................................. 72 
7. 
BIOMARKER RESEARCH STUDIES .................................................. 72 
7.1. 
Evaluation of FRα Expression in Tumor Tissue ..................................... 72 
7.2. 
Exploratory Biomarker Studies ............................................................... 72 
7.2.1. 
Potential Predictive Markers of Drug Response ...................................... 73 
8. 
STUDY PROCEDURES ......................................................................... 73 


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8.1. 
Informed Consent .................................................................................... 73 
8.2. 
Inclusion and Exclusion Criteria ............................................................. 73 
8.3. 
Confirmation of Disease Diagnosis ......................................................... 74 
8.4. 
BRCA Mutation Status ............................................................................ 74 
8.5. 
Demographic/Medical History ................................................................ 74 
8.6. 
Physical Examination, Weight, and Height ............................................. 74 
8.7. 
Vital Signs ............................................................................................... 74 
8.8. 
Electrocardiogram (ECG) ........................................................................ 74 
8.9. 
Pulmonary Function Tests ....................................................................... 74 
8.10. 
Ocular Symptom Assessment and Ophthalmic Examination .................. 75 
8.10.1. 
Ocular Symptom Assessment .................................................................. 75 
8.10.2. 
Ophthalmic Examination ......................................................................... 75 
8.11. 
Laboratory Assessments .......................................................................... 75 
8.11.1. 
Clinical Laboratory Panels ...................................................................... 75 
8.12. 
Pregnancy Screen ..................................................................................... 76 
8.13. 
Eastern Cooperative Oncology Group Performance Status ..................... 76 
8.14. 
ECHO/MUGA Scan ................................................................................ 77 
8.15. 
Tumor Response Assessment .................................................................. 77 
8.15.1. 
Radiological Imaging ............................................................................... 77 
8.15.2. 
CA-125 .................................................................................................... 78 
8.16. 
Quality of Life - EORTC QLQ-C30, EORTC QLQ-OV28, Eight-item 
FOSI and EQ-5D-5L Questionnaires....................................................... 78 
8.17. 
Health-care Resource Utilization ............................................................. 78 
9. 
ASSESSMENT OF SAFETY .................................................................. 78 
9.1. 
Recording Adverse Events and Serious Adverse Events ........................ 78 
9.1.1. 
Definition of Adverse Events .................................................................. 79 
9.1.1.1. 
Adverse Event (AE) ................................................................................. 79 
9.1.1.2. 
Serious Adverse Event (SAE) ................................................................. 80 
9.1.1.3. 
Adverse Events of Special Interest (AESI) ............................................. 80 
9.1.2. 
Classification of Adverse Events ............................................................. 81 
9.2. 
Adverse Events ........................................................................................ 82 
9.2.1. 
Reporting Serious Adverse Events .......................................................... 82 
9.2.1.1. 
Reporting of Disease Progression ............................................................ 83 


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9.2.2. 
Reporting a Pregnancy ............................................................................. 83 
10. 
STUDY ACTIVITIES ............................................................................. 84 
10.1. 
Screening Visit ......................................................................................... 84 
10.1.1. 
Standard of Care Assessments ................................................................. 84 
10.2. 
End of Treatment Visit ............................................................................ 84 
10.3. 
Follow-up Assessments ........................................................................... 85 
10.3.1. 
Safety Follow-up ..................................................................................... 85 
10.3.2. 
Response Follow-up ................................................................................ 85 
10.3.3. 
PFS2 and Survival Follow-up .................................................................. 85 
11. 
STATISTICAL METHODS .................................................................... 85 
11.1. 
Sample Size ............................................................................................. 86 
11.2. 
Stratification ............................................................................................ 86 
11.3. 
Pharmacokinetic Analyses ....................................................................... 87 
11.4. 
Safety Analyses ....................................................................................... 87 
11.5. 
Efficacy .................................................................................................... 87 
11.6. 
Interim Analysis ....................................................................................... 88 
11.7. 
Patient-Reported Outcomes ..................................................................... 88 
11.8. 
Multiple Comparisons ............................................................................. 89 
11.8.1. 
Multiple Comparisons for Primary Efficacy Endpoints .......................... 89 
11.8.2. 
Multiple Comparisons for Key Secondary Efficacy Endpoints .............. 89 
12. 
QUALITY CONTROL AND ASSURANCE ......................................... 89 
12.1. 
Recording of Data and Data Quality Assurance ...................................... 89 
13. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES ....................................................................................... 90 
13.1. 
Ethical and Regulatory ............................................................................ 90 
13.1.1. 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval ........................................................................................ 90 
13.1.2. 
Patient Information and Consent ............................................................. 90 
13.2. 
Investigators and Study Administrative Structure ................................... 91 
13.3. 
Patient Confidentiality ............................................................................. 92 
13.4. 
Study Monitoring ..................................................................................... 92 
13.5. 
Study Committees .................................................................................... 92 
13.5.1. 
Steering Committee (SC) ......................................................................... 92 


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13.5.2. 
Independent Data Monitoring Committee (IDMC) ................................. 93 
13.6. 
Case Report Forms and Study Reports .................................................... 93 
13.7. 
Critical Documents .................................................................................. 93 
13.8. 
Protocol Adherence ................................................................................. 94 
13.9. 
End of Study ............................................................................................ 94 
13.10. 
Study Termination ................................................................................... 94 
13.11. 
Site Termination ...................................................................................... 95 
13.12. 
Access to Source Documentation ............................................................ 95 
13.13. 
Audits and Inspections ............................................................................. 95 
13.14. 
Data Generation and Analysis ................................................................. 96 
13.15. 
Retention of Data ..................................................................................... 96 
13.16. 
Financial Disclosure ................................................................................ 96 
13.17. 
Insurance Compensation .......................................................................... 96 
13.18. 
Publication and Disclosure Policy ........................................................... 96 
14. 
LIST OF REFERENCES ......................................................................... 98 
APPENDIX A. SCHEDULE OF CLINICAL ASSESSMENTS - ARM 1 
(IMGN853) AND ARM 2 (IC: TOPOTECAN) – 3 WEEK CYCLE ... 104 
APPENDIX B. SCHEDULE OF CLINICAL ASSESSMENTS – ARM 2 (IC: PLD, 
PACLITAXEL AND TOPOTECAN) - 4 WEEK CYCLE ................... 108 
APPENDIX C. BIOMARKER, PHARMACOKINETIC AND 
IMMUNOGENICITY ASSESSMENTS............................................... 114 
APPENDIX D. SCHEDULE OF ASSESSMENTS FOR PATIENTS WHO 
CONTINUE TO RECEIVE IMGN853 AFTER THE STUDY IS 
COMPLETED BY THE SPONSOR – 3 WEEK CYCLE .................... 115 
APPENDIX E. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS SCALE .................................................... 116 
APPENDIX F. RESPONSE DEFINITION (RECIST 1.1) .................................... 117 
APPENDIX G. GYNECOLOGIC CANCER INTERGROUP (GCIG) CRITERIA 
FOR EVALUATION OF CA-125 ......................................................... 123 
APPENDIX H. LIST OF CONCOMITANT MEDICATIONS REQUIRING 
CAREFUL MONITORING .................................................................. 124 
APPENDIX I. ADJUSTED IDEAL BODY WEIGHT (AIBW) CALCULATION
 
 ........................................................................................................ 125 
APPENDIX J. SIMULATION REPORT .............................................................. 126 
APPENDIX K. HISTORY OF AMENDMENTS.................................................. 129 


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APPENDIX L. PHASE 2 STUDY PROTOCOL REVISED IN AMENDMENT 6 
AS A PIVOTAL PHASE 3 STUDY ..................................................... 136 
APPENDIX M. CRITERIA FOR CROSSOVER TO IMGN853 AFTER 
PROGRESSIVE DISEASE AS ASSESSED BY BIRC (PATIENTS 
ENROLLED TO AMENDMENT 6 ONLY) ........................................ 138 
APPENDIX N. INVESTIGATOR’S DECLARATION FOR CONTINUED 
TREATMENT ....................................................................................... 139 
 


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LIST OF TABLES 
Table 1: 
Dose and Dosing Schedules ..................................................................... 43 
Table 2: 
Dose Modifications for IMGN853 Related Adverse Events ................... 49 
Table 3: 
IMGN853 Dose Reduction Dose Levels ................................................. 50 
Table 4: 
Management of Nausea and Vomiting .................................................... 50 
Table 5: 
Management of Ocular Disorders ............................................................ 53 
Table 6: 
Management of Non-Infectious Pneumonitis .......................................... 55 
Table 7: 
Management Guidelines for Potential Infusion-related Reactions .......... 58 
Table 8: 
Paclitaxel Dose Modification Guidelines ................................................ 60 
Table 9: 
Paclitaxel Dose Reductions ..................................................................... 61 
Table 10: Topotecan Dose Modification Guidelines ............................................... 61 
Table 11: Topotecan Dose Reductions (Weekly Schedule) .................................... 62 
Table 12: Topotecan Dose Reductions (Five Days Schedule) ................................. 62 
Table 13: Adverse Events Requiring Permanent Discontinuation of Topotecan .... 63 
Table 14: Pegylated Liposomal Doxorubicin (PLD) Dose Modification Guidelines 
for Hematological Adverse Events .......................................................... 64 
Table 15: PLD Dose Modification Guidelines for Hand and Foot Syndrome and 
Mucositis.................................................................................................. 65 
Table 16: PLD Dose Reductions .............................................................................. 66 
Table 17: Clinical Laboratory Tests ........................................................................ 76 
Table 18: Adverse Event Severity ........................................................................... 81 
Table 19: Adverse Event Causal Relatedness .......................................................... 82 
 
LIST OF FIGURES 
Figure 1: 
IMGN853 Structure ................................................................................. 28 
Figure 2: 
Study Design Schema .............................................................................. 42 
 
 


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1. 
INTRODUCTION 
1.1. 
Target Background 
Folate receptor α (FRα) is a glycosylphosphatidylinositol-anchored cell surface protein 
encoded by the folate receptor 1 (FOLR1) gene. FRα internalizes folate, which is an essential 
co-factor for one-carbon transfer reactions that are required for deoxyribonucleic acid (DNA) 
and ribonucleic acid (RNA) synthesis, cell growth and proliferation. Marked up regulation of 
FRα 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 FRα expression and employ alternative transporters such as folate receptor β, reduced 
folate carrier and proton-coupled folate transporter for folate uptake (Weitman 1992, 
Mantovani 1994, Elnakat 2004, Kelemen 2006, and Investigator Brochure).  
Published studies have demonstrated FRα over expression by immunohistochemistry (IHC) 
in various epithelial tumors, particularly serous and endometrioid ovarian cancers, and serous 
and endometrioid endometrial cancers (Scorer 2010, Garin-Chesa 1993, Kalli 2008, Crane 
2012, Dainty 2007, Jones 2008, Ab 2015, and Allard 2007). IHC results obtained from 
patients screened or enrolled in the Phase 1 Study (IMGN853 study 0401) are generally 
consistent with the literature (Investigator Brochure). While assessing the FRα distribution in 
the platinum-resistant EOC expansion cohort, 81.8. % patients had high/medium FRα 
expression, (high, defined as ≥ 75% of tumor staining at ≥ 2+ intensity, vs. medium, defined 
as ≥ 50% and < 75% at > 2+ intensity) (Borghei 2015). 
Several additional studies have further validated FRα as a target in serous ovarian cancer. 
First, quantitative polymerase chain reaction studies show ubiquitous FRα mRNA expression 
in serous ovarian cancer (Hanker 2012, Hoskins 1998, Hough 2001) and high levels of FRα 
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 FRα expression comparably to primary tumors as shown by serial biopsy 
sampling and IHC (Kalli 2008, Crane 2012). Third, studies with FRα -specific imaging 
agents have demonstrated real-time FRα expression at primary and metastatic tumor sites 
(Fisher 2008, Garcia 2013, Garin-Chesa 1993, and van Dam 2011). Finally, a truncated form 
of FRα has been detected in ascites and blood of ovarian cancer patients (Basal 2009, 
Markman 2000, Mantovani 1994), further confirming expression in this disease and 
suggesting that the receptor may serve as a circulating biomarker. Collectively, these data 
suggest that FRα 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, FRα has emerged as a promising target for ADC therapy. ADCs 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 ADC designed to target FRα. It consists of the humanized anti- FRα 
monoclonal antibody M9346A attached via a cleavable disulfide linker to the cytotoxic 
maytansinoid, DM4 (Figure 1). 
 




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classified as platinum resistant, whereas, disease recurring greater than 6 months after 
therapy is termed platinum sensitive. Patients with platinum resistant disease typically receive 
single agent chemotherapy (eg, liposomal doxorubicin, topotecan, gemcitabine, paclitaxel, or 
other) at relapse. Unfortunately, response rates associated 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. Recently, bevacizumab was approved for use in combination with chemotherapy 
for recurrent ovarian cancer in the platinum resistant setting (Pujade-Lauraine 2014). Because 
platinum resistant ovarian cancer remains a significant unmet medical need, the National 
Comprehensive Cancer Network (NCCN) guidelines recommend that platinum resistant 
patients participate in clinical trials (NCCN Guidelines 2015). 
Commonly used agents for platinum resistant EOC are paclitaxel, topotecan and pegylated 
liposomal doxorubicin, all of which have modest levels of activity. In a single-agent Phase 2 
study of liposomal doxorubicin in patients who progressed following previous paclitaxel and 
platinum-based regimens, the response rate was 27% and PFS was 5.7 months. In a number 
of Phase 2 studies, response rates between 10 and 15% were reported (Gordon 2000, 
Markman 2000). Modest results associated with these single-agent salvage regimens 
underscore the need for improved therapies. 
1.4. 
Current Therapies 
Current management of advanced stage disease includes surgical tumor debulking, followed 
by adjuvant platinum- and taxane-based chemotherapy. However, the majority of the patients 
will recur (Garcia 2013). Patients with relapsed platinum sensitive disease are often treated 
with carboplatin alone or as part of a combination regimen (Pfisterer 2006), whereas those 
with platinum-resistant disease may be treated with a variety of agents, including paclitaxel, 
topotecan and pegylated liposomal doxorubicin (PLD).  
1.4.1. 
Paclitaxel 
Paclitaxel is a taxane that can stabilize microtubules to inhibit cell division. The drug was 
approved for treatment of recurrent EOC when response rates (RR) of 25% to 37% were 
observed in multiple Phase 2 trials testing the 3-weekly schedule (McGuire 1989, 
Thigpen 1994, Rowinsky 1995). In the study by Thigpen et al, a median PFS of 4.2 months 
and an OS of 16 months were observed. A Phase 2 trial showed that weekly dosing could 
lead to a 20.9% RR in platinum- and paclitaxel-resistant EOC patients (Gynecologic 
Oncology Group 2006). This alternative weekly dosing schedule for paclitaxel was studied in 
many trials in refractory, persistent, or recurrent EOC patients, as reviewed by Baird et al. 
(Baird 2010). A randomized Phase 3 study comparing weekly versus 3-weekly paclitaxel in 
recurrent EOC patients (of whom half were platinum-resistant) showed no difference in RR, 
PFS, or OS. However, the weekly schedule had a better safety profile than the 3-weekly 
schedule, as considerably less neutropenia, neuropathy, and myalgia were observed 
(Rosenberg 2002). Of note, the occurrence of neutropenia was also reduced when paclitaxel 
was infused over 3 hours instead of 24 hours (Eisenhauer 1994). A recent randomized Phase 
2 clinical trial (CARTAXHY) tested the efficacy of weekly paclitaxel as a single agent, or in 
combination with carboplatin, or weekly topotecan in patients with platinum-resistant EOC. 
The results showed that the combination treatments increased hypersensitivity reactions, 


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febrile neutropenia, and anemia, and did not improve RR or median PFS when compared to 
single agent weekly paclitaxel (Lortholary 2012). 
1.4.2. 
Topotecan 
Topotecan’s mechanism of action is different from that of paclitaxel, as it does not directly 
block cell division, but instead induces irreversible DNA damage. Topotecan inhibits 
topoisomerase 1, leading to both single and double stranded DNA breaks that eventually 
promote apoptosis. Topotecan (administered once daily the first 5 days of 21-day cycles) was 
approved for treatment of EOC after failure of initial or subsequent chemotherapy. This 
approval was based on a Phase 3 trial that showed it to be at least as effective as paclitaxel, 
with RR of 21% versus 13%, and median PFS of 23 weeks versus 14 weeks, respectively (ten 
Bokkel Huinink 1997). Unfortunately, topotecan treatment led to severe bone marrow 
suppression with 80% Grade 4 neutropenia, 25% Grade 4 thrombocytopenia, and 41% Grade 
3 or 4 anemia (ten Bokkel Huinink 1997). 
As such toxicities are often dose limiting, multiple clinical trials have studied alternative 
dosing schedules to improve the tolerability of topotecan treatment (Armstrong 2004, 
Hoskins 1998, Markman 2000). For example, one Phase 2 trial tested the effect of the 
“standard” dosing of topotecan (1.5 mg/m2, daily the first 5 days of 21-day cycles) compared 
with an alternative dosing regimen (1.75 mg/m2, once a week for 4 weeks, repeated every six 
weeks) in patients with recurrent EOC. The alternative dosing regimen led to a lower RR 
(9.6% compared with 22.6% in the standard dosing arm), but also decreased myelotoxicity 
(52% of patients had Grade 3 or 4 granulocytopenia in comparison with 94% in the standard 
dosing arm) (Hoskins 1998). A subsequent Phase 2 trial tested the effect of yet another 
dosing schedule (1.5 mg/m2, daily the first three days of 21-day cycles) (Markman 2000). 
Compared to historical controls, this alternative dosing regimen seemed to decrease the 
toxicity of topotecan. In a meta-analysis of various clinical trials, it was concluded that 
modification of the topotecan dose, and potentially the dosing schedule, can indeed reduce 
hematologic toxicity without decreasing the efficacy of the drug (Armstrong 2004). 
1.4.3. 
Pegylated Liposomal Doxorubicin (PLD) 
PLD is another standard chemotherapy regimen used for treating platinum-resistant EOC. 
The active component of this drug (doxorubicin) is an anthracycline that intercalates DNA, 
leading to inhibition of replication and, subsequently, the inhibition of proper cell division. 
Efficacy of PLD in platinum-resistant EOC has been confirmed in several Phase 2 trials. In 
detail, the trial by Muggia et al reported a 26% RR, median PFS of 5.7 months, and OS of 11 
months (Muggia 1997). A subsequent trial showed a 17% RR and median PFS of 4.5 months 
(Gordon 2000). Of note, a Phase 3 trial testing topotecan treatment versus PLD treatment 
showed a trend toward a higher RR in the platinum-resistant EOC patients subset treated with 
PLD, although there was no improvement of PFS or OS (Gordon 2001, Gordon 2004). 
1.5. 
Non-Clinical Studies of IMGN853 
1.5.1. 
Impact of FRα Expression 
Studies assessing the potency and specificity of IMGN853 were conducted on a panel of 
FRα-positive cell lines with a wide range of FRα expression, as well as on FRα-negative cell 


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lines (Investigator Brochure). These studies revealed a positive correlation between the level 
of FRα expression on the cell surface, the amount of maytansinoid catabolites generated, and 
the degree of sensitivity of the cells to IMGN853 in vitro. IMGN853 is not active against low 
and negative FRα expressing cells. 
1.5.2. 
Pharmacology 
Results of nonclinical pharmacology studies demonstrate the following: 
• FRα has limited normal tissue expression and marked expression in solid tumors, 
particularly cancers of the ovary and endometrium (Investigator Brochure). In 
vitro studies demonstrated that IMGN853 binds cell surface FRα with high 
apparent affinity (≤ 0.1 nM) and shows potent (IC50 ≤ 1 nM) and selective 
cytotoxicity against cells expressing FRα. IMGN853-mediated cytotoxicity 
involves binding, internalization, and degradation of IMGN853, which releases 
DM4. DM4 can be methylated to yield S-methyl-DM4. Both DM4 and S-methyl-
DM4 can inhibit tubulin polymerization and microtubule assembly, causing cell 
death. The lipophilic molecules S-methyl DM4 and DM4 can also diffuse to 
neighboring cells and induce bystander killing.  
• In vitro cytotoxicity studies suggest that cells sensitive to IMGN853 express 
higher levels of FRα 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 FRα, 
capacity for uptake, internalization and degradation by FRα-positive target cells, 
and ability to induce antibody-dependent cell-mediated cytotoxicity (ADCC) in 
vitro.  
• IMGN853 demonstrates significant activity against FRα -positive xenografts. 
Partial and/or complete regressions in xenograft models of epithelial ovarian 
cancer were seen at doses of IMGN853 well below its maximum tolerated dose 
(MTD).  
1.5.3. 
Pharmacokinetics 
Nonclinical studies with IMGN853-cross reactive (monkey) and non-cross reactive (mouse) 
species were conducted to define pharmacokinetics (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. PK studies demonstrated the stability of 
IMGN853 in circulation following IV administration, with a distribution phase lasting about 
24 hours followed by a slower terminal elimination phase. The data indicated that the PK of 
IMGN853 were approximately dose proportional within the ranges evaluated 
(1 mg/kg – 10 mg/kg). These studies are further detailed in the Investigator Brochure.  
1.5.4. 
Toxicology 
IMGN853 was evaluated for toxicity after a single intravenous injection in cross reactive 
(monkey) and non-cross reactive (mouse) species. Results of these studies supported the first-


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in-human (FIH) study exploring the safety and tolerability of IMGN853 when administered 
once every three weeks to patients with advanced solid tumors. Potential risks suggested by 
these studies as well as clinical experience with other maytansinoid ADCs include 
hematologic abnormalities, electrolyte alterations, injection site reactions, infusion reactions, 
immunogenicity, hepatic abnormalities, and peripheral neuropathy. Toxicology studies are 
further detailed in the Investigator Brochure. 
1.6. 
Clinical Studies of IMGN853 
1.6.1. 
First-in-Human Phase 1 Clinical Trial: Study 0401 
The FIH Phase 1 study is evaluating the safety, pharmacokinetics and pharmacodynamics of 
single-agent IMGN853 in patients with EOC and other FRα -positive tumors. The 
recommended Phase 2 dose (RP2D) for single agent IMGN853 administered once every three 
weeks was determined to be 6.0 mg/kg AIBW. Data from this study, including PK and 
TEAEs reported by patients enrolled in the dose escalation cohorts are detailed in the 
Investigator Brochure.  
As of 31 January 2017, 206 patients had been dosed. At least one TEAE was reported by 205 
patients (> 99%). TEAEs of Grade 1 or 2 were most common (102 patients, 50%), 86 patients 
(42%) reported Grade 3 TEAEs, 10 patients (5%) reported Grade 4 and seven patients (3%) 
experienced a Grade 5 TEAE.  
The most common TEAEs, reported in ≥ 20% of patients included diarrhea (94 patients, 
46%); fatigue (91 patients, 44%); nausea (84 patients, 41%); blurred vision (72 patients, 
35%); neuropathy peripheral (47 patients, 23%); headache (55 patients, 27%); vomiting (54 
patients, 26%); abdominal pain (47 patients, 23%); decreased appetite and aspartate 
aminotransferase (AST) increased (46 patients, 22%). Safety data are further detailed in the 
IMGN853 Investigator Brochure. 
1.6.2. 
Phase 1b Combination Trial: Study 0402 
A Phase 1b study is ongoing to evaluate the safety, tolerability and pharmacokinetics of 
IMGN853 in combination with bevacizumab, carboplatin, pegylated liposomal doxorubicin 
or pembrolizumab in adults with FRα -positive advanced epithelial ovarian cancer, primary 
peritoneal cancer, fallopian tube cancer, or endometrial cancer. 
1.7. 
Rationale for the Selection of Drug Dose Levels and Dosing 
Schedules 
1.7.1. 
IMGN853: Rationale for 6 mg/kg AIBW Q3W Dosing Schedule  
IMGN853 will be administered at 6 mg/kg, with the dose calculated using AIBW. The use of 
AIBW to calculate the dose of IMGN853 has been shown to reduce intra-cohort variability in 
Cmax and AUC0-24 (Moore 2014). 
IMGN853 administered at 6 mg/kg AIBW once every three weeks was found to be the RP2D 
in the FIH study (Phase 1 study, 0401). As of 29 April 2016, data from the 46 patients 
(treated at 6mg/kg AIBW Q3W) in the platinum-resistant EOC expansion cohort of the 
Phase 1 study was analyzed for safety profile, tumor response, FRα expression, prior 


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therapies and drug exposure. Adverse events occurring in > 20% of patients in this cohort 
included diarrhea, blurred vision, fatigue, nausea, vomiting, and peripheral neuropathy, and 
were mostly low grade.  
Blurred vision is likely related to corneal keratopathy, characterized by transient microcysts 
that form in the corneal epithelium, causing temporary astigmatism. In the initial part of the 
expansion cohort, blurred vision occurred in 54.5% of patients and was mostly Grade 2 (data 
presented at ASCO 2015, Moore 2015). The latter half expansion cohort was associated with 
lower frequency (38.5%) and grade of blurred vision, mostly Grade 1. This improvement may 
be explained by the use of more effective management procedures such as exclusion of 
patients with active or chronic corneal disorders or other active ocular conditions requiring 
ongoing treatment/monitoring, and patients experiencing eye disorders are advised to use 
baby shampoo and soft cloth to clean the eyes, and warm compress at bedtime. Additionally, 
recommendation of daytime use of UVA/UVB sunglasses, avoidance of contact lenses and 
use of preservative-free lubricating eye drops are recommended for all patients during active 
study treatment. These management guidelines were first recommended in September 2014 
then mandated in April 2015. Following implementation of these guidelines, the rate of 
blurred vision in the platinum resistant EOC expansion cohort is now near the 35% that was 
targeted by the goal of exploring a once every four weeks dosing schedule in the Phase 2 
study. Safety data from study 0401 showed a 29% reduction in the rate of blurred vision 
(38.5% versus 54.5%). (For details, refer to Appendix L). Additionally, increased investigator 
awareness of expected ocular events may have improved the evaluation and management of 
ocular treatment emergent adverse events (TEAEs) in these patients. Preliminary data from 
Study 0401 suggest further reduction in the intensity and frequency of ocular AEs with the 
prophylactic use of corticosteroid eye drops. 
Based on these findings, the sponsor determined that it is not essential to explore the once 
every four weeks dosing schedule as per the study design in the original Phase 2 study 
protocol. The data were presented to the Independent Data Monitoring Committee (IDMC) 
and the Schedule Selection Committee (SSC), and both committees supported this 
assessment. The SSC approved the decision to use 6 mg/kg AIBW Q3W for patients 
randomized to IMGN853.The Phase 2 study was amended to a Phase 3 study (Appendix L). 
For study treatment and clinical assessment guidelines for the four patients enrolled on the 
Phase 2 versions of the study, please refer to Appendix L. 
1.7.2. 
Chemotherapeutic Agents in the Investigator’s Choice (IC) Arm 
Three drugs most commonly used in the setting of platinum resistance are pegylated 
liposomal doxorubicin, paclitaxel and topotecan (Ledermann 2013 (ESMO Guidelines), 
NCCN Guidelines 2014, and Luvero 2014). The ability of patients to tolerate the bone 
marrow suppressive effects of cytotoxic chemotherapy is less than that of patients receiving 
initial therapy. Modified doses and administration schedules (outside of the label for first line 
or second-line EOC) are therefore, typically used to treat ovarian cancer in such settings.  
1.7.2.1. 
Paclitaxel 
The approved schedule of paclitaxel every 3 weeks for second-line treatment of ovarian 
cancer is associated with a high rate of myelosuppression, particularly neutropenia, and 
peripheral neuropathy. Investigators therefore developed interest in evaluating the antitumor 


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activity and tolerability of a weekly schedule. The weekly schedule is associated with similar 
efficacy and an improved toxicity profile, with less bone marrow suppression and 
neuropathy. Supporting evidence for the 80 mg/m2 weekly dosing schedule has been reported 
for several Phase 2 and Phase 3 studies (Rosenberg 2002, Markman 2002, Gynecologic 
Oncology Group 2006, and Baird 2010) as described in Section 1.4.1. 
1.7.2.2. 
Topotecan 
The approved topotecan dosing for relapsed ovarian cancer is 1.5 mg/ m2/d, administered on 
days 1 to 5 of a 3-week schedule. However, reduced doses (ie, 1.25 mg/m2/d) are associated 
with decreased toxicity and similar outcome, thereby being widely used in routine clinical 
practice (Sehouli 2009). Results from several studies suggest that women with relapsed 
ovarian cancer may benefit from similar effectiveness but significantly lower hematologic 
toxicity if topotecan is administered in a weekly schedule. A Phase 2 trial of the North-
Eastern German Society of Gynaecology Oncology Ovarian Cancer Study Group, has 
compared weekly schedule versus the conventional 5-day schedule, reporting comparable OS 
rates and a favorable toxicity profile for weekly 4.0 mg/m2/week topotecan, making it another 
viable option in platinum resistant ovarian cancer (Sehouli 2011). Based on this evidence 
from the literature, a conventional (1.25 mg/m2/d, on days 1 to 5 of a 3-week schedule) and 
an alternative (4.0 mg/m2/week, days 1, 8, and 15 of a 4-week cycle) schedules of topotecan 
were selected for the study. 
1.7.2.3. 
Pegylated Liposomal Doxorubicin (PLD)  
PLD is approved as monotherapy in recurrent platinum-resistant ovarian cancer. The 
approved dose and schedule of 50 mg/m2 every 28 days of PLD results in a substantial 
incidence (approximately 20% to 30%) of Grade 3 “hand-foot-syndrome” (Markman 2011). 
Considerable clinical experience generated since the initial regulatory approval of PLD has 
revealed equivalent clinical activity with substantially less severe adverse events when this 
agent is administered at a dose of 40 mg/m2 (rather than 50 mg/m2) on a 4-week schedule 
(Markman 2011). Results of two randomized Phase 2 trials (Markman 2000 and 
Wilailak 2004) provide strong support for the conclusion that the 40 mg/m2 dose level of PLD 
is therapeutically equivalent to the higher (and more toxic) dose approved for standard use in 
the second-line management of ovarian cancer. Recently a study was conducted to show 
equivalence in efficacy of PLD 40 mg/m2 and PLD 50 mg/m2 (Yoshizawa 2015). This 
randomized controlled study also supports the use of an initial dose of 40 mg/m2 PLD.  
1.8. 
Rationale for the Study Plan 
This Phase 3, open label, randomized study is designed to compare the efficacy of IMGN853 
to that of selected standard of care chemotherapy (Investigator’s choice [IC]) in women with 
platinum- resistant, advanced EOC, primary peritoneal cancer or fallopian tube cancer.  
This study will compare the safety and efficacy of IMGN853 administered at 6 mg/kg AIBW 
Q3W with IC standard of care chemotherapy (paclitaxel, PLD or topotecan). Patients will be 
enrolled 2:1 into one of two arms as follows:  
• Arm1: IMGN853 6mg/kg AIBW Q3W 
• Arm 2: IC chemotherapy  


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1.8.1. 
Rationale for the Study Population 
Preliminary results from the FIH study of IMGN853 suggest that higher FRα levels correlate 
with response to treatment (Martin 2015). Therefore, this study will enroll patients who meet 
the FRα eligibility criterion of ≥ 50% of tumor staining at ≥ 2+ intensity. Additionally, a 
more stringent stratification cut-off of ≥ 75% of tumor staining at ≥ 2+ intensity will be 
evaluated.  
Results from 46 patients from the platinum-resistant EOC expansion cohort of the Phase 1 
study, also suggest that the response rate correlates with the number of prior therapies. 
IMGN853 has a 44% confirmed overall response rate (95% CI: 20% to 70%) and a median 
PFS of 6.7 months (95% CI: 3.9 to 11 months) in the subset of 16 patients with FRα−positive 
(medium/high expression) platinum-resistant EOC with one to three prior regimens treated as 
part of a 46 patient expansion cohort in the Phase 1 study (Moore 2016). These data suggest 
that patients with medium to high FRα expression who have received no more than three 
prior therapies are more likely to respond to IMGN853. Based on the above observations, the 
current study will enroll patients who have received one to three prior therapies and who 
meet the FRα eligibility criterion (≥ 50% tumor staining at ≥ 2+ intensity).  
1.8.2. 
Crossover to IMGN853 after Progressive Disease as Assessed by BIRC 
(Patients Enrolled Under Amendment 6 Only) 
Patients who consented to this study under Amendment 6 and who discontinue IC 
chemotherapy for BIRC-confirmed, RECIST-defined PD will be given the option to 
crossover to the IMGN853 arm (Arm 1). Patients who choose to crossover to IMGN853 must 
meet entry criteria (Appendix M) prior to treatment with IMGN853. The EOT visit will be 
completed before crossing over to the IMGN853 arm. The schedule of events for patients 
who crossover is located in Appendix A. Patients will continue to receive study treatment 
until they present with PD per RECIST 1.1, as assessed by investigator, develop unacceptable 
toxicity or withdraw consent, whichever comes first, or until the Sponsor terminates the study 
(Section 5.6.1.10, Section 5.7.2, Section 5.7.4, and Section 5.7.5). Study treatment and/or 
participation in the study may be discontinued at any time at the discretion of the 
Investigator. The Crossover End of Treatment (CO-EOT) visit will be performed when the 
patient discontinues study treatment. Follow-up assessments as per Section 10.3 will be 
followed. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
• To compare the progression free survival (PFS) of patients randomized to 
IMGN853 versus selected standard of care chemotherapy (IC), as assessed by the 
blinded independent review committee (BIRC), in the intent to treat (ITT) 
population (defined as all randomized patients) and in the high FRα subgroup 
(≥ 75% of tumor staining at ≥ 2+ intensity)  


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2.1.2. 
Secondary Objectives 
2.1.2.1. 
Key Secondary Objectives 
• To compare the objective response rate (ORR) of patients randomized to 
IMGN853 versus selected standard of care chemotherapy (IC) 
− Primary analysis of ORR will be based on BIRC assessments. ORR based on 
investigator’s assessment will be analyzed as sensitivity analysis 
• To compare the primary PRO endpoint using QLQ-OV28 assessments from 
patients randomized to IMGN853 versus selected standard of care chemotherapy 
(IC) as described in Section 11.7  
• To compare the overall survival (OS) of patients randomized to IMGN853 versus 
selected standard of care chemotherapy (IC) 
2.1.2.2. 
Other Secondary Objectives 
• To compare the safety and tolerability of IMGN853 with that of selected standard 
of care chemotherapy (IC) 
• To compare the DOR of patients randomized to IMGN853 versus selected 
standard of care chemotherapy (IC) 
− Primary analysis of DOR will be based on BIRC assessments. DOR based on 
investigator’s assessment will be analyzed as sensitivity analysis 
• To compare the CA-125 response rate per Gynecologic Cancer Intergroup (GCIG) 
CA-125 criteria of patients randomized to IMGN853 versus selected standard of 
care chemotherapy (IC) 
• To compare the progression free survival (PFS) of patients randomized to 
IMGN853 versus selected standard of care chemotherapy (IC), as assessed by the 
investigator 
• To evaluate the pharmacokinetics of IMGN853 
• To assess the immunogenicity of IMGN853(Anti-drug antibodies, ADA) 
• To assess PRO using the EORTC QLQ-C30, EORTC QLQ-OV28, EQ-5D-5L, 
and eight-item FOSI questionnaires  
2.1.3. 
Exploratory Objectives 
• To evaluate potential biomarkers in blood and tumor tissue that might predict 
response to IMGN853 
• To compare the time to second disease progression (PFS2) of patients randomized 
to IMGN853 versus selected standard of care chemotherapy (IC) 
• To identify DM4 metabolites in urine 


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2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
• Progression-free survival (PFS): the time from the date of randomization until the 
time of death or PD, as assessed by the BIRC 
− In all patients randomized to the study 
− In patients with high FRα level (≥ 75% of tumor staining at ≥ 2+ intensity) 
2.2.2. 
Secondary Endpoints 
2.2.2.1. 
Key Secondary Endpoints 
• Objective response rate (ORR) per RECIST 1.1 criteria as assessed by BIRC 
• Primary PRO endpoint using the QLQ-OV28 questionnaire as described in 
Section 11.7  
• Overall survival (OS): the time from the date of randomization until the date of 
death 
2.2.2.2. 
Other Secondary Endpoints 
• Treatment-emergent adverse events and laboratory test results, physical 
examination, ECGs or vital signs 
• Gynecologic Cancer Intergroup (GCIG) CA-125 criteria (Appendix G) clinical 
response rate 
• Time to event endpoints: 
− PFS as assessed by investigator 
− Duration of response (DOR): the time from first objective response (CR/PR) 
to the time of PD among those who have achieved a PR or CR 
• PK parameters of IMGN853 
• Immunogenicity of IMGN853: ADA 
• Patient scores on EORTC QLQ-C30, EORTC QLQ-OV28, EQ-5D-5L and eight-
item FOSI questionnaires  
2.2.3. 
Exploratory Endpoints 
• Evaluate association of breast cancer susceptibility gene (BRCA) mutation status 
in tumor tissue and FRα expression level with anti-tumor activity of IMGN853 
• Evaluate the association of anti-tumor activity and/or safety with the following: 
− Mutational status as well as other genomic alterations in tumor samples  
− Activation status of oncogenic pathways in tumor samples  


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− Expression of drug transporters such as MDR1 (ie, P-Glycoprotein [PgP]) as 
well as other proteins that may influence anti-tumor activity or safety 
− Blood-based biomarkers (such as soluble FRα)  
− Genotyping of Fc gamma receptor (FcγR)  
• PFS2 as assessed by investigator: the time from randomization to the time of 
second PD or death 
• Qualitative analysis of DM4 metabolites in urine 
3. 
STUDY POPULATION 
3.1. 
Criteria for Selection of Patient Population 
3.1.1. 
Inclusion Criteria 
1. Patients must have one of the following pathologically documented, definitively 
diagnosed tumor types: 
a. Advanced EOC  
b. Primary peritoneal cancer  
c. Fallopian tube cancer  
2. Patients must have platinum-resistant ovarian cancer, defined as progression within 6 
months from completion of a minimum of four cycles of platinum-containing therapy. 
This should be calculated from the date of the last administered dose of platinum 
therapy to the date of the radiographic imaging showing progression. 
3. Patients must have at least one lesion that meets the definition of measurable disease 
by RECIST v1.1. 
4. Patients must have received at least one but no more than three prior systemic lines of 
anti-cancer therapy and for whom single agent chemotherapy is appropriate as the 
next line of treatment. 
a. Adjuvant ± Neoadjuvant will be considered as one line of therapy 
b. Maintenance therapy (examples: bevacizumab or PARP inhibitors) will be 
considered as part of the preceding line of therapy (ie, not counted independently) 
5. Patients must be willing to provide an archival tumor tissue, or fresh biopsy collected 
using a non-significant risk procedure. Patients who do not have archival tissue and 
for whom the only sites of disease would require biopsy procedure considered to be of 
significant risk must not be enrolled in the study. These significant risk procedures 
include (but are not limited to) biopsies of the brain, lung/mediastinum, pancreas, or 
endoscopic procedures extending beyond the esophagus, stomach or bowel.  
6. Patients must have confirmation of FRα positivity by Ventana IHC test (≥ 50% of 
tumor staining at ≥ 2+ intensity) in archival or fresh biopsy tumor sample. If the 
archival tumor tissue does not meet FRα criteria, a fresh biopsy tumor sample may be 
submitted and if positive, it may be used to meet this criterion. 


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7. Female patients ≥ 18 years of age 
8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 
9. Time from prior therapy: 
a. Systemic anti-neoplastic therapy: five half-lives or four weeks, whichever is 
shorter  
b. Focal radiation completed at least two weeks, prior to starting study drug 
10. Patients must have stabilized or recovered (Grade 1 or baseline) from all 
therapy-related toxicities. 
11. 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 
12. 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) 
b. Platelet count ≥ 100 x 109/L (100,000/μL); no transfusion 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 ≤ 3.0 x ULN; ALT ≤ 3.0 x ULN  
f. Serum bilirubin ≤ 1.5 x ULN (Patients with documented diagnosis of Gilbert 
syndrome are eligible if total bilirubin < 3.0 x ULN) 
g. Serum albumin ≥ 2 g/dL  
13. Patients must be willing and able to sign the informed consent form, and to adhere to 
the study visit schedule and other protocol requirements. 
14. Women of childbearing potential (WCBP) are 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 (ie, who has had menses any time 
in the preceding 12 consecutive months). WCBP must agree to use effective 
contraceptive methods (examples include oral, parenteral, or implantable hormonal 
contraceptive, intra-uterine device, or vasectomy) while on study treatment and for at 
least twelve weeks after the last dose of IMGN853 and for at least six months after the 
last dose of paclitaxel, PLD or topotecan (Refer to Section 5.9.6). 
15. WCBP must have a negative pregnancy test prior to the first dose of study treatment. 
3.1.2. 
Exclusion Criteria  
1. Male patients. 
2. Patients with clear cell, mucinous histology, mixed histology with mucinous 
component, sarcoma, sarcomatous component, or low grade ovarian cancer. 
3. Patients with primary platinum-refractory disease as defined by those who progressed 
during or within four weeks of completion of first platinum-based chemotherapy 
(Friedlander 2011).  


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4. Patients who have received prior wide-field radiotherapy affecting at least 20% of the 
bone marrow. 
5. Patients with uncontrolled bleeding disorders or inadequate coagulation parameters: 
a. Activated partial thromboplastin time (aPTT) > 1.5 x ULN, unless related to lupus 
anticoagulant. Patients receiving unfractionated heparin must have aPTT between 
1.5 and 2.5 x ULN or within a range determined by their physician. 
b. International normalized ratio (INR) > 1.5. Patients receiving warfarin must have 
an INR between 2.0 and 3.0 or within a range determined by their physician. 
6. Patients with > Grade 1 peripheral neuropathy. 
7. Active or chronic corneal disorders such as Sjogren’s syndrome, Fuchs corneal 
dystrophy (requiring treatment), history of corneal transplantation, active herpetic 
keratitis, active ocular conditions requiring on-going treatment/monitoring such as 
uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal 
injections, active diabetic retinopathy with macular edema, macular degeneration, 
presence of papilledema, and /or monocular vision.  
8. Serious concurrent illness or clinically-relevant active infection, including, but not 
limited to the following: 
a. Known active hepatitis B or C whether or not on active antiviral therapy  
b. Known Human Immunodeficiency Virus (HIV) infection 
c. Varicella-zoster virus (shingles)  
d. Cytomegalovirus infection  
e. Any other known concurrent infectious disease, requiring IV antibiotics within 2 
weeks of starting study treatment. 
9. Clinically-significant cardiac disease including any one of the following: 
a. Recent myocardial infarction (≤ 6 months prior to day 1) 
b. Unstable angina pectoris  
c. Uncontrolled congestive heart failure (New York Heart Association > class II) 
d. Uncontrolled hypertension (≥ CTCAE v4.03 Grade 3)  
e. If the choice of chemotherapy agent is PLD for patients randomized to the IC 
chemotherapy arm, LVEF (measured by Echocardiography (ECHO) or Multigated 
Acquisition (MUGA) scan) that is below the institutional limit of normal 
f. Prior history of hypertensive crisis or hypertensive encephalopathy 
g. Uncontrolled cardiac arrhythmias 
h. Clinically-significant vascular disease (eg, aortic aneurysm, or dissecting 
aneurysm) 
i. Severe aortic stenosis 
j. Clinically significant peripheral vascular disease, or ≥ Grade 3 cardiac toxicity 
following prior chemotherapy 
k. Corrected QT (QTc) > 470 msec using on-screening ECG.  
10. History of neurological condition, or concurrent neurological condition that would 
confound assessment of treatment-emergent neuropathy. 


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11. History of multiple sclerosis or other demyelinating disease and/or Eaton-Lambert 
syndrome (para-neoplastic syndrome). 
12. History of hemorrhagic or ischemic stroke within the last 6 months 
13. History of cirrhotic liver disease. 
14. Previous clinical diagnosis of non-infectious interstitial lung disease, including non-
infectious pneumonitis.  
15.  Required use of folate –containing supplements (eg, folate deficiency). 
16.  Prior hypersensitivity to monoclonal antibodies. 
17.  Women who are pregnant or lactating. 
18.  Patients with known hypersensitivity to any of the standard of care (SOC) 
chemotherapy agents included in the study (paclitaxel, PLD, or topotecan) are 
excluded from receiving that particular medicinal product, but can receive one of the 
other chemotherapy agents included in the study. 
19. Untreated CNS disease or symptomatic CNS metastasis. 
20. Prior treatment with IMGN853 or prior treatment on the study. 
21. History of other clinically active malignancy within 3 years of enrollment, except for 
tumors with a negligible risk for metastasis or death, such as adequately controlled 
basal-cell carcinoma or squamous-cell carcinoma of the skin or carcinoma in situ of 
the cervix or breast. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Study Design 
4.1.1. 
Overview and Schema 
This Phase 3, open label, randomized study is designed to compare the efficacy of IMGN853 
to that of selected standard of care chemotherapy (Investigator’s choice) in women with 
advanced EOC, primary peritoneal cancer or fallopian tube cancer.  
Patients will be stratified by number of prior lines (1 or 2 vs. 3), FRα levels (≥ 75% tumor 
staining at ≥ 2+ intensity vs. ≥ 50% and < 75% tumor staining at ≥ 2+ intensity) and IC 
chemotherapy (paclitaxel, PLD or topotecan). Patients will be randomized 2:1 into one of two 
arms as follows:  
• Arm 1: IMGN853 6mg/kg AIBW Q3W 
• Arm 2: IC chemotherapy (weekly paclitaxel every four weeks, PLD administered 
once every four weeks, or topotecan administered either on Days 1, 8, and 15 
every four weeks or for five consecutive days every three weeks). 




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30 minutes on days 1, 8 and 15 of a four-week cycle. Alternatively, topotecan can be 
administered at a 1.25 mg/m2 dose over 30 minutes on days 1–5 of a three-week cycle. The 
dose of chemotherapeutic agents will be calculated using body surface area (BSA). 
Institutional conventions can be used to calculate BSA.  
For logistical reasons such as holidays, delays in the scheduled study treatment for up to three 
days will be permitted in Cycles 1 and 2. Additionally, shifts in the start of a new cycle by -1 
or +3 days will be permitted in Cycles ≥ 3. 
Table 1: 
Dose and Dosing Schedules 
Randomization 2:1 
Group 
Drug 
Dose 
Dosing Schedule 
Arm 1 
IMGN853 
6 mg/kg AIBW 
Day 1, of a 3-week cycle  
Arm 2 
Paclitaxel 
80 mg/m2 
Days 1, 8, 15 and 22 of a 4-week 
cycle 
PLD 
40 mg/m2  
Day 1 of a 4-week cycle 
Topotecan (4-week 
cycle) 
4 mg/m2 
Days 1, 8 and 15 of a 4-week cycle 
Topotecan (3-week 
cycle) 
1.25 mg/m2  
Days 1 through 5 of a 3-week cycle  
 
4.1.3. 
Continuation of Treatment Beyond Study Closure 
The study will be completed by the Sponsor one year after the final analysis for the primary 
endpoint of PFS is conducted. Patients still receiving clinical benefit from IMGN853 at the 
time the study is completed by the Sponsor may continue to receive IMGN853 under this 
protocol. Treatment with IMGN853 will continue as outlined in Section 5.  
Patients who choose to continue to receive IMGN853 after the study is completed by the 
Sponsor will continue to be followed by their treating physician as per standard of care for 
their disease (including radiological assessments). These patients may remain on IMGN853 
until disease progression as assessed by the Investigator, development of unacceptable 
toxicity, withdrawal of consent, initiation of a new anticancer therapy, or death, whichever 
comes first (refer to Appendix D for Schedule of Assessments).  
Patients who continue to receive IMGN853 after the study is completed by the Sponsor will 
only have SAE and AESI data reported and collected per the SAE Form as detailed in 
Section 9.2.1. AEs that do not meet SAE or AESI criteria will not be reported for these 
patients. Data for these patients who continue to receive IMGN853 after the study is 
completed will not be captured in the clinical study database.  Information collected from 
these patients will be maintained by ImmunoGen, Inc. in the safety database. 
Patients who continue to receive IMGN853 after the study is completed by the Sponsor will 
not be followed for survival data. 


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The Investigator is required to complete the Investigator’s Declaration for Continued 
Treatment form (Appendix N) and submit drug accountability logs every 3 months in order to 
continue to provide IMGN853 access to a patient that is deriving clinical benefit from 
IMGN853 treatment. 
5. 
STUDY TREATMENT 
5.1. 
IMGN853 
The investigational study drug, IMGN853, will be provided by ImmunoGen, at a protein 
concentration of 5.0 mg/mL in an aqueous pH 5.0 buffered solution.  
5.1.1. 
IMGN853 Packaging  
IMGN853 will be provided in a 20 mL glass, single-use Type I 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. 
5.1.1.1. 
IMGN853 Storage, Handling and Accountability 
Specific details regarding storage and handling of IMGN853 can be found in the Pharmacy 
Manual. 
Accountability and shipping documents for IMGN853 must be maintained by the Principal 
Investigator or designee (eg, the study pharmacist). The Investigator or designee must 
maintain an accurate record of the receipt and dispensing of IMGN853 in a drug 
accountability log or equivalent. These records must always be available for inspection, and a 
copy will be supplied to ImmunoGen 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.  
Any investigator site-to-site transfers (eg, investigator satellite sites) of the study drug must 
follow local laws. At a minimum, the originating site and the receiving site should document 
the transfer and receipt of the study drug in their respective drug accountability logs; the 
originating site must ensure proper packing (eg, cold packs to maintain the temperature 
control) of the study drug during the transport (refer to Pharmacy Manual).  
Upon completion of the study, all IMGN853 dispatched to a site must be accounted for and 
unused supplies returned to ImmunoGen or destroyed according to the site’s Standard 
Operating Procedures (SOPs). 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. 


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5.1.1.1.1. IMGN853 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.  
IMGN853 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 Food and Drug Administration (FDA) Form 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 
(ie, hospital pharmacy, satellite pharmacy), it is the responsibility of the Principal 
Investigator to ensure that all study drug is maintained in the manner described (refer to 
Pharmacy Manual for instructions). 
5.2. 
Investigator’s Choice Chemotherapeutic Agents 
Since the type of IC chemotherapy received is one of the stratification factors, it is required 
that the choice of the chemotherapy agent, paclitaxel or PLD or topotecan, be made prior to 
randomization. Paclitaxel, PLD and topotecan are supplied as commercially available 
formulations. Refer to the prescribing information or Summary of Product Characteristics for 
complete information.  
A separate Investigational Product Dispensing/Accountability Log or equivalent should be 
maintained for paclitaxel, PLD, and topotecan. Vials should be visually inspected for vial 
integrity (ie, cracks or leaks) and a record of any damaged or suspect drug should be kept on 
the Investigational Product Dispensing/Accountability Log or equivalent. 
5.3. 
Assignment of Patient Number 
Patient numbers are assigned in sequential order as patients sign informed consent to 
participate.  
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.  
5.3.1. 
Enrolled Patient Definition 
Patients who have consented to the study and randomized, are considered enrolled. Patients 
who are issued a patient number, but who do not successfully complete the screening process 
and are not randomized will be considered screen failures. Patient numbers for patients who 
screen fail will not be re-issued. 
5.3.2. 
Patient Assignment to Dosing Regimens 
Eligible patients will be randomly assigned 2:1 to IMGN853 6 mg/kg AIBW Q3W (Arm 1) 
or IC chemotherapy (Arm 2; paclitaxel, PLD or topotecan).  
Cycle 1 Day 1 should occur within seven calendar days from randomization.  
Patients will be stratified as follows:  


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• FRα levels (≥ 75% of tumor staining at ≥ 2+ intensity vs. ≥ 50% and < 75% of 
tumor staining at > 2+ intensity) 
• Number of prior therapies (1 or 2 vs. 3) 
• IC of chemotherapy (paclitaxel, PLD, or topotecan) 
5.4. 
Blinding Methods 
Not applicable as this is an open-label study. 
5.5. 
Study Treatment Administration 
5.5.1. 
Premedication for Study Treatment 
5.5.1.1. 
IMGN853 
All patients receiving IMGN853 must receive 325-650 mg of acetaminophen/paracetamol 
(PO or IV), 10 mg IV dexamethasone, and 25-50 mg diphenhydramine (IV or PO) 
(equivalent drugs of similar drug classes is also acceptable) approximately 30 minutes prior 
to each infusion of IMGN853. If individual patients require more intensive treatment to 
prevent infusion-related reactions, investigators may modify the regimen accordingly.  
5.5.1.1.1. Prophylactic use of Corticosteroid Eye Drops 
Patients receiving IMGN853 will be mandated to use corticosteroid eye drops as prescribed 
by the treating physician unless the risk outweighs the benefit as per the 
ophthalmologist/physician. All patients enrolled will be instructed to self-administer 1% 
prednisolone (Pred Forte® or generic equivalent) six times daily on Days 1-4 and four times 
daily on Days 5-8 of each cycle during the study. For individual patients who cannot tolerate 
the preservative contained in 1% prednisolone, other corticosteroid eye drops may be 
substituted (eg, difluprednate 0.05%; Durezol®) and administered on Days 1-8 of each cycle 
at a frequency prescribed by the ophthalmologist.  
5.5.1.1.2. Lubricating Artificial Tears  
Patients receiving IMGN853 will be mandated to use preservative-free, lubricating artificial 
tears on a daily basis (as directed by the product label or the treating physician). Patients 
should be advised to wait at least 15 minutes following corticosteroid eye drop administration 
before instilling lubricating eye drops.  
5.5.1.2. 
IC Chemotherapy 
Patients receiving paclitaxel, PLD or topotecan may receive premedication at the discretion 
of the investigator or according to institutional guidelines. 
5.5.2. 
Preparation and Administration of IMGN853 
5.5.2.1. 
Calculation for Adjusted Ideal Body Weight 
The total dose of drug is calculated based on each patient’s AIBW using the following 
formula: 


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Adjusted Ideal Body Weight (AIBW)  
AIBW = IBW1 + 0.4 (Actual weight – IBW1) 
Where: 
Ideal Body Weight (IBW)  
IBW1 (female) = 0.9H1-92 
(1H = height in cm; W = weight in kg) 
The weight used for calculation should be obtained prior to study drug administration on 
Cycle 1 Day 1 (-14 days) and thereafter should only be modified for significant (≥ 10%) 
changes in body weight (not influenced by weight gain or loss attributed to fluid retention).  
5.5.2.1.1. Preparation  
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. The desired amount of drug 
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 labeled according to institutional protocol. Once 
the solution is prepared, the infusion bag should be stored at ambient temperature protected 
from direct sunlight, and the infusion must be completed within eight hours of preparation. 
Please refer to Pharmacy Manual for further details. 
Study drug from two different drug lots cannot be mixed in a single dose 
administration. 
5.5.2.1.2. Administration 
IMGN853 is administered at 6 mg/kg (Table 1) as an IV infusion following preparation as 
outlined in the Pharmacy Manual. Details on required and compatible infusion materials are 
also included in the Pharmacy Manual. 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 minutes at 3 mg/min, the IMGN853 infusion rate may be increased to 
5 mg/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 are carefully observed during each infusion and vital signs are taken as outlined in 
the Schedule of Clinical Assessments (Appendix A and Appendix B). Patients will remain in 
the clinic under observation for four hours after the first infusion, and for at least one hour 
after each subsequent infusion. While in the treatment area, patients are closely monitored for 
toxicity. 


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5.5.3. 
Preparation and Administration of IC Chemotherapy 
Precautions should be taken when handling paclitaxel, PLD and topotecan. Refer to the 
Pharmacy Manual and package inserts for more information. 
5.5.3.1. 
Preparation and Administration of Paclitaxel 
Paclitaxel will be prepared as described in the prescribing information and administered IV at 
80 mg/m2 (Table 1). Body weight at Cycle 1 Day 1 (-14 days) is to be used to calculate BSA 
in order to determine the required dose. No dose modifications are foreseen unless the 
patient’s body weight changes by ± 10% from baseline. 
5.5.3.2. 
Preparation and Administration of Pegylated Liposomal Doxorubicin 
PLD will be prepared as described in the prescribing information and administered IV at 
40 mg/m2 (Table 1). Body weight at Cycle 1 Day 1 (-14 days) is to be used to calculate BSA 
in order to determine the required dose. No dose modifications are foreseen unless the 
patient’s body weight changes by ± 10% from baseline. 
5.5.3.3. 
Preparation and Administration of Topotecan 
Topotecan will be prepared as described in the prescribing information and administered IV 
at 4 mg/m2 (Table 1). Alternatively, topotecan will be administered at 1.25 mg/m2. Body 
weight at Cycle 1 Day 1 (-14 days) is to be used to calculate BSA in order to determine the 
required dose. No dose modifications are foreseen unless the patient’s body weight changes 
by ± 10% from baseline. 
5.6. 
Dose Modification Guidelines 
Detailed IMGN853 and chemotherapy-specific dose modification guidelines are described 
below.  
5.6.1. 
IMGN853 
5.6.1.1. 
Treatment Criteria 
In the absence of a TEAE that requires dose modification, a patient must meet the following 
criteria in order to receive study treatment: 
• ANC must be ≥ 1.5x109/L (1,500/µL) 
• Platelet count must be ≥ 100 x 109/L (100,000/µL) 
• All non-hematologic toxicities for which a causal association to study treatment 
cannot be ruled out, must be ≤ Grade 2 or returned to baseline; the exceptions to 
this rule being: 
− Treatment-emergent ocular disorders, which must have recovered to < Grade 1 
or baseline 
5.6.1.2. 
IMGN853-Related Adverse Events 
Dose modifications for IMGN853 related adverse events are described in Table 2.  


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Table 2: 
Dose Modifications for IMGN853 Related Adverse Events 
Severity Grade 
(CTCAE v4.03) 
Dose Modifications for IMGN853 
Hematological  
Neutropenia 
Grade 2 and Grade 3  
 
Hold drug until ANC is ≥ 1.5 x109/L (1500 /µL) 
and resume at the same dose level  
Grade 4 
Hold drug until ANC is ≥ 1.5 x109/L (1500 /µL) 
and then resume at a lower dose level 
Febrile neutropenia Grade 3 or 4 
(with a single temperature reading ≥ 38.3°C or a 
sustained temperature of > 38°C for > one hour) 
Hold drug until ANC is ≥ 1.5 x109/L (1500 /µL) 
and then resume at a lower dose level 
Thrombocytopenia 
 
Grade 2 and Grade 3  
Hold drug until Platelet count is ≥ 100 x 109/L 
(100,000/µL) and resume at same dose level  
Grade 3 associated with clinically significant 
bleeding that requires transfusion therapy and 
Grade 4 
Hold drug until Platelet count is ≥ 100 x 109/L 
(100,000/µL) and then resume at a lower level 
 
Non-hematological 
Nausea and Vomiting 
Grade 3 (despite use of optimal anti-emetics) 
Hold drug until resolved to ≤ Grade 1, then 
resume at lower level 
Grade 4  
Permanently discontinue 
Diarrhea 
Grade 3 (despite use of optimal anti-diarrheal 
treatment) 
Hold drug until resolved to ≤ Grade 1, then 
resume at lower level 
Grade 4 
Permanently discontinue 
Ocular Disorders  
Refer to Section 5.6.1.6  
Non-infectious Pneumonitis 
Refer to Section 5.6.1.7  
Infusion-related Reactions 
Refer to Section 5.6.1.9  
All Other Non-hematological Toxicities  
(except AEs related to underlying disease, Grade 3 fatigue, isolated symptomatic Grade 3 
biochemistry laboratory abnormalities that last for < 7 days including electrolyte abnormalities that 
respond to medical intervention) 


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Severity Grade 
(CTCAE v4.03) 
Dose Modifications for IMGN853 
Grade 3  
Hold drug until resolved to ≤ Grade 1, then 
resume at lower level 
For any Grade 3 hepatic toxicity that does not 
resolve to baseline within seven days, an 
abdominal CT scan must be performed to assess 
whether it is related to disease progression. 
≥ Grade 3 Cardiac events  
Permanently discontinue 
Grade 4 non-hematological toxicities 
Permanently discontinue 
5.6.1.3. 
IMGN853 Dose Reduction Dose Levels 
IMGN853 dose reduction will be as described in Table 3.  
Table 3: 
IMGN853 Dose Reduction Dose Levels 
If the patient was receiving IMGN853 at: 
Dose should be reduced to: 
6.0 mg/kg AIBW 
5.0 mg/kg AIBW 
5.0 mg/kg AIBW 
4.0 mg/kg AIBW 
Reduction of IMGN853 below 4.0 mg/kg will not be permitted.  
5.6.1.4. 
Monitoring and Management of Nausea and Vomiting  
Nausea and vomiting have been reported in patients treated with IMGN853. 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 4. 
Table 4: 
Management of Nausea and Vomiting 
Severity Grade 
(CTCAE v4.03 
Grade) 
Management 
Grade 1 
Administer a single 8-mg dose of dexamethasone before therapy. 
Grade 2 
Administer a 5- HT3 receptor antagonist on Day 1 (eg, 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 (eg, 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. 


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5.6.1.5. 
Monitoring and Management of Diarrhea  
Mild to moderate diarrhea has been reported in patients treated with IMGN853. 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 
two hours until symptoms resolve (Wadler 1998). 
5.6.1.6. 
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). 
Patients receiving IMGN853 in the Phase 1 trial (IMGN853 study 0401) reported ocular 
adverse events consistent with reversible keratopathy/corneal epitheliopathy. At the 6 mg/kg 
AIBW Q3W dose level, 46% of patients reported Grade 1 or 2 blurred vision. Grade 1 and 
Grade 2 keratopathy was reported in 26% of patients. There were no Grade 3 ocular adverse 
events reported at this dose level.  
5.6.1.6.1. Monitoring and Preventative Measures 
In early dose escalation, there was a relationship between IMGN853 plasma exposure with 
increased likelihood of an ocular event as well as with response. Exposure-response modeling 
suggested that a dose of 6.0 mg/kg AIBW provided adequate exposure for response while 
also maintaining overall exposure within a range that decreased the potential for ocular 
adverse events. Due to the observation of ocular disorders consistent with reversible 
keratopathy/corneal epitheliopathy in patients treated with IMGN853, ocular function will be 
carefully monitored. Ocular symptom assessments will be performed at baseline and at Day 1 
of every cycle thereafter (Appendix A and Appendix B). Complete ophthalmologic exams 
will be performed in all patients at baseline and every other cycle thereafter if there is a 
TEAE reported (Appendix A and Appendix B). 
Patients are strongly advised to avoid using contact lenses while on IMGN853. 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. Please refer to 
Section 5.5.1.1.1 for details on the prophylactic use of steroid eye drops and lubricating 
artificial tears. The use of UVA/UVB sunglasses is recommended in full daylight during the 
course of the study. The use of temporary lower punctal plugs to increase lubrication of the 
eyes is optional if lubricating artificial tears and corticosteroid eye drops are not sufficient. If 
patients report signs or symptoms of ocular disorders, including, but not limited to, blurred 
vision or eye irritation, the management and dose modification guidelines outlined in Table 5 
should be followed.  
5.6.1.6.2. Management and Dose Modification Guidelines 
If a patient develops ocular symptoms of any grade, the patient is required to have a complete 
examination by an ophthalmologist. If a patient develops ≥ CTCAE Grade 2 ocular 
symptoms, treatment with IMGN853 will be interrupted. Treatment should not be interrupted 
solely for Grade 2 ocular signs (eg, Grade 2 keratopathy) unless they are also associated with 
Grade 2 ocular symptoms. Therapy may resume if ocular symptoms improve to Grade 1 or 


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baseline within 28 days of the next scheduled IMGN853 dose (refer to Table 5 for details). 
Subsequent eye 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 Treatment visit or 
30-day follow-up visit following treatment discontinuation, even if the results of the patient’s 
ocular exam shows no obvious clinical findings. Management of treatment-emergent ocular 
AEs with inflammatory characteristics should include corticosteroid eye drops and/or other 
measures as indicated by an ophthalmologist. 


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Table 5: 
Management of Ocular Disorders 
Severity Grade 
(CTCAE v4.03 
Grade) 
Management 
Guidelines for IMGN853 Dose 
Modifications 
Grade 1  
• 
Complete eye exam as outlined in 
schedule of clinical assessments 
(Appendix A and Appendix B). 
• 
Monitor for worsening symptoms 
Continue IMGN853 dosing 
Grade 2 
Symptoms  
• 
Complete eye exam as outlined in 
schedule of clinical assessments 
(Appendix A and Appendix B).  
• 
Repeat complete exam as clinically 
indicated  
• 
Patients should have weekly 
symptomatic ocular assessments until 
the symptoms resolve to Grade 1 or 
baseline or are deemed to be 
irreversible by the investigator 
• Hold IMGN853 dosing until 
AE has resolved to Grade 1 or 
better.  
• Patients with ocular 
symptoms lasting < 14 days 
may be allowed to resume 
IMGN853 at the same dose 
level  
• Patients with ocular 
symptoms lasting ≥ 14 days 
but no more than 28 days 
may resume IMGN853 at a 
lower dose level  
Grade 3  
• 
Complete eye exam as outlined in 
schedule of assessments (Appendix A 
and Appendix B). Repeat complete 
exam as clinically indicated. 
• 
Patients should have weekly 
symptomatic ocular assessments until 
the symptoms resolve to Grade 1 or 
baseline or are deemed to be 
irreversible by the investigator. 
• Hold IMGN853 dosing.  
• Patients may be allowed to 
resume IMGN853 at a lower 
dose after AE has resolved to 
Grade 1 or better within 28 
days. 
Grade 4  
• 
Complete eye exam as outlined in 
schedule of assessments (Appendix A 
and Appendix B). Repeat complete 
exam as clinically indicated. 
• 
Patients should have weekly 
symptomatic ocular assessments until 
the symptoms resolve to Grade 1 or 
baseline or are deemed irreversible by 
the investigator. 
• Permanently discontinue 
IMGN853  
 
5.6.1.7. 
Monitoring of Non-Infectious Pneumonitis  
Non-infectious pneumonitis has been observed following the administration of IMGN853. 
Non-infectious pneumonitis 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 other clinically meaningful signs 


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or symptoms of pulmonary toxicity, the patient should be immediately evaluated. 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 
treatment guidelines outlined in Table 6 should be followed. 


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Table 6: 
Management of Non-Infectious Pneumonitis 


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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 
resolve to ≤ Grade 1. 
• 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. 
• Permanently discontinue 
IMGN853.  
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.  
 


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5.6.1.8. 
Management of Electrolytes Imbalance 
Prompt attention should be given to the correction of potential electrolytes imbalance, 
especially hypokalemia and hypomagnesemia. 
5.6.1.9. 
Potential Infusion-Related Reactions  
Some patients treated with IV infusions of therapeutic drugs have experienced concurrent 
infusion-related reactions (see CTCAE Version 4.03). The signs and symptoms may vary and 
include for example, 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 (eg, epinephrine, inhaled beta agonists, antihistamines, and corticosteroids), and 
other required resources to treat anaphylaxis must be readily available. In general, 
Investigators should manage acute allergic or hypersensitivity reactions according to 
Institutional practices. General guidelines for the management of acute infusion-related 
reactions and for subsequent retreatment are provided in Table 7. Delayed infusion-related 
reactions may occur; therefore, patients should be advised to seek immediate medical 
treatment if symptoms newly develop and/or recur after discharge from clinic. 
Patients who experience ≥ Grade 2 infusion-related reaction during or immediately following 
administration of IMGN853 will have blood drawn for determination of drug concentration 
and antibodies to IMGN853 (ADA). The sample should be obtained within three hours of the 
onset of the reaction and one week later. Such patients should undergo all scheduled efficacy 
and safety evaluations. Patients still receiving clinical benefit from IMGN853 at the time the 
study is completed by the Sponsor may continue to receive IMGN853 under this protocol 
(see Section 4.1.3), but will not have additional blood drawn for ADA assessment. 
 


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Table 7: 
Management Guidelines for Potential Infusion-related Reactions  


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Infusion Reaction CTCAE 
v4.03 Severity 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 per day (Q4h) prn for 
nausea  
• 
Diphenhydramine (or equivalent) 25-50 mg PO or IV prn 
• 
Methylprednisolone (or equivalent) 125 mg IV prn 
Grade 2: Moderate  
• 
Interrupt infusion and disconnect infusion tubing from patient 
• 
Promethazine (or equivalent) 150 mg PO per day (Q4h) prn for 
nausea 
• 
Diphenhydramine (or equivalent) 25-50 mg PO or IV prn 
• 
Acetaminophen (or equivalent) 650 mg PO prn 
• 
Methylprednisolone (or equivalent) 125 mg 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, patients should be pre-
medicated with dexamethasone (or equivalent) 8 mg PO BID the 
day prior to drug administration and acetaminophen (or equivalent) 
650 mg PO and diphenhydramine (or equivalent) 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 
OR 
Grade 4: Life-threatening 
consequences, urgent 
intervention indicated 
• 
Immediately stop infusion and disconnect infusion tubing from 
patient. 
• 
Administer diphenhydramine (25-50 mg) IV (or equivalent) 
• 
Administer IV steroids (methylprednisolone (or equivalent) up to 
0.5mg/kg Q 6h) to treat ongoing reaction and prevent recurrence 
• 
Administer bronchodilators (nebulized albuterol/salbutamol, 2.5-5 
mg in 3 mL of saline or equivalent) as medically indicated 
• 
Administer normal saline as medically indicated 
• 
Administer epinephrine (0.2-0.5 mL of a 1:1000 dilution (0.2-0.5 mg) 
SQ or IM) as medically indicated. Epinephrine should only be used if 
all other treatment methods fail to manage the infusion-related 
reaction. 
• 
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). 
• 
Permanently discontinue study medication treatment 


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5.6.1.10. Discontinuation of IMGN853 Due to Toxicity 
IMGN853 should not be resumed in the case of the following treatment-related events: 
• ≥ Grade 3 cardiac event 
• Non-hematologic events of Grade 4 severity 
• Failure to meet re-treatment criteria within one cycle following the missed dose 
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. 
5.6.2. 
Paclitaxel  
Label warnings, manufacturer’s recommendations and standard clinical practice should be 
followed. Guidelines for dose interruptions and dose modifications are described in Table 8. 
Table 8: 
Paclitaxel Dose Modification Guidelines 
Severity Grade 
(CTCAE v4.03 Grade) 
Dose Modification 
Hematological Toxicities 
Grade 1 
No action 
Grade 2 & 3 
Hold paclitaxel until ANC and platelet levels meet the following 
criteria: 
Day 1: ANC ≥ 1.5 x 109/L (1,500/μL) and platelets ≥ 100 x 109/L 
(100,000/μL) 
Day 8, 15 & 22: ANC ≥ 1.0 x 109/L (1,000/μL) and 
platelets ≥ 100 x 109/L (100,000/μL)  
Retreat at same dose level. 
Grade 4 
Hold paclitaxel until ANC and platelet levels meet the following 
criteria: 
Day 1: ANC ≥ 1.5 x 109/L (1,500/μL) and platelets ≥ 100 x 109/L 
(100,000/μL) 
Day 8, 15 & 22: ANC ≥ 1.0 x 109/L (1,000/μL) and 
platelets ≥ 100 x 109/L (100,000/μL) 
Dose reduce by 1 level 
For febrile neutropenia and/or severe bleeding, permanently discontinue paclitaxel 
Non-hematological Toxicities 
Grade 1 
No action 
Grade 2 
No action; for patients experiencing neurotoxicity, dose reduce by 1 
level. 
Grade 3 
Dose reduce by 1 level 


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Administration of granulocyte colony stimulating factor (G-CSF) or erythropoietin (EPO) is 
permitted as per institutional guidelines.  
5.6.2.1. 
Dose Reduction Dose Levels 
Paclitaxel dose reduction will be as described in Table 9.  
Table 9: 
Paclitaxel Dose Reductions 
If the patient was receiving paclitaxel at: 
Dose should be reduced to: 
80 mg/m2 
70 mg/m2 
70 mg/m2 
60 mg/m2 
*Reduction of the paclitaxel below 60 mg/m2will not be permitted. Instead of a second dose reduction, 
70mg/m2 can be maintained if a one weekly dose is omitted within one cycle 
5.6.2.2. 
Criteria for Permanent Discontinuation of Paclitaxel 
Paclitaxel will be permanently discontinued for febrile neutropenia and/or severe bleeding.  
5.6.3. 
Topotecan  
Label warnings, manufacturer’s recommendations and standard clinical practice should be 
followed. Guidelines for dose interruptions and dose modifications are described in Table 10. 
Table 10: 
Topotecan Dose Modification Guidelines 
Severity Grade  
(CTCAE v4.03 Grade) 
Dose Modification 
Hematological Toxicities 
Grade 1 
No action required. 
Grades 2 or 3 
Hold topotecan until ANC and platelet levels meet the 
following criteria: 
Day 1: ANC ≥ 1.5 x 109/L (1,500/μL) and platelets ≥ 100 x 
109/L (100,000/μL) 
Day 8, & 15: ANC ≥ 1.0 x 109/L (1,000/μL) and platelets ≥ 
100 x 109/L (100,000/μL)  
Retreat at same dose level. 
Grade 4 or any grade neutropenia 
complications (fever, infection)  
Hold topotecan until ANC and platelet levels meet the 
following criteria: 
Day 1: ANC ≥ 1.5 x 109/L (1,500/μL) and platelets ≥ 100 x 
109/L (100,000/μL) 
Day 8, & 15: ANC ≥ 1.0 x 109/L (1,000/μL) and platelets ≥ 
100 x 109/L (100,000/μL)  
Grades 3 and 4 
Hold paclitaxel until the event resolves or improves to Grade 1. 
Dose reduce by 1 level. 


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Dose reduce by one level.  
Non-hematological Toxicities 
Grade 1 
No action required. 
Grade 2 
No action required. 
Grades 3 or 4 
Hold topotecan until the event improves to Grade 1 or 
resolves. Dose reduce by one level. 
Administration of G-CSF or EPO is permitted according to approved institutional guidelines.  
Patients who receive topotecan and develop a TEAE requiring an interruption of topotecan 
may resume treatment at a reduced dose level as shown in Table 11. 
5.6.3.1. 
Dose Reduction Dose Levels 
Topotecan dose reduction will be as described in Table 11 and Table 12. 
Table 11: 
Topotecan Dose Reductions (Weekly Schedule) 
If the patient was receiving topotecan at: 
Dose should be reduced to: 
4 mg/m2 
3.5 mg/m2 
3.5 mg/m2 
3 mg/m2 
*Reduction of the topotecan below 3mg/m 2will not be permitted. Dose re-escalation is not permitted. 
Table 12: 
Topotecan Dose Reductions (Five Days Schedule) 
If the patient was receiving topotecan at: 
Dose should be reduced to: 
1.25 mg/m2 
1.0 mg/m2 
1.0 mg/m2 
0.75 mg/m2 
*Reduction of the topotecan below 0.75mg/m2 will not be permitted. Dose re-escalation is not permitted. 
5.6.3.2. 
Criteria for Permanent Discontinuation of Topotecan 
Treatment should be permanently discontinued according to the guidelines shown in Table 13, 
in case the observed TEAE is unmanageable despite dose reductions. 


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Table 13: 
Adverse Events Requiring Permanent Discontinuation of Topotecan 
Severity Grade 
(CTCAE v4.03 Grade) 
Adverse Event 
Hematological Toxicities 
Grade 4 
ANC < 0.5 x 109/L for more than two weeks 
Grade 4 
Thrombocytopenia for more than 2 weeks 
Non-hematological Toxicities 
Grade 3 or 4 
Mucositis 
Grade 3 or 4 
Neurotoxicity 
Grade 3 or 4 
Toxicities (except nausea, vomiting, and alopecia) lasting for more 
than three weeks 
5.6.4. 
Pegylated Liposomal Doxorubicin (PLD)  
Label warnings, manufacturer’s recommendations and standard clinical practice should be 
followed.  
5.6.4.1. 
Hematological Toxicities 
Patients receiving PLD are at risk of bone marrow suppression. Leukopenia is usually 
transient; hematological AEs may require dose delays or reductions as indicated in Table 14. 


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Table 14: 
Pegylated Liposomal Doxorubicin (PLD) Dose Modification Guidelines 
for Hematological Adverse Events 
Severity Grade 
ANC 
Platelets 
Modification 
Grade 1 
< LLN-1.5 x 109/L 
(< LLN-1,500/μL) 
< LLN - 75.0 x 109/L 
(< LLN - 75,000/μL) 
Resume treatment; no 
dose reduction 
Grade 2  
< 1.5 - 1.0 x 109/L 
(< 1,500-1,000/μL) 
< 75.0 - 50.0 x 109/L 
(< 75,000 - 50,000/ μL) 
Delay until ANC 1.5 x 
109/L (≥ 1,500/μL) and 
platelets ≥ 75.0 x 109/L 
(75,000/μL); re-dose with 
no dose reduction 
Grade 3 
< 1.0 - 0.5 x 109/L 
(< 1,000-500/μL) 
< 50.0 - 25.0 x 109/L 
(50,000 - 25,000/ μL) 
Delay until ANC 1.5 x 
109/L (≥ 1,500/μL) and 
platelets ≥ 75.0 x 109/L 
(75,000/μL); re-dose with 
no dose reduction 
Grade 4 
< 0.5 x 109/L 
(< 500/μL) 
< 25.0 x 109/L 
(< 25,000/ μL) 
Delay until ANC 1.5 x 
109/L (≥ 1,500/μL) and 
platelets ≥ 75.0 x 109/L 
(75,000/μL); re-dose at 
25% dose reduction or 
continue previous dose 
with cytokine support 
5.6.4.2. 
Non-hematological Toxicities 
5.6.4.2.1. Hand-Foot Syndrome 
Hand-Foot syndrome (HFS) is a disease characterized by palmar-plantar skin eruptions with 
swelling, pain, erythema and, for some patients, desquamation of the skin of the hands and 
feet. HFS has been observed in patients receiving PLD at doses of 50 mg/m2 and, with less 
frequency, in those receiving PLD at 30 mg/m2. If patients present with symptoms/signs 
consistent with HFS, the dose of PLD should be modified as indicated in Table 15.  
 


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Table 15: 
PLD Dose Modification Guidelines for Hand and Foot Syndrome and 
Mucositis 
Severity 
Grade 
(CTCAE 
v4.03 Grade) 
HFS  
Symptoms 
Mucositis 
Symptoms 
Dose Reduction/Discontinuation 
Grade 1 
Mild erythema, 
swelling, or 
desquamation not 
interfering with 
daily activities 
Painless ulcers, 
erythema, or mild 
soreness 
Continue PLD, unless previous 
Grade 3 or 4 HFS.  
In case of previous Grade ¾ HSF, 
delay up to 2 weeks and decrease 
dose by 25%.  
Grade 2  
Erythema, 
desquamation, or 
swelling interfering 
with, but not 
precluding normal 
physical activities; 
small blisters or 
ulcerations less than 
2 cm in diameter 
Painful erythema, 
edema, or ulcers, but 
can eat 
Hold PLD until resolved to Grade 
1 or baseline. If after 2 weeks 
there is no resolution, PLD should 
be discontinued. If no prior Grade 
3-4 HFS, resume at the dose prior 
to the event. If previous HFS 
Grade 3-4 toxicity, decrease dose 
by 25%. 
Grade 3  
Blistering, 
ulceration, or 
swelling interfering 
with walking or 
normal daily 
activities; cannot 
wear regular 
clothing. 
Painful erythema, 
edema, or ulcers; 
cannot eat 
Hold PLD until resolved to Grade 
1 or baseline. Decrease dose by 
25%. If after 2 weeks there is no 
resolution, PLD should be 
discontinued. 
Grade 4 
Diffuse or local 
process causing 
infectious 
complications, a bed 
ridden state, or 
hospitalization. 
Requires parenteral or 
enteral support 
If patients receiving PLD experience a TEAE, their PLD dose should be reduced as indicated 
in Table 16. Patients who require dose reductions below 20 mg/m2 should discontinue their 
PLD treatment. 
5.6.4.2.2. Cardiac Toxicity 
Patients receiving PLD are at risk for cardiac toxicity. Cardiac function should be carefully 
monitored in these patients. If the patient’s left ventricular ejection fraction drops below 
normal or by at least 15% from the baseline value, study treatment should be interrupted and 
event should be discussed with Sponsor before resuming treatment (Appendix B).  


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5.6.4.3. 
Criteria for Permanent Discontinuation of PLD  
Patients who require dose reductions below 20 mg/m2 should permanently discontinue their 
PLD treatment. 
5.6.4.4. 
Dose Reduction Dose Levels 
PLD dose reduction will be as described in Table 16.  
Table 16: 
PLD Dose Reductions 
If the patient was receiving PLD at: 
Dose should be reduced to: 
40 mg/m2 
30 mg/m2 
30 mg/m2 
20 mg/m2 
*Reduction of the PLD dose below 20 mg/ m2 will not be permitted. Patients who require dose 
reductions below 20mg/m2 should discontinue their PLD treatment. 
5.7. 
Discontinuation of the Patients from the Study or Study 
Treatment 
5.7.1. 
End of Treatment (EOT) 
Patients will continue to receive study treatment until they present with PD per RECIST 1.1, 
as assessed by BIRC, develop unacceptable toxicity or withdraw consent, whichever comes 
first, or until the Sponsor terminates the study. Study treatment and/or 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 treatment: 
• 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 reason for treatment discontinuation must be captured in the eCRF. Any AEs 
experienced up to the point of discontinuation and 30 days thereafter must be documented on 
the AE eCRF. All serious adverse events (SAEs), and those AEs assessed by the Investigator 
as at least possibly related to study treatment should continue to be followed until they 
resolve or stabilize, whichever comes first. Patients will continue to be followed for PFS2 and 
OS, after discontinuing study treatment (Section 10.3.3).  
5.7.2. 
End of Study (EOS) 
Discontinuation from participation in the study will be documented on the End of Study 
(EOS) eCRF. Reasons for EOS include withdrawal of consent, lost to follow up or death, or 
study termination by Sponsor.  
5.7.3. 
Study Closure  
The study will be completed by the Sponsor one year after the final analysis for the primary 
endpoint of PFS is conducted. 


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Patients still receiving clinical benefit from IMGN853 at the time the study is completed by 
the Sponsor may continue to receive IMGN853 under this protocol (see Section 4.1.3).   
Patients who choose to continue to receive IMGN853 after the study is completed by the 
Sponsor will continue to be followed by their treating physician as per standard of care for 
their disease (including radiological assessments). These patients may remain on IMGN853 
until disease progression as assessed by the Investigator, development of unacceptable 
toxicity, withdrawal of consent, initiation of a new anticancer therapy, or death, whichever 
comes first (refer to Appendix D for Schedule of Assessments).  
5.7.4. 
Withdrawal of Consent 
The patient or legal guardian acting on behalf of the patient is free to withdraw consent to 
study treatment and/or participation in the study at any time irrespective of the reason. The 
investigator must make every effort (eg, telephone, email, letter) to determine the primary 
reason for this decision and record this information. Study treatment must be discontinued 
and no further assessments conducted. Further attempts to contact the patient are not allowed 
unless safety findings require communication or follow up. If the patient or legal guardian 
withdraws consent for disclosure of future information, the sponsor may retain and continue 
to use any data collected before withdrawal of consent. All biological samples that have been 
already collected will be retained and analyzed at a later date. The patient or legal guardian 
may also request destruction of any samples taken and not tested, and the investigator must 
document this in the site study records. The statistical analysis plan will specify how early 
withdrawals from treatment will be accounted for in the analyses of efficacy endpoints. 
Patients who have withdrawn from the study cannot be re-treated in the study. Their inclusion 
and patient number must not be reused. 
5.7.5. 
Lost to Follow up 
A study participant will be considered lost to follow-up if the participant repeatedly fails to 
return for scheduled visits and is unable to be contacted by the study site. The Investigator 
should make all efforts to contact the patient (eg, contacting patient’s family or private 
physician, reviewing available registries or health care databases), and to determine the 
patient’s health status, including at least his/her vital status. A patient should not be 
considered lost to follow up until due diligence has been completed. The following actions 
must be taken if a participant fails to return to the clinic for a required study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study. 
• In cases in which the participant is deemed lost to follow up, the investigator or 
designee must make every effort to regain contact with the participant (where 
possible, 3 telephone calls and, if necessary, a certified letter to the participant’s 
last known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record. 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 


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5.8. 
Period of Observation 
For purposes of this study, the period of safety observation extends from the time of informed 
consent until the 30-day follow-up safety visit unless additional follow up safety information 
is requested as described in Section 9.1 and Section 10.3.1. Short-term follow-up for patients 
who discontinue study treatment without documented progressive disease will be followed 
per RECIST 1.1 every 12 weeks (± 3 weeks) until PD, until the patient begins subsequent 
anti-cancer treatment, or until the patient dies, whichever comes first. All patients will be 
followed every three months (± 2 weeks) for survival until death, lost to follow-up, 
withdrawal of consent for survival or until End of Study, whichever comes first. 
Patients who continue to receive IMGN853 after the study is completed by the Sponsor will 
not be followed for survival data. 
5.9. 
Concomitant Medications and Procedures 
All concomitant medications and supportive therapy taken within four weeks of Cycle 1, 
Day 1 and through 30 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. 
5.9.1. 
Antiemetic and Antidiarrheal Medications 
Antiemetic (eg, 5-HT3 serotonin receptor antagonists such as palonosetron, granisetron or 
ondansetron) and antidiarrheal (eg, loperamide) medications may be used at the discretion of 
the treating physician, but they are not to be used prophylactically. 
5.9.2. 
Folate-Containing Supplements 
Folate-containing supplements should not to be taken during the course of the study. 
5.9.3. 
Antineoplastic Therapy 
Chemotherapy (other than agents specified for patients enrolled in Arm 2 of the study), and 
other investigational agents, or biologic therapy will not be permitted during the study. 
Palliative radiotherapy during study treatment should be discussed with the Sponsor prior to 
implementation. If the Investigator and Sponsor agree it is in the best interest of the patient, 
palliative radiotherapy may be performed; however, the patient will be censored in the PFS 
analysis from the time radiotherapy was performed.  
5.9.4. 
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. 


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5.9.5. 
Anticoagulants 
The use of the following anticoagulant agents is allowed: Warfarin (prophylactic or 
therapeutic), Unfractionated Heparin (prophylactic or therapeutic), Low Molecular Weight 
Heparins (prophylactic or therapeutic), Fondaparinux (prophylactic or therapeutic), 
Dabigatran and Edoxaban. Please see Section 5.9.8 if using Apixaban and Rivaroxaban due 
to CYP3A interaction potential. 
5.9.6. 
Contraception 
5.9.6.1. 
Acceptable Methods of Contraception  
• Single method (one of the following is acceptable) 
• Intrauterine Device (IUD) 
• Vasectomy of a female patient’s male partner  
• Contraceptive rod implanted into the skin 
Combination method (requires use of two of the following): 
• Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• Cervical cap with spermicide (nulliparous women only)  
• Contraceptive sponge (nulliparous women only)  
• Male condom or female condom (cannot be used together) 
• Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
Abstinence (relative to heterosexual activity) can be used as the sole method of contraception 
if it is consistently employed as the patient’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence (eg, calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception.  
If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for patients participating at sites in 
this country/region. 
Patients should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study WCBP must adhere to the contraception requirement (described above) from the 
day of study medication initiation (or 14 days prior to the initiation of study medication for 
oral contraception) throughout the study period up and for at least twelve weeks after the last 
dose of IMGN853 and for at least six months after the last dose of paclitaxel, topotecan and 
pegylated liposomal doxorubicin. If there is any question that a WCBP will not reliably 
comply with the requirements for contraception, that patient should not be entered into the 
study. 


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5.9.7. 
Other Concomitant Medications 
Medications for the treatment of adverse events or cancer symptoms (eg, 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.  
5.9.8. 
Medications that are CYP3A Substrates or CYP3A Substrates with Narrow 
Therapeutic Index 
In vitro metabolism studies demonstrated that DM4 is predominantly metabolized by thiol s-
methyltransferase (TMT) to form Me-DM4, which is further metabolized into sulfoxide-
methyl-DM4. As Me-DM4 has been shown to be primarily metabolized by CYP3A, its 
exposure could potentially be increased in the presence of strong CYP3A inhibitors. Drinking 
greater than one serving (250 ml) of grapefruit juice per day should be avoided. 
Available in vitro metabolism data suggest DM4 has a potential to inhibit CYP3A activity in 
vivo. The risk of a significant in vivo drug-drug interaction caused by DM4 inhibition of 
CYP3A is not currently known, therefore, treatment of patients with concomitant medications 
that are sensitive substrates of CYP3A or are CYP3A substrates with a narrow therapeutic 
index (Appendix H) should be carefully monitored.  
5.10. 
Overdose and Medication Error 
5.10.1. 
Overdose 
There is no known treatment/antidote available for IMGN853. For IC chemotherapy agents, 
please follow management guidelines for overdose as described in the prescribing 
information and/or institutional guidelines. Supportive measures should be instituted if an 
instance arises in which a patient suffers an overdose of any study drug. 
5.10.2. 
Medication Error 
The Sponsor must be immediately notified in the event of error in prescribing, dispensing, 
administering and/or use of any study drug, and the event must be reported on the eCRF. If 
an error resulted in a serious adverse event, a Serious Adverse Event form must be submitted 
within 24 hours of the event (see Section 9.2.1). 
6. 
PHARMACOKINETIC (PK) AND IMMUNOGENICITY 
ASSESSMENTS 
6.1. 
PK Assessments – IMGN853 
The PK properties of IMGN853 and possibly its metabolites will be evaluated following IV 
administration, as outlined in Appendix C. Plasma samples will be collected to determine the 
PK of IMGN853 (conjugate, total M9346A antibody, free DM4, DM4-Me and possibly other 
metabolites).  Urine samples will be collected for qualitative analysis of DM4 metabolites at 
designated sites in North America. 


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Patients still receiving clinical benefit from IMGN853 at the time the study is completed by 
the Sponsor may continue to receive IMGN853 under this protocol (see Section 4.1.3), but 
will not have additional blood drawn for PK assessment or for infusion-related reactions. 
6.1.1. 
Blood Samples for PK Measurements 
Blood samples for PK measurements will be taken as follows (Appendix C): 
Cycles 1 and 3: 
Day 1 – pre-dose, and immediately following the completion of the IMGN853 infusion (+5 
minutes)  
Day 8 – single blood sample  
Day 15 – single blood sample  
Cycles 2 and 4  
Day 1– pre-dose, and immediately following the completion of the IMGN853 infusion (+5 
minutes).  
Unscheduled Visit: Any patient who experiences a ≥ Grade 2 infusion-related reaction 
during the administration of IMGN853 will have blood drawn within three hours of the onset 
of the reaction and one week later for determination of drug concentration, antibodies to 
IMGN853. 
PK samples may also be obtained as feasible at any time during the treatment period for 
assessment of treatment-related SAEs if deemed appropriate by the Investigator and Sponsor. 
End of Treatment Visit: A blood sample for PK analysis will be collected at the End of 
Treatment Visit.  
30-day Follow Up Visit: A blood sample for PK analysis will be obtained if feasible.  
Procedures for collection, storage and shipment of samples are provided in the applicable Lab 
Manual. 
6.1.2. 
Urine Samples for Identification of DM4 Metabolites Collection 
Urine samples for the identification of the DM4 metabolites will be collected during Cycle 2, 
Cycle 3, or Cycle 4 as follows: 
Day 1 – pre-dose 
Day 1 – 0 to 4 hours after completion of infusion of IMGN853 
Day 1 – 4 to 24 hours after completion of infusion of IMGN853 
Samples are to be collected prior to and following the same infusion (ie, all samples are to be 
collected in the same cycle).  Sample collection may occur with Cycle 2, Cycle 3, or Cycle 4.  
Procedures for collection, storage and shipment of samples are provided in the applicable Lab 
Manual.  


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6.2. 
Immunogenicity Assessments – IMGN853 
The potential immunogenicity against IMGN853 will be assessed in Cycles 1 through 6, as 
outlined in Appendix C. The potential impact of immunogenicity on PK, safety, and efficacy 
of IMGN853 and total M9346A antibody will be explored.  
The sample for ADA analysis is taken from the PK tube on Day 1 Pre-Dose for Cycles 1, 2, 
and 4 and at the End of Treatment and 30-day Follow-up visits. An additional blood draw for 
ADA is required on Day 1 Pre-Dose for Cycle 6. 
Patients still receiving clinical benefit from IMGN853 at the time the study is completed by 
the Sponsor may continue to receive IMGN853 under this protocol (see Section 4.1.3), but 
will not have additional blood drawn for ADA assessment. 
7. 
BIOMARKER RESEARCH STUDIES 
Several biomarkers, including FRα, are evaluated as potential biomarkers of clinical response 
to IMGN853. These will help guide further clinical development of IMGN853. 
7.1. 
Evaluation of FRα Expression in Tumor Tissue  
FRα expression varies with tumor histology, as reported in the literature and demonstrated in 
pre-clinical studies (Section 1.1 and Investigator Brochure). FRα expression in tumors will be 
analyzed using an IHC based Investigational Use Only assay co-developed by ImmunoGen 
and Ventana Medical Systems Inc. This assay will be conducted at a central lab for testing of 
patient samples. All patients must submit tumor tissue, or formalin-fixed, paraffin embedded 
(FFPE) slides for analysis of FRα expression by IHC prior to enrollment.  
Only patients with the required FRα expression levels by IHC are eligible to enroll in the 
study. If a patient wishes to enroll and does not have archival material available for analysis, 
she must undergo a biopsy to assess FRα expression. Patients for whom the only sites of 
disease would require biopsy procedures considered to be of significant risk must not be 
enrolled in the study. These procedures include (but are not limited to) biopsies of the brain, 
lung/mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus, 
stomach or bowel.  
The required FRα expression level is ≥ 50% of tumor staining at ≥ 2+ intensity. A 
stratification cut-off of ≥ 75% at ≥ 2+ will also be implemented.  
Instructions regarding processing and shipment of all samples for FRα IHC testing are 
detailed in the applicable Lab Manual. 
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 activities that are planned, 
but other additional biomarkers/biological pathways may be investigated based on emerging 
data. 


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7.2.1. 
Potential Predictive Markers of Drug Response 
Cancer is a disease driven by molecular level changes, which include mutations, DNA 
rearrangements and copy number changes, as well as changes in gene expression of key 
oncogenic pathways. Many of these changes determine or influence the aggressiveness of the 
disease, how the cancer responds to standard of care and/or novel therapeutic agents, and 
development of resistance to treatment. To evaluate how these molecular changes are 
associated with response to IMGN853, we are planning to characterize the genomic profile of 
archival tumor samples using a fit for purpose technology such as the Foundation Medicine’s 
next generation sequencing (NGS) panel, including BRCA1, BRCA2, and other oncogenes 
and tumor suppressors. We are also planning to study oncogenic pathway activation using a 
fit for purpose technology such as the NanoString gene expression Pan Cancer panel. New 
assays for candidate biomarkers associated with sensitivity or resistance to IMGN853, 
identified in the current study or earlier studies, may also be developed and tested on patient 
samples. 
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 using peripheral 
blood mononuclear cells on Cycle 1 Day 1. Potential associations between FcγR genotype 
and clinical response will be examined. 
Drug efflux transporters and PgP in particular play an important role in cancer cell resistance 
to cytotoxic agents, including microtubule-targeting agents. Therefore, PgP expression levels 
will be assessed as a marker of drug resistance in tumor tissues for all patients. Potential 
associations between PgP levels and clinical response will be examined. 
8. 
STUDY PROCEDURES 
8.1. 
Informed Consent 
Each patient or legally authorized representative sign an IRB/IEC-approved informed consent 
form before any study-required procedures are conducted, unless those procedures are 
performed as part of the patient’s standard care (Appendix A and Appendix B).  
8.2. 
Inclusion and Exclusion Criteria 
The inclusion and exclusion criteria are assessed during Screening (within 28 days prior to 
the first dose of any study drug on Cycle 1, Day 1). All screening evaluations must be 
completed and reviewed to confirm that potential patients meet all eligibility criteria. The 
investigator will maintain a screening log to record details of all participants screened and to 
confirm eligibility or record reasons for screening failure, as applicable. Procedures 
conducted as part of the patient’s routine clinical management and obtained before signing an 
informed consent form may be utilized for screening or baseline purposes provided the 
procedure met the protocol-specified criteria and were performed within the timeframe 
defined in the schedule of assessments. A patient is considered enrolled when randomized to 
a study treatment (Appendix A and Appendix B). 


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8.3. 
Confirmation of Disease Diagnosis 
At Screening, disease diagnosis, and current disease status are confirmed from information in 
the source record (Appendix A and Appendix B). 
8.4. 
BRCA Mutation Status 
The BRCA mutation status from prior testing (information in the source record) will be 
recorded (Appendix A and Appendix B). Patients with a BRCA mutation (germline mutation 
or somatic mutation in tumor tissue) are classified as positive and patients without a known 
mutation will be classified as negative. Patients without known BRCA mutation status in the 
source record are classified as unknown. If a patient with unknown status is tested and is 
found to have a BRCA mutation, this patient is considered BRCA mutation positive in 
analyses. 
8.5. 
Demographic/Medical History 
The age, race, and gender of the patient are to be recorded during Screening for all patients 
who consent to the study (Appendix A and Appendix B). 
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. 
8.6. 
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 Clinical Assessments. 
8.7. 
Vital Signs 
Vital signs include body temperature, blood pressure, pulse measurements, and the 
respiratory rate. These signs are measured as outlined in Appendix A and Appendix B. 
8.8. 
Electrocardiogram (ECG) 
A standard, single 12-lead electrocardiogram (ECG) will be performed within 14 days prior 
to first dose to determine study eligibility and at EOT or 30-day follow-up safety visit and as 
clinically indicated.  
8.9. 
Pulmonary Function Tests 
Pulmonary function tests (PFT) should include spirometry, diffusion capacity, and lung 
volumes. PFT will be performed at Screening and as clinically indicated (Appendix A and 
Appendix B). 


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8.10. 
Ocular Symptom Assessment and Ophthalmic Examination  
8.10.1. 
Ocular Symptom Assessment 
Ocular symptom assessment will be performed prior to the start of each cycle by the treating 
physician or other qualified individual. For patients reporting > CTCAE Grade 1 ocular 
symptoms, treatment will be held until the patient is evaluated by an ophthalmologist for a 
complete examination. 
8.10.2. 
Ophthalmic Examination 
An ophthalmic examination will be performed at Screening (within 14 days prior to first dose 
of study drug) by an ophthalmologist and will include the following: distant visual acuity, 
best corrected visual acuity, slit lamp examination, intraocular pressure measurement, 
Schirmer’s test and indirect fundoscopy. Patients who experience ocular TEAEs while on 
study will have a complete ophthalmologic exam performed at the emergence of the 
symptoms and at every other cycle thereafter. All patients will have a complete 
ophthalmologic exam performed at the End of Treatment visit or 30-day follow-up visit 
(Appendix A and Appendix B). 
8.11. 
Laboratory Assessments 
A central laboratory will be used for the analysis of scheduled hematology, biochemistry and 
other tests collected as part of safety monitoring. Patients should be in a seated or supine 
position during blood collection. Screening labs (Table 17) will be performed within 14 days 
of first dose. Repeat testing on Cycle 1, Day 1 is not required if tests were obtained within 
four 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 study treatment, laboratory results must be reviewed 
to evaluate for potential toxicity.  
The site does not need to wait for the results of centrally analyzed laboratory assessments 
when an immediate clinical decision needs to be made and in those cases locally, 
unscheduled testing may be performed. Details on collection, shipment of samples and 
reporting of results by central laboratory are provided in the laboratory manual.  
8.11.1. 
Clinical Laboratory Panels 
A list of clinical laboratory tests may be found in Table 17. 


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Table 17: 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Coagulation 
Tests 
Urinalysis 
• 
Hematocrit 
• 
Hemoglobin 
• 
WBC (w/5-part 
differential) 
• 
RBC 
• 
Platelet count 
• 
Albumin 
• 
Alkaline 
phosphatase 
• 
ALT 
• 
AST 
• 
BUN 
• 
Calcium 
• 
Carbon dioxide 
• 
Chloride 
• 
Creatinine 
• 
Glucose 
• 
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 
beyond trace) 
WBC = white blood cell count; RBC = red blood cell count; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; INR = International Normalized Ratio; PT = Prothrombin time; 
aPTT = Activated partial thromboplastin time 
8.12. 
Pregnancy Screen 
All 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 
treatment (Appendix A and Appendix B). 
If a patient becomes pregnant or suspects pregnancy while participating in this study, the 
Investigator and Sponsor must be informed immediately (Section 9.2.2) and the patient will 
be withdrawn from study treatment. 
8.13. 
Eastern Cooperative Oncology Group Performance Status 
Eastern Cooperative Oncology Group (ECOG) performance status (Appendix E) 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 three days prior to Day 1. 


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8.14. 
ECHO/MUGA Scan  
ECHO or MUGA scans will be performed only in patients receiving PLD (Appendix B). 
ECHO or MUGA scans will be performed at Screening and every four cycles of treatment or 
as medically indicated. The same test should be performed throughout the trial.  
8.15. 
Tumor Response Assessment 
8.15.1. 
Radiological Imaging 
Radiographic tumor evaluation by computed tomography (CT) or MRI of chest, abdomen, 
and pelvis will be performed within 28 days prior to first dose of study treatment and every 
six weeks (±1 week) for the first 36 weeks on study and every 12 weeks (±1 week) thereafter 
(Appendix A and Appendix B). The same method of radiographic assessment used at 
Screening must be used at all subsequent radiographic evaluations. Copies of all imaging 
scans must be obtained and sent to a central imaging vendor designated by ImmunoGen as 
outlined in the Imaging Manual. The central imaging vendor will assess the quality of the 
images. The imaging vendor will be responsible for the formation and management of the 
BIRC. 
Tumor response will be assessed by the investigator and by the BIRC using RECIST 1.1 
(Eisenhauer 2009). Response as determined by the investigator will be recorded in the 
eCRFs. The BIRC assessment will be used for the primary endpoint analysis.  
All time points without investigator determined progression will be assessed by BIRC in a 
non-expedited manner. Results of these assessments will not be communicated to the sites.  
For time points with investigator-determined progression, the BIRC will perform an 
expedited review. While the images are assessed by the BIRC, patients should continue on 
the study treatment as planned if it is clinically acceptable. If the BIRC confirms disease 
progression, the patient must be discontinued from study treatment. If the BIRC does not 
confirm disease progression, the patient should continue receiving the study treatment unless 
there is a medical need (ie, rapid progression or clinical deterioration) that requires an 
immediate change in therapy. 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 in the eCRFs. 
The central imaging vendor will ensure that the central radiologists remain blinded to the 
local assessment from the investigator and other unblinding information. This and all other 
imaging procedures will be documented in an independent review charter agreed upon 
between ImmunoGen and the imaging vendor before initiation of any BIRC reviews. BIRC 
assessment of disease progression will be used for the primary end point analysis.  
Note: It is very important that the same method of radiologic assessment be used 
throughout the study and that the same lesions are followed.  
Patients still receiving clinical benefit from IMGN853 at the time the study is completed by 
the Sponsor may continue to receive IMGN853 under this protocol (see Section 4.1.3).  
Patients who choose to continue to receive IMGN853 after the study is completed by the 
Sponsor will continue to be followed by their treating physician as per standard of care for 


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their disease (including radiological assessments). There will be no BIRC review of disease 
progression in these patients who continue to receive IMGN853 after the study is completed 
by the Sponsor. 
8.15.2. 
CA-125 
Serum CA-125 assessments will be performed within 14 days prior to the first dose of study 
treatment, at day 1 (± 1 week) of each cycle and at each radiologic tumor evaluation 
thereafter (Appendix A and Appendix B). CA-125 should be assessed by the same laboratory 
throughout the study.  
8.16. 
Quality of Life - EORTC QLQ-C30, EORTC QLQ-OV28, Eight-
item FOSI and EQ-5D-5L Questionnaires 
Quality of life questionnaires EORTC QLQ-C30, EORTC QLQ-OV28, eight-item FOSI and 
EQ-5D-5L (Greimel 2003, Osoba 1994, and King 2014) will be used in this trial. The 
questionnaires should be given to the patient and completed during their Screening visit and 
at other times specified in the Schedule of Clinical Assessments (Appendix A and 
Appendix B). The patient should not be sent home with the questionnaires to complete and 
return at their next visit. An assessment is not necessary on Cycle 1 Day 1 if the Screening 
assessment was completed within 14 days prior to Day 1. 
All questionnaires should be provided in the patient’s local language at the beginning of the 
study visit prior to any interaction with the study investigator, including procedures and 
treatments, and receipt of results from any tests to avoid bias to patient’s response to the 
study questionnaire. Patient should be given sufficient space and time to complete all study 
questionnaires at the visit. Patients should be encouraged to complete any missing responses. 
8.17. 
Health-care Resource Utilization 
Resource Utilization Data will be collected on the following healthcare resources: 
hospitalizations, unscheduled office visits, and admission to hospice care or nursing home 
facility. 
9. 
ASSESSMENT OF SAFETY 
9.1. 
Recording Adverse Events and Serious Adverse Events 
Adverse Events (AEs), including those attributed to study procedures, will be documented on 
the AE eCRF and monitored continuously throughout the study from the time of informed 
consent until 30 days after the patient’s last study treatment. 
However, serious AEs will be followed up by ImmunoGen Pharmacovigilance until 
resolution, stabilization or return to baseline. Beyond this defined reporting period, any 
unsolicited SAE assessed as related to the study drug by the Investigator and reported to 
ImmunoGen will be collected and processed. Additional information obtained after database 
lock, will reside solely in the safety database. 


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The Investigator should take appropriate measures to follow and provide updates for all AEs 
until clinical recovery is complete, laboratory values return to normal, the patient stabilizes or 
death occurs, in order to ensure the safety of the patients. This may mean that observations 
continue beyond the last planned visit per protocol and that additional investigations may be 
requested by the Sponsor. 
Patients who continue to receive IMGN853 after the study is completed by the Sponsor will 
only have SAE and AESI data reported and collected per the SAE Form as detailed in 
Section 9.2.1. AEs that do not meet SAE or AESI criteria will not be reported for these 
patients. Data for these patients who continue to receive IMGN853 after the study is 
completed will not be captured in the clinical study database.  Information collected from 
these patients will be maintained by ImmunoGen in the safety database. 
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 unless it is considered to be 
drug-related by the investigator. 
All AEs, including AEs attributed to study procedures, occurring from the time of informed 
consent until 30 days after last study treatment or closure of the study, 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, return to baseline 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 
symptoms, are considered clinically significant (eg, cause study drug discontinuation or 
constitutes in and of itself a Serious Adverse Event, or require therapy, eg, any hematologic 


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abnormality that requires transfusion or growth factor 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 baseline 
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 
• Pneumonitis is an AESI; any symptom or sign potentially suggestive of 
pneumonitis should be promptly reported as a SAE 
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 (eg, a homeless patient) or admission not associated with 
a precipitating clinical adverse event (eg, elective ore pre-planned surgery, or in-patient 
administration of subsequent chemotherapy, etc.). 
9.1.1.3. 
Adverse Events of Special Interest (AESI) 
An adverse event of special interest (AESI) (serious or non-serious) is one of scientific and 
medical concern specific to the sponsor’s product for which ongoing monitoring and rapid 
communication by the investigator to the sponsor is appropriate.  
9.1.1.3.1. IMGN853 
IMGN853 has one AESI: pneumonitis.  
Any symptom or sign potentially suggestive of pneumonitis should be promptly reported as 
per Section 9.2.1 radiologic findings suggestive of pneumonitis include new onset of any of 
the following: 


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• Pulmonary consolidation 
• Pulmonary infiltrate 
• Reticular infiltrate 
• Nodular infiltrate 
• Reticulo-nodular infiltrate 
• Ground-glass pulmonary infiltrate 
• Increased interstitial markings 
• Interstitial infiltrate 
• Honeycomb’s appearance 
9.1.2. 
Classification of Adverse Events 
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 18. 
Table 18: 
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) 
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 19. 


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Table 19: 
Adverse Event Causal Relatedness  
Relationship to Product(s) Definition 
Not Related 
No relationship between the event, including laboratory test 
abnormality, and the administration of study drug. There is no 
temporal relationship and there is unambiguous evidence supporting 
another cause.  
Unlikely Related 
A clinical event, including laboratory test abnormality, with a 
temporal relationship to study drug administration which makes a 
causal relationship improbable, and in which other drugs, chemicals 
or underlying disease provide plausible explanations.  
Possibly Related 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of study drug, but which 
could also be explained by concurrent disease or other drugs or 
chemicals. Information on study drug withdrawal may be lacking or 
unclear.  
Probably Related 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of study drug, unlikely to 
be attributed to concurrent disease or other drugs or chemicals, and 
which follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this 
definition. The association of the clinical event, including laboratory 
test abnormality, must also have some biologic plausibility, at least 
on theoretical grounds. 
Definitely Related 
A clinical event, including laboratory test abnormality occurring in a 
plausible time relationship to study drug administration, and which 
cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the study drug 
(dechallenge) should be clinically plausible. The event must be 
definitive pharmacologically or phenomenologically, using a 
satisfactory rechallenge procedure if necessary.  
9.2. 
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 informed consent until 30 days after the last study treatment, must be recorded by the 
clinical site on an SAE report form. The SAE must also be recorded on the patient’s AE 
eCRF (unless experienced by a patient who continued IMGN853 treatment beyond the 
closure of the study), including the Investigator’s assessment regarding the relationship of the 
SAE to the study treatment (IMGN853, PLD, paclitaxel or topotecan). The Investigator will 
promptly supply all information requested by the Sponsor (or contract research organization 
[CRO]) regarding the SAE.  
The Investigator must submit the SAE report form to ImmunoGen Pharmacovigilance (or 
designee). This form must be completed and submitted within 24 hours of the Investigator’s 
learning of the event using the contact information printed on the SAE form and contained 


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within the SAE form completion instructions. Follow-up information must also be submitted 
using a new SAE Report Form. 
When reporting SAEs, the following additional points should be noted:  
• 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). 
• An event term of “Death” should not be reported as an SAE, but rather be 
recorded as an outcome of a specific SAE term. Initially, the event term of “death” 
can be used until the actual cause of death is known. If an autopsy was performed, 
the autopsy report should be provided. 
• Pneumonitis is an AESI; any symptom or sign potentially suggestive of 
pneumonitis should be promptly reported as a SAE. 
It is the responsibility of the Sponsor to ensure that each Investigator receives a copy of any 
suspected unexpected serious adverse reaction (SUSAR) report (CIOMS/MedWatch) 
regarding the study drug and as submitted to the appropriate national regulatory agencies.  
The Investigator (or Sponsor or designee) 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 (through annual 
updates to the IB) the Investigators and IRBs/IECs of all deaths that occur during the study, 
irrespective of relationship to study medication. 
9.2.1.1. 
Reporting of Disease Progression 
Disease progression and/or progression of the disease under study are anticipated occurrences 
in oncology drug development. They are not adverse events unto themselves.  
“Progression of disease” should not be used as an AE term per se. However, any medical 
event/condition that is untoward in the context of disease progression and/or for the specific 
patient’s disease course should be reported as an AE and assessed accordingly by the 
investigator.  
Progression of disease with a fatal outcome does not need to be reported as an AE term. 
However, the applicable protocol CRF page(s) pertaining to death should be completed 
immediately in order to record the disease progression/death. 
9.2.2. 
Reporting a Pregnancy 
Pregnancy and lactation are exclusion criteria. 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 (ie, who has had 
menses any time in the preceding 12 consecutive months) must agree to use effective 
contraceptive methods while on study treatment and for at least twelve weeks after the last 


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dose of IMGN853 and for at least six months after the last dose of paclitaxel, topotecan and 
pegylated liposomal doxorubicin. 
The Sponsor must be immediately notified in the event of a pregnancy occurring during the 
course of the study and through 30 days after a patient’s last dose of study drug. Pregnancy is 
not an adverse event unto itself and therefore should not be reported as an AE. 
All pregnancies will be recorded on a Pregnancy Report and submitted according to the 
contact information on the form and in the completion guidelines. 
Pregnancies, with the permission of the mother, will be followed to completion or 
termination using the designated sections of the Pregnancy report form. 
Any SAE, occurring during the pregnancy to the mother or fetus, would require that a study 
SAE form also be completed/submitted. 
10. 
STUDY ACTIVITIES 
All study visits and assessments that must be performed during the study and follow-up are 
included in Appendix A and Appendix B. Procedures and assessments for patients who 
continue to receive IMGN853 after the study is completed by the Sponsor are listed in 
Appendix D. 
10.1. 
Screening Visit 
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.  
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 if performed within the screening window. 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.  
Note that safety blood tests, and physical examination do not need to be repeated if normal 
and conducted within four days prior to Cycle 1, Day 1. 
10.2. 
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 5.6.1.10, Section 5.6.2.2, Section 5.6.3.2, and 
Section 5.6.4.3. 


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Patients who withdraw or are removed from the study treatment will have an End of 
Treatment (EOT) visit within seven days of the decision to discontinue study treatment.  
Additionally, these patients will undergo a 30-day follow-up safety visit. The eCRF will 
capture reasons for withdrawal.  
10.3. 
Follow-up Assessments 
10.3.1. 
Safety Follow-up  
A safety follow-up visit will occur 30 days (+ 14 days) after the last treatment.  
In some cases, non-serious AE observations may continue beyond the safety visit. All ocular 
AEs will be followed until resolution, stabilization, or return to baseline. In these instances, 
additional information may be requested by ImmunoGen in order to adequately categorize the 
nature of the toxicity. 
All serious adverse events will be followed until they resolve, stabilize or return to baseline, 
regardless of time from last dose or last visit. 
10.3.2. 
Response Follow-up 
Patients who have discontinued study treatment for reasons other than PD will continue 
tumor assessments every 12 weeks (+/- 3 weeks) until documentation of PD, withdrawal of 
consent or until the patient starts subsequent anti-cancer therapy, whichever comes first.  
10.3.3. 
PFS2 and Survival Follow-up  
All patients who discontinue study treatment for any reason will be followed for survival 
after disease progression as per BIRC, or after start of anti-cancer therapy. All patients will 
be followed for survival every three months (± 2 weeks) until death, lost to follow-up, 
withdrawal of consent for survival follow-up or until End of Study, whichever comes first.  
For the purposes of evaluating PFS2, information related to disease progression during 
survival follow-up and details regarding subsequent anti-cancer therapies will be collected. 
11. 
STATISTICAL METHODS 
This is a Phase 3 study designed to evaluate the efficacy of IMGN853 compared with that of 
standard of care chemotherapy in women with advanced EOC, primary peritoneal cancer or 
fallopian tube cancer.  
All statistical analyses will be performed using the most recently released SAS statistical 
software, unless otherwise noted. For categorical variables, the number (n) 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. 
A SAP will fully describe the planned analyses for this trial and will be finalized prior to 
database lock. The safety analyses will be based on patients who receive at least one dose of 


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IMGN853 or investigator choice chemotherapy. The primary efficacy analyses will be 
performed on the intent-to-treat (ITT) population. The ITT population is defined as all 
randomized patients. 
11.1. 
Sample Size 
The primary endpoint for this Phase 3 study is PFS as assessed by BIRC in all randomized 
patients and PFS as assessed by BIRC in the FRα high expression subgroup. The study is 
designed to test the null hypothesis that the survival function for PFS is the same between 
IMGN853 arm and IC chemo arm versus the alternative hypothesis that the survival function 
for PFS is different between IMGN853 and IC chemo arm. The Hochberg procedure will be 
used to control the study-wise type I error (Appendix J). Approximately 333 patients will be 
randomized 2:1 (222 IMGN853 arm: 111 IC arm) over a period of approximately 21 months. 
The final analysis will be conducted when at least 236 PFS events are observed. An interim 
futility analysis will be conducted when at least 80 PFS events have been observed. The study 
will be terminated for futility at interim analysis if the observed hazard ratio is greater than 1 
in all randomized patients as well as in the FRα high expression subgroup. The study will 
have 91% power to detect a hazard ratio of 0.583 in the FRα high expression subgroup and 
96% power in all randomized patients at a study-wise alpha level of 5% and the study will 
have a 39% probability of stopping for futility at interim analysis under the null hypothesis. 
Sample size and power was determined by simulations using SAS® software with the 
following assumptions:  
• median PFS for the IC arm is 3.5 months 
• median PFS for the IMGN853 arm is 6 months 
• exponential distribution for both event and censoring processes 
• ratio of FRα high to FRα medium is 2:1  
• annual censoring rate is 20% in both arms 
11.2. 
Stratification 
Randomization will be stratified by: 
• Number of prior lines of therapy (1 or 2 vs. 3) 
• FRα levels (≥ 75% of tumor staining at ≥ 2+ intensity vs. ≥ 50% and < 75% at 
> 2+ intensity)  
• IC chemotherapy (paclitaxel, PLD or topotecan) 
The required FRα expression level is ≥ 50% of tumor staining at ≥ 2+ intensity. A 
stratification cut-off of ≥ 75% at ≥ 2+ will also be implemented to evaluate anti-tumor 
activity of IMGN853 based on higher levels of FRα expression.  
Since the type of IC chemotherapy received is one of the stratification factors, it is required 
that the choice of the chemotherapy agent, paclitaxel or PLD or topotecan, be made prior to 
randomization.  


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11.3. 
Pharmacokinetic Analyses 
PK parameters will not be calculated due to the sparse sampling scheme in this study. 
Summary statistics of the concentration at each time point (nominal time) will be presented. 
Graphical presentation of the data may also be completed using nominal time.  
11.4. 
Safety Analyses 
Safety analyses will be based on patients who receive at least one dose of IMGN853 or 
investigator choice chemotherapy. 
Adverse events and concomitant medication will be listed.  
Adverse events will be coded using the latest MedDRA version and summarized per system 
organ class and preferred term. 
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, ECHO/MUGA scan (patients receiving 
PLD), 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 ADA.  
11.5. 
Efficacy 
Efficacy analyses will be performed on an ITT basis. The ITT population is defined as all 
randomized patients. 
An interim futility analysis will be conducted when at least 80 PFS events, as assessed by the 
BIRC, have been observed. If the observed hazard ratio is greater than 1 in both all 
randomized patients and FRα high expression subgroup, the study will be terminated for 
futility. 
If the study continues to full enrollment of 333 patients, final analysis will be conducted 
when at least 236 PFS events have been observed. Hochberg procedure will be used to 
control the study-wise type I error. 
The primary endpoint of PFS, as assessed by BIRC, will be estimated using Kaplan-Meier 
method. Comparison between treatment arms will be conducted using Cox proportional 
hazard regression and log rank test, stratified by FRα expression level (for ITT analysis only, 
high vs. medium), IC chemo (paclitaxel vs. PLD vs. topotecan), and number of prior lines of 
therapy (1 or 2 vs. 3). Unstratified analysis will also be conducted as sensitivity analysis.  
The secondary endpoint of ORR (objective response = complete response [CR] + partial 
response [PR]) will be estimated along with a 95% CI. The ORR of the IMGN853 arm and 
that of the IC arm will be compared using appropriate statistics tests; all results will be 
presented in a table.  


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The secondary endpoints of overall survival (OS), duration of response (DOR), and PFS (as 
assessed by the investigator) will be estimated using Kaplan-Meier method. Comparison 
between treatment arms will be conducted using Cox proportional hazard regression and log 
rank test. 
For ORR and DOR, the primary analysis will be based on BIRC assessment. ORR and DOR 
as assessed by the investigator will be summarized as sensitivity analysis. 
CA-125 response will be determined using the GCIG criteria (see Appendix G). CA-125 
response per GCIG criteria will be determined programmatically (see Appendix G). 
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).  
Progression Free Survival (PFS) – PFS defined as the time from date of randomization until 
progressive disease or death whichever occurs first. Results will be summarized by arm. 
Time to Second Disease Progression (PFS2) – PFS2 defined as the time from date of 
randomization until second disease progression or death whichever occurs first. Results will 
be summarized by arm. 
Overall Survival (OS) – OS is defined as the time from the date of randomization until the 
date of death. Patients who do not experience the event of death will be censored at their last 
date known to be alive. 
11.6. 
Interim Analysis 
Safety analysis data will be monitored by the IDMC (Section 13.5.2) as described in the 
IDMC charter. An interim futility analysis will be conducted when at least 80 PFS events as 
assessed by BIRC have been observed. The study will be terminated for futility at interim 
analysis if the observed hazard ratio is greater than 1 in all randomized patients as well as in 
the FRα high expression subgroup. No alpha spending is planned for this futility. The SAP 
describes the planned IA in greater detail.  
Under the enrollment assumptions (Appendix J), the interim analysis will occur when 
approximately 160-180 patients have been randomized. This is expected to occur 
approximately one year after the first patient is randomized. 
11.7. 
Patient-Reported Outcomes 
The EORTC QLQ-C30, EORTC QLQ-OV28, eight-item FOSI and the EQ-5D-5L 
questionnaires will be used to collect data on the patient’s functioning, health-related quality 
of life, disease symptoms and health status. 
The primary PRO endpoint is the number of patients achieving at least a 15% (≥ 15-point) 
absolute improvement on the QLQ-OV28 abdominal/GI symptom subscale (items 31-36) at 
week 8/9 assessment (Stockler 2014). Patients with missing week 8/9 questionnaires will be 
included as unimproved.  


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Results will be summarized and presented by each treatment arm. Comparison between the 
two treatment arms will be carried out using appropriate statistical tests. Details of the 
analysis methods for PRO endpoints will be described in a PRO Statistical Analysis Plan. 
11.8. 
Multiple Comparisons 
11.8.1. 
Multiple Comparisons for Primary Efficacy Endpoints 
For the primary endpoint of PFS as assessed by BIRC  
• in all patients randomized to the study (intent-to-treat or ITT population) and 
• in patients with high FRα level (≥ 75% of tumor staining at ≥ 2+ intensity) 
• the Hochberg procedure (Appendix J) will be used to control the overall type I 
error 
11.8.2. 
Multiple Comparisons for Key Secondary Efficacy Endpoints 
For the key secondary endpoints, a hierarchical testing procedure will be used to control the 
overall type I error, only if the primary endpoint is statistically significant in both ITT 
population and FRα high subgroup. The hierarchical testing procedure will be carried out in 
the following order: 
• Objective response rate (ORR) per RECIST 1.1 criteria as assessed by BIRC 
• Primary PRO endpoint as described in Section 11.7.  
• Overall survival (OS): the time from the date of randomization until the date of 
death 
This procedure will stop at the first test not significant at a two-side alpha level of 0.05. 
12. 
QUALITY CONTROL AND ASSURANCE 
12.1. 
Recording of Data and Data Quality Assurance 
Data will be captured using validated, electronic data capture (EDC) systems. Data will be 
documented in various source documents (eg, the patient medical chart) and then manually 
entered into the eCRF by study site personnel. Clinical sites will be monitored by 
ImmunoGen or its designee to ensure the accuracy of data against source documents. If 
necessary, the study site will be contacted for corrections or clarifications. 
Adverse events will be coded using the latest MedDRA version. Concomitant medications 
will be coded using the (WHO-DD; June 1, 2012 or later version. Training will occur at an 
Investigator meeting or at the site initiation visit or both, and instruction manuals (eg, 
laboratory manuals and pharmacy manuals) will be provided to aid consistency in data 
collection and reporting across sites. 
Patients still receiving clinical benefit from IMGN853 at the time the study is completed by 
the Sponsor may continue to receive IMGN853 under this protocol.  Sites with ongoing 


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patients at the time of study completion will be trained by the Sponsor/CRO on the patient 
oversight requirements. 
All required data will be entered into the clinical 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. 
13. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES  
13.1. 
Ethical and Regulatory 
This clinical trial will be conducted by the Sponsor, the Investigator, delegated Investigator 
staff and sub-Investigator(s), in accordance with the principles laid down by the 18th World 
Medical Assembly (Helsinki, 1964) and all applicable amendments laid down by the World 
Medical Assemblies, and the ICH guidelines for good clinical practice (GCP), all applicable 
laws, rules and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no 
later than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with ImmunoGen public disclosure commitments. 
13.1.1. 
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 prescreening ICF (latter ICF 
is applicable for sites requesting permission to prescreen for FRα 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 FDA or other regulatory agencies 
(SUSARs), must be submitted promptly to the IRB/IEC. 
13.1.2. 
Patient Information and Consent 
Before enrolling in the clinical study, the patient or the patient’s legally authorized 
representative(s) must sign an IRB/IEC -approved ICF 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 


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all FDA and ICH-required 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 the patient has been given ample time to read and ask questions regarding the informed 
consent form and has been informed that participation is voluntary, 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 13.3. 
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained. 
A model of the prescreening and the main study ICF will be provided to the sites separately 
for this protocol. The main study consent can be used to confirm a patient’s consent to all 
study procedures and all study-specific screening tests. The prescreening ICF can be used to 
prescreen patients for FRα status prior to performing any additional study related tests. If 
patient is eligible based on FRα expression level, the patient will be provided the main study 
consent and only after signing the main study ICF will additional study-specific screening 
tests be performed. Alternatively, patient can be consented on both prescreening and main 
study ICF at the same time; and FRα testing and study-specific screening assessments can be 
carried out in parallel.  
Participants must be consented to the most current version of the ICF during the participation 
in the study.  
13.2. 
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. 


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13.3. 
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, and radiological images sent to outside laboratories 
and/or CROs (eg, 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 patient. 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. 
13.4. 
Study Monitoring 
ImmunoGen personnel and the designee (CRO) will review the protocol and the eCRFs with 
the Investigator and the site staff at a site initiation visit. Monitoring procedures that comply 
with current GCP guidelines will be followed. On-site monitoring will be performed by a 
representative of the Sponsor (Clinical Study Monitor). On-site review of the eCRFs for 
completeness and clarity, cross-checking with source documents, and clarification of 
administrative matters will be performed. During the monitoring visits the field monitor will 
check the progress of enrollment, and ensure that study treatment is being stored, dispensed, 
and accounted for according to specifications. Key study personnel from the site must be 
available to assist the field monitor during these visits. 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). 
The investigator must maintain source documents for each patient in the study, consisting of 
all visit notes, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). The investigator must give the monitor access to all 
relevant source documents to confirm their consistency with the eCRF entries. Full 
verification for the presence of informed consent, adherence to the inclusion/exclusion 
criteria and documentation of SAEs is required. Additional checks of the consistency of the 
source data with the eCRFs are performed according to the study-specific monitoring plan. 
13.5. 
Study Committees 
13.5.1. 
Steering Committee (SC)  
A Steering Committee (SC) will comprise of lead principal investigators from US and 
Europe. The purpose of the SC is to provide overall guidance regarding design of the study, 
conduct and execution of the trial. This includes (but not limited to) safety, efficacy, 
enrollment and contribution to scientific input for publications. Responsibilities of the SC and 


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communication flow between IDMC, SC and ImmunoGen will be included in the SC charter 
document.  
13.5.2. 
Independent Data Monitoring Committee (IDMC) 
An IDMC has been established for this study and specific guidelines on the operation and 
purpose of the IDMC is documented in a Charter. The committee includes at least three 
members, including a statistician and medical oncologists experienced in the treatment of 
ovarian cancer. Safety review meetings will be held as per the IDMC charter and as needed if 
any unexpected safety signals emerge during the course of the study. The IDMC will be 
responsible for independently evaluating safety data of patients enrolled to the study. 
Decisions on study termination, amendment of the protocol, or cessation of patient 
recruitment will be made after recommendations from the IDMC have been assessed by the 
Sponsor. 
13.6. 
Case Report Forms and Study Reports 
Case report forms (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. 
13.7. 
Critical Documents 
Before ImmunoGen initiates the study (ie, 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 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 


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• 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. 
13.8. 
Protocol Adherence 
Each Investigator must adhere to the protocol as detailed in this document and agree that any 
changes to the protocol must be approved by ImmunoGen’s authorized representative in 
writing prior to seeking approval, where necessary, from the IRB/EC, Research Ethics 
Committee (REC), or Ethics Review Board (ERB). Each Investigator will be responsible for 
allowing only those patients who have met protocol eligibility criteria to be enrolled. 
Modifications to the protocol should not be made without agreement of the Investigators and 
ImmunoGen. Changes to the protocol will require written IRB/EC, REC, or ERB 
approval/favorable opinion prior to implementation, except when the modification is needed 
to eliminate an immediate hazard(s) to patients. The IRB/EC/REC/ERB may provide 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/EC/REC/ERB. ImmunoGen will submit all 
protocol modifications to the appropriate regulatory authorities in accordance with the 
governing regulations. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) 
to patients, the Investigator will contact ImmunoGen, if circumstances permit, to discuss the 
planned course of action. Any departures from the protocol must be fully documented in the 
source documentation and recorded onto eCRF (if applicable). 
Prospective waivers or exemptions are not permitted.  
13.9. 
End of Study 
The end of the study or study completion is defined as one year after the final analysis for the 
primary endpoint of PFS is conducted.  
Patients still receiving clinical benefit from IMGN853 at the time the study is completed by 
the Sponsor may continue to receive IMGN853 under this protocol (see Section 4.1.3).   
Patients who choose to continue to receive IMGN853 after the study is completed by the 
Sponsor will continue to be followed by their treating physician as per standard of care for 
their disease (including radiological assessments). These patients may remain on IMGN853 
until disease progression as assessed by the Investigator, development of unacceptable 
toxicity, withdrawal of consent, initiation of a new anticancer therapy, or death, whichever 
comes first (refer to Appendix D for Schedule of Assessments).  
13.10. 
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 


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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. 
Site Termination 
If ImmunoGen, an Investigator, or regulatory authorities discover conditions during the study 
that indicates that the study or related activities at a particular center should be terminated, 
this action may be taken after appropriate consultation between ImmunoGen and the 
Investigator. Conditions that may warrant study or center termination include but are not 
limited to: 
• Discovery of an unexpected, serious, and/or unacceptable risk to patients enrolled 
in the study. 
• Decision on the part of ImmunoGen to suspend or discontinue testing, evaluation, 
or development of the clinical program. 
• Unacceptable benefit: risk relationship of the investigational product. 
• Recommendations of the IDMC or regulatory body. 
• Investigator failure to comply with applicable regulatory authority requirements or 
protocol requirements. 
• Submission of knowingly false information from the center to ImmunoGen or 
regulatory authorities 
Study or center termination and follow up will be performed in compliance with the 
conditions set forth in 21 Code of Federal Regulations (CFR) Section 312 and in compliance 
with the principles set forth in International Conference on Harmonisation (ICH) Good 
Clinical Practices (GCPs). 
13.12. 
Access to Source Documentation 
According to the ICH GCP, the monitoring team must check the eCRF entries against the 
source documents. The informed consent form will include a statement by which the patient 
allows the Sponsor’s duly authorized personnel, the Ethics Committee (IRB/IEC), and the 
regulatory authorities to have direct access to original medical records which support the data 
on the CRFs (eg, patient's medical file, appointment books, original laboratory records, etc.). 
These personnel, bound by professional secrecy, must maintain the confidentiality of all 
personal identity or personal medical information (according to confidentiality and personal 
data protection rules). 
13.13. 
Audits and Inspections 
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 


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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, 
crosschecking with source documents, and clarification of administrative matters will be 
performed. 
13.14. 
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 and analyses. 
13.15. 
Retention of Data 
Essential documents should be retained until the following requirements are met: 
• a minimum of two years has elapsed following the last approval of a marketing 
application and, 
• there are no pending or contemplated marketing applications, or 
• at least two 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. 
13.16. 
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. 
13.17. 
Insurance Compensation 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical 
trials under its sponsorship. This insurance policy is in accordance with local laws and 
requirements. The insurance of the Sponsor does not relieve the Investigator and the 
collaborators from any obligation to maintain their own liability insurance policy. An 
insurance certificate will be provided to the IECs/IRBs or regulatory authorities in countries 
requiring this document. 
13.18. 
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 


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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 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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14. 
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d. Vital signs (blood pressure, pulse, respiration rate, and temperature) will be measured predose within 10 minutes prior to start of infusion and at 10 minutes following 
completion of the infusion. 
e. 
Pulmonary function tests (PFTs) should include spirometry, diffusion capacity, and lung volumes. PFTs will be performed at Screening, within 28 days prior to C1D1, 
and in the event of pulmonary symptoms as clinically indicated. 
f. 
Day 1 laboratory assessments and physical exam may be performed up to 4 days prior to study agent administration. Laboratory results must be reviewed prior to each 
scheduled drug administration. In the event of severe toxicity, laboratory tests must be repeated as necessary until the toxicity resolves or stabilizes.  
g. For WCBP, a urine or serum pregnancy test will be performed at Screening, prior to dosing on Day 1 of every cycle (it can be performed up to 3 days prior to Day 1) and 
at the 30-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 an ophthalmologist within 14 days of first dose and will include the following: visual acuity (with/without corrective 
lens; whichever best reflects the patient’s usual functioning), slit lamp examination, intraocular pressure measurement, Schirmer’s test and indirect fundoscopy. All 
patients will have a complete ophthalmologic exam performed at the End of Treatment visit or 30-Day Follow-up visit. 
i. 
Ocular symptoms assessment will be performed prior to the start of each cycle by the treating physician or other qualified individual. For patients reporting > CTCAE 
Grade 1 ocular symptoms, treatment will be held until the patient is evaluated by an ophthalmologist for a complete examination.  
j. 
Radiographic tumor assessment by CT/MRI scan is to be performed every 6 weeks (± 1 week) for the first 36 weeks then every 12 weeks (± 1 week). CA-125 will be 
measured at Day 1 of each cycle (± 1 week) and at approximately the same time they undergo radiologic assessment, in accordance with GCIG criteria (responses will be 
confirmed according to GCIG criteria).  
k. If a patient discontinues prior to documentation of PD, a tumor assessment and CA-125 will be assessed at the End of Treatment visit or 30-day Follow-up visit, if not 
performed within the previous 6 weeks. Tumor assessments and CA-125 will continue to be performed every 12 weeks (± 1 week) 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 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. 
l. 
Topotecan administered daily on Days 1-5; no assessments performed on Days 2-5. 
m. ECG will be performed at EOT or 30-day follow-up visit. 
n. EQ-5D-5L assessment will also be performed at the first post-progression survival follow-up visit. 
o. As listed in Table 17  
p. As defined in Section 8.4  












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k. Radiographic tumor assessment by CT/MRI scan is to be performed every 6 weeks (± 1 week) for the first 36 weeks then every 12 weeks (± 1 week). CA-125 will be 
measured at Day 1 of each cycle and at approximately the same time they undergo radiologic assessment, in accordance with GCIG criteria (responses will be confirmed 
according to GCIG criteria). 
l. 
If a patient discontinues prior to documentation of PD, a tumor assessment and CA-125 will be assessed at the End of Treatment visit or 30-day Follow-up visit, if not 
performed within the previous 6 weeks. Tumor assessments and CA-125 will be assessed 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 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. 
m. Only for topotecan and paclitaxel arm 
n. Only for the paclitaxel arm 
o. ECG will be performed at EOT or 30-day follow-up visit. 
p. EQ-5D-5L assessment will also be performed at the first post-progression survival follow-up visit. 
q. On Day 8 only. 
r. 
As listed in Table 17 
s. 
As defined in Section 8.4 




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APPENDIX D. SCHEDULE OF ASSESSMENTS FOR PATIENTS WHO 
CONTINUE TO RECEIVE IMGN853 AFTER THE 
STUDY IS COMPLETED BY THE SPONSOR – 3 WEEK 
CYCLE 
Activity 
All Cycles 
Day 1 
Day 8 
Day 15 
Patient assessments as per standard of care  
As per Standard of Care 
Disease assessment 
As per Standard of Care 
IMGN853 Administration 
● 
 
 
Investigator’s declaration for continuance to 
treat and submit drug accountability logs 
Every 3 months (Appendix N) 
SAE/AESI assessments  
SAEs and AESI collected throughout the study 
and reported to ImmunoGen 
NOTE: This schedule of assessments will be used for patients who continue to receive IMGN853 after the study 
is completed by the Sponsor under Amendment 9 of the protocol. 
NOTE: The study will be completed by the Sponsor one year after the final analysis for the primary endpoint of 
PFS is conducted. Patients still receiving clinical benefit from IMGN853 at the time the study is 
completed by the Sponsor may continue to receive IMGN853 under this protocol. Patients who choose 
to continue to receive IMGN853 after the study is completed by the Sponsor will continue to be 
followed by their treating physician as per standard of care for their disease (including radiological 
assessments). These patients may remain on IMGN853 until disease progression as assessed by the 
Investigator, development of unacceptable toxicity, withdrawal of consent, initiation of a new anticancer 
therapy, or death, whichever comes first. 
NOTE: Patients who continue to receive IMGN853 after the study is completed by the Sponsor will not have an 
additional EOT or EOS visit. 
AESI = adverse event of special interest; EOS = End of Study; EOT = End of Treatment; SAE = serious adverse 
event 
 


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APPENDIX E. 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, eg, 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 F. 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 two lesions per organ and five 
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 five 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 cannot be imaged but are assessable by clinical exam (referring to biopsy-proven 
visible lesions(s) at the vaginal apex).  


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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 (eg, for body scan) except for lung.  
CA-125: Tumor marker CA-125 alone cannot be used to assess response or determine 
progression; however, it will be followed. CA-125 measurements should be scheduled to 
approximately coincide with radiological assessment (every 6 weeks±1 week). Patients 
whose CA-125 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 
six 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 (eg, ‘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 
(eg, 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 
longest diameters (SLD) will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. The lowest SLD (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).  
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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Best Overall Response - Best overall response, incorporating confirmation requirements, 
will be derived during statistical analysis from the series of time point responses and need not 
be considered when assigning response at any time point. 
 


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APPENDIX G. 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 two 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:  
• Intervening samples and the 28-day confirmatory sample must be less than or 
equal to (within an assay variability of 10%) the previous sample 
• Variations within the normal range of CA-125 levels will not interfere with the 
response definition.  
Timing of CA-125 assessments: 
The GCIG recommends that CA-125 measurements be taken at specific time intervals.  
• The first sample would be collected within two weeks before treatment is started 
• Later samples would be collected at intervals of two to four 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 (eg, 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  
 
 


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APPENDIX H. LIST OF CONCOMITANT MEDICATIONS 
REQUIRING CAREFUL MONITORING  
 
CYP Enzymes 
Sensitive Substrates 
Substrates with Narrow 
Therapeutic Range 
Hochberg 
Alfentanil, aprepitant, budesonide, 
buspirone, conivaptan, darifenacin, 
darunavir, dasatinib, dronedarone, 
eletriptan, eplerenone, everolimus, 
felodipine, indinavir, fluticasone, 
lopinavir, lovastatin, lurasidone, 
maraviroc, midazolam, nisoldipine, 
quetiapine, saquinavir, sildenafil, 
simvastatin, sirolimus, tolvaptan, 
tipranavir, triazolam, vardenafil 
Alfentanil, astemizole, 
cisapride, cyclosporine, 
dihydroergotamine, 
ergotamine, fentanyl, 
pimozide, quinidine, 
sirolimus, tacrolimus,  
terfenadine 
 
Ref: FDA drug development resources: 
(http://www fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm09
3664.htm#classSub) 
 
 
 


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APPENDIX I. ADJUSTED IDEAL BODY WEIGHT (AIBW) 
CALCULATION 
 
Adjusted Ideal Body Weight (AIBW) 
AIBW = IBW1 + 0.4 (Actual weight – IBW1) 
 
Ideal Body Weight (IBW) 
IBW1 (female) = 0.9H1-92 
 
(1H=height in cm; W=weight in kg) 
 
 
 


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APPENDIX J. SIMULATION REPORT 
This section describes the assumptions, algorithms, and results of Monte-Carlo simulation 
studies evaluating the type I error and power under different scenarios. 
Randomization and Stratification 
The study will randomize 333 patients over a period of 21 months with a randomization ratio 
of 2:1 (222 to IMGN853 arm and 111 to IC chemo arm). The randomization will be stratified 
by the following factors: 
• FRα expression level by IHC (≥ 75% tumor staining at ≥ 2+ intensity vs. ≥ 50% 
and < 75% tumor staining at > 2+ intensity) 
• Number of prior lines of therapy (1 or 2 vs. 3) 
• IC chemotherapy (paclitaxel, PLD or topotecan) 
Interim Futility Analysis 
The study will have an interim futility analysis when at least 80 PFS events have occurred in 
the intent-to-treat (ITT) population. If the hazard ratio (HR, IMGN853 relative to IC 
chemotherapy) estimate for PFS is greater than 1 in both, ITT population and the FRα high 
expression subgroup, the study will be stopped for futility. Otherwise, the study will continue 
to full enrollment of 333 patients in the ITT population.  
Primary Efficacy Endpoint 
The final analysis will occur when at least 236 PFS events have occurred in the ITT 
population and the primary efficacy endpoint of PFS as assessed by BIRC in all randomized 
patients and in the FRα high expression group will be analyzed: 
Hypothesis Testing 
The null hypotheses are: 
• H01: the survival function for PFS is the same between IMGN853 arm and IC 
chemo arm in the ITT population, and  
• H02: the survival function for PFS is the same between IMGN853 arm and IC 
chemo arm in the FRα high expression subgroup  
And the alternative hypotheses are: 
• Ha1: the survival function for PFS is different between IMGN853 arm and IC 
chemo arm in the ITT population, and  
• Ha2: the survival function for PFS is different between IMGN853 arm and IC 
chemo arm in the FRα high expression subgroup  
Each endpoint will be tested using stratified log-rank test (stratified by the stratification 
factors used in randomization).  
Multiple Testing Procedure 
The Hochberg procedure will be used to control the study-wise type I error. Assume the log-
rank p-values for the two endpoints are P(1) and P(2) (P(1) ≤ P(2)). Let H0(1) be the null 




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Simulation Results 
Under different scenarios, the probability of stopping for futility at interim and probability of 
rejecting H01 (for ITT population) and H02 (for FRα high expression subgroup) are 
summarized in a table below. If the FRα high/medium ratio is 2:1, there is 39% probability of 
stopping for futility at interim if both null hypotheses H01 and H02 are true and the overall 
type I error is controlled at 4.0%. Using Hochberg procedure, the study will have a 96% and 
91% power to detect a median PFS of 6.0 months in the IMGN853 arm (HR=0.583) in the 
ITT population and FRα high expression subgroup, respectively. If the FRα high/medium 
ratio is 1:1, there is 37% probability of stopping for futility at interim if both null hypotheses 
H01 and H02 are true and the overall type I error is controlled at 3.6%. Using Hochberg 
procedure, the study will have a 96% and 81% power to detect a median PFS of 6.0 months 
in the IMGN853 arm (HR=0.583) in the ITT population and FRα high expression subgroup, 
respectively. 
Summary of Monte-Carlo Simulations 
True Median PFS (months) 
FRα 
High/Medium 
Ratio 
Probability of 
Stopping for 
Futility at 
Interim 
Analysis 
Probability of 
Rejecting 
IC 
Chemo 
IMGN853 
(FRα medium) 
IMGN853 
(FRα high) 
H01 
H02 
3.5 
3.5 
3.5 
2:1 
39% 
2.1% 
1.9% 
3.5 
3.5 
6.0 
2:1 
2.1% 
75% 
85% 
3.5 
4.5 
6.0 
2:1 
1.2% 
89% 
89% 
3.5 
5.0 
6.0 
2:1 
0.8% 
93% 
90% 
3.5 
5.5 
6.0 
2:1 
0.6% 
95% 
90% 
3.5 
6.0 
6.0 
2:1 
0.5% 
96% 
91% 
3.5 
3.5 
3.5 
1:1 
37% 
1.9% 
1.7% 
3.5 
3.5 
6.0 
1:1 
3.4% 
51% 
72% 
3.5 
4.5 
6.0 
1:1 
1.8% 
80% 
77% 
3.5 
5.0 
6.0 
1:1 
1.2% 
88% 
79% 
3.5 
5.5 
6.0 
1:1 
0.8% 
93% 
80% 
3.5 
6.0 
6.0 
1:1 
0.5% 
96% 
81% 


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APPENDIX K. HISTORY OF AMENDMENTS 
This section summarizes all amendments to the Phase 2 protocol. It is noted that amendments 
1 through 4 were made prior to the enrollment of the first patient on the Phase 3 study.  
Amendment 1 Summary of Key Changes 
The primary reasons for amending the protocol were to revise the secondary objectives for 
Stage 1, revise exclusion criterion #3 to avoid inclusion of patients with pre-existing ocular 
conditions, update the management of ocular adverse events to align with IMGN853 program 
level changes, and to improve clarity and consistency between sections. 
The following key changes were made to the original protocol:  
• Determining the anti-tumor activity in patients with the FRα expression level ≥ 75% 
at ≥ 2+ intensity was removed as a secondary objective of Stage 1. Assessing the 
correlation between FRα level and anti-tumor activity was added as an exploratory 
objective in Stage 1. Study design schema was revised to reflect the same.  
• Identification/evaluation of potential biomarkers in blood and tumor tissue that might 
predict response to IMGN853 was added as a new exploratory objective for Stage 1 
and Stage 2, and relevant exploratory endpoints were included. 
• Exclusion criteria 3 was revised to avoid inclusion of patients with pre-existing ocular 
conditions as confounding factors for the analysis.  
• Stratification criteria for Stage 2 was updated to include the FRα levels, to balance the 
number of patients with high and low folate expression in both the arms in Stage 2. 
• Number of patients planned was revised from 246 to 247 to make the total number of 
patients enrolled in Stage 2 divisible by 3, given the 2:1 randomization 
(approximately 100 patients to enroll in Stage 1; 147 patients to enroll in Stage 2). 
• Management of ocular adverse events was revised to align with IMGN853 program 
level changes.  
• Monitoring and Management of Adverse Events and for Treatment Guidelines 
sections were combined for easy readability and clarity.  
• Dose modification guidelines for IMGN853 were tabulated for clarity and easy 
reference. Table 8: IMGN853 DME Definitions was replaced with Table 3: Dose 
modifications for IMGN853 adverse events. Table for the vital sign measurements 
was removed and details were outlined in Appendix A and Appendix B. 
• In addition, editorial changes and text corrections were made as required. 
Amendment 2 Summary of Key Changes 
The primary reason for amending the protocol was to revise the table for management of 
potential infusion-related reactions. 
Amendment 3 Summary of Key Changes 
The primary reason for amending the protocol was to provide details on the rationale for the 
selection of dose levels and the dosing schedule for the chemotherapeutics agents in the 


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investigator’s choice (IC) arm of Stage 2, clarification around high-risk biopsies in inclusion 
criteria 2, modification of the CA-125 assessment schedule and corrections for 
inconsistencies between sections.  
The following key changes were made to amendment 3: 
• Details on the rationale for the selection of dose levels and dosing schedule for 
paclitaxel, topotecan, PLD and gemcitabine was added. 
• Inclusion criterion #4 was revised to clarify that biopsies for FRα screening be limited 
to procedures known to have a low risk of complications (eg, exclusion of biopsies 
from brain or lung).  
• Frequency of CA-125 assessments was modified from every six weeks to being 
assessed at day 1 of each cycle and at each radiologic tumor evaluation. 
• Editorial and text corrections were made as required.  
Amendment 4 Summary of Key Changes 
The primary reason for amending the protocol was to add an exclusion criteria for patients 
with known hypersensitivity to any of the SOC drugs (gemcitabine, PLD, paclitaxel or 
topotecan) and revise inclusion criteria 13 regarding the use of contraception methods.  
The following key changes were made to amendment 4: 
• Inclusion criterion #13 was updated to exclude the use of barrier contraceptive with 
spermicide and partner’s latex condom from the list of acceptable highly effective 
contraceptive methods. The length of time for the use of contraception after the last 
dose of SOC chemotherapy agents was added. 
• Exclusion criterion #12 was added to clarify that patients with known hypersensitivity 
to any of the SOC chemotherapy agents are excluded from receiving that particular 
medicinal product but can receive one of the other possible SOC agents.  
Amendment 4A Summary of Key Changes 
The primary reason for amending the protocol was to add exclusion criteria for patients with 
inadequate coagulation parameters, untreated CNS disease or symptomatic CNS metastasis, 
and for women who are pregnant or lactating.  
Amendment 5 Summary of Key Changes 
The primary reason for amending the protocol was to close enrollment to Stage 1 of the 
study, and revise the trial from a Phase 2 to a Phase 3 study.  
The following key changes were made: 
1. The trial has been revised as a Phase 3 study in women with Folate Receptor α-
positive Advanced Epithelial Ovarian Cancer, Primary Peritoneal Cancer or Fallopian 
Tube Cancer. The title of the study was revised to reflect these changes, and exclusion 
criterion #1 for male patients was added. 
2. Stage 1 of the protocol was closed for enrollment. Study design schema was revised 
to reflect the same. 


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3. Dosing Schedule for Arm 1 (IMGN853) was selected to be 6mg/kg AIBW Q3W.  
4. Chemotherapy agents for the IC (Arm 2) chemotherapy were updated to include only 
paclitaxel, PLD and topotecan.  
5.  Stratification factors have been revised to include, number of prior lines of therapy, 
FRα levels, and IC chemotherapy while BRCA mutation status has been excluded. 
6. The primary endpoint was revised. Progression free survival assessed by the BIRC is 
the primary endpoint.  
7. Secondary objectives were revised. Key secondary objectives include ORR, primary 
PRO endpoint using QLQ-OV28, and OS. 
8. Blood-based biomarkers, such as soluble FRα was added as an exploratory end-point. 
9. Patients on IC chemotherapy will have the option to crossover to the IMGN853 arm 
after BIRC confirmed PD. Study design schema was revised to reflect this option. 
10. A window for start of treatment from randomization was added. Cycle 1 Day 1 should 
be within seven calendar days of randomization.  
11. Inclusion criterion # 2 was added to include patients with platinum-resistant ovarian 
cancer.  
12. Inclusion criterion #4 was revised to include patients who have received at least one 
but no more than three prior systemic lines of therapy and for whom single agent 
chemotherapy is appropriate as the next line of treatment. Clarification regarding 
PARP inhibitor therapy considered as a prior treatment regimen while hormonal 
therapy not considered as a prior systemic treatment, was added.  
13. If the archival tumor tissue does not meet FRα positivity by IHC (> 50% of tumor 
staining at > 2+ intensity), a fresh biopsy tumor sample may be obtained for 
reassessment of FRα positivity. Inclusion criterion #6 was updated to reflect this 
change. 
14. Inclusion criterion #12 was updated to include testing of serum albumin.  
15. Exclusion criterion #3 was added to exclude primary platinum refractory patients. 
16. Exclusion criterion # 4 for prior radiotherapy was added.  
17. Exclusion criterion # 8 was updated to specify patients with known active hepatitis B 
or C whether or not on active antiviral therapy are excluded. 
18. Exclusion criterion # 9 was updated to exclude patients with corrected QT (QTc) 
> 470 msec on the screening ECG.  
19. Exclusion criterion #10 for history of neurological condition, or concurrent 
neurological condition that would confound assessment of treatment-emergent 
neuropathy was added. 
20. Exclusion criterion for patients treated with another investigational drug within four 
weeks of starting the study treatment was removed, as inclusion criteria #9 adequately 
describes the wash out period from prior therapies. 


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21. Exclusion criterion #20 was updated to exclude patients who have been previously 
treated on the study.  
22. Tumor assessment schedule was revised to be performed every 6 weeks (± 1 week) 
for first 36 weeks and then every 12 weeks (± 1 week).  
23. Quality of Life Questionnaires to be used in the study have been revised to include 
EORTC QLQ-C30, EORTC-OV28, eight-item FOSI and EQ-5D-5L questionnaires 
instead of the FACT-O questionnaire. 
24. Prophylactic use of corticosteroid eye drops was mandated. 
25. Collection of AEs has been revised to collect events from the time of informed 
consent until 30 days after patient’s last study treatment. 
26. Pneumonitis was added as the adverse event of special interest (AESI) for IMGN853 
and reporting details were included.  
27. Acceptable methods of contraception were added under Section 5.9.8.  
28. Section 10 for Study Activities was revised with reference to Appendix A and 
Appendix B for all assessments to be performed for the respective study visits. 
29. Requirement for pulse oximetry assessment was removed.  
30. Requirement for post dose ECG assessments was removed. ECGs will be performed 
at Screening and at EOT or 30-day follow-up. 
31. Requirement for triplicate ECGs as well measuring vital signs within 10 minutes 
following completion of ECG recording was removed.  
32. Section 11 for Statistical Methods was updated with change in sample size and 
primary endpoint. An interim futility analysis was included with rules for study 
termination. 
33. Statistical tests for patient reported outcomes were added.  
34. Pharmacokinetic analyses were updated in view of the sparse sampling scheme to 
include only summary statistics of the concentration at each time point. 
35. Copies of the PRO questionnaires will not be provided as part of the protocol.  
36. Appendix for the CTCAE grading for the selected adverse events has been removed.  
37. Simulation report describing the assumptions, algorithms, and results of Monte-Carlo 
simulation studies has been added under Appendix J. 
38. Section on history of amendments has been moved under Appendix K.  
39. Appendix L was added to provide details on the study design of the Phase 2 protocol, 
closing enrollment to Stage 1, revising Stage 2 of the protocol as a pivotal Phase 3 
study, selection of the dosing schedule by the SSC, and how the data from the four 
ongoing patients from Stage 1 will be handled. 
Amendment 6 Summary of Key Changes  
The primary reason for amending the protocol was to correct an important typographical 
error in inclusion criterion # 2, which impacts the definition of the patient population under 


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study. In the previous version of the protocol, platinum-resistant ovarian cancer was defined 
as disease having progressed within six months of completion of a minimum of four cycles of 
first-line platinum containing therapy. The descriptor “first-line” for platinum therapy was a 
typographical error and has been deleted.  
Amendment 7 Summary of Key Changes 
The primary reason for amending the protocol was to remove the option for patients on IC 
chemotherapy to crossover. Study schema was updated to reflect this change.  
The following key changes were made: 
1. The option to crossover to IMGN853 (Arm 1) after disease progression on the IC 
chemotherapy arm (Arm 2) was removed. The crossover option could confound 
overall survival, a key secondary endpoint. The study design schema and other 
applicable sections were revised to reflect the same.  
2. Section 1.8.2 was revised to clarify that patients enrolled under amendment 6 will 
have the option to crossover and discontinuation of treatment for PD for these patients 
will be as assessed by the investigator. 
3. For patients enrolled on Amendment 6, eligibility criteria to crossover to IMGN853 
was moved to Appendix M.  
4. Time to second disease progression (PFS2) was added as an exploratory objective and 
endpoint. Text was added to the statistical methods section (Section 11.5) to define 
PFS2.  
5. Collection of information on disease progression and subsequent anti-cancer therapies 
during survival follow-up was added.  
6. CA-125 response rate per Gynecologic Cancer Intergroup (GCIG) CA-125 criterion 
was added as a secondary objective for the corresponding secondary endpoint. 
7. EQ-5D-5L questionnaire was added in the other secondary endpoints since it was 
inadvertently omitted.  
8. Inclusion Criterion #4 was revised to clarify that PARP regimen given as maintenance 
therapy will not be counted as a prior treatment, immunotherapy such as check point 
inhibitors will be considered as a prior therapy, and cancer vaccines will not be 
considered as a prior treatment. 
9. Exclusion Criterion #3 was edited to clarify the definition of primary platinum 
refractory epithelial ovarian cancer.  
10. Exclusion Criterion #5 was edited for coagulation parameters.  
11. Exclusion Criterion #9 was revised to add the LVEF parameter for patients intended 
to be treated with PLD if randomized to the IC chemotherapy arm. This parameter is a 
standard exclusion criterion for patients treated with PLD.  
12. Language was added to clarify the requirement of selecting Investigator’s Choice of 
chemotherapy agent prior to randomization. 


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13. Management of Ocular Disorders (Table 5) was updated with clarifications on the 
dose modification guidelines for Grade 2 and Grade 3 ocular TEAEs.  
14. Section 8.10 on Ocular Symptom Assessment and Ophthalmic Examination was 
edited for clarity.  
15. Justification for the prophylactic use of corticosteroid eye drops was added.  
16. Text was added in the statistical methods for Quality of Life Questionnaires (patient-
reported outcomes) for the analysis methods for PRO endpoints.  
17. Laboratory safety assessments (Hematology and Chemistry) will also be performed 
on Day 8 for cycles ≥ 4 for patients on both treatment arms. Appendix A and 
Appendix B were updated to reflect the change. 
18. End of Study definition was revised as one year after the final analysis for the primary 
endpoint of PFS has been conducted.  
Amendment 8 Summary of Key Changes 
The primary reason for amending the protocol was to revise inclusion criterion # 4 to 
include hormonal therapies and cancer vaccines as prior lines of anti-cancer therapy.  
The following key changes were made: 
1. Inclusion criterion #4 was revised to include hormonal therapies and cancer vaccines 
as prior lines of anti-cancer therapy.  
2. Patients with a history of clinically active malignancy within 3 years of enrollment 
will be excluded. Exclusion criterion # 21 was added which provides details regarding 
the criterion. 
3. Exclusion criterion # 8 was revised to add clarity on excluding patients with known 
HIV infection.  
4. Synopsis was updated to reflect the revision to inclusion criterion # 4, the date of the 
first patient enrolled on the Phase 3 study was added and exclusion criterion # 1 was 
edited to be consistent with the protocol text.  
5. Section 1.6.1 was revised with updates from the first-in-human Phase 1 study 0401 to 
align with version 6.0 of the Investigator Brochure.  
6. Further clarification was added on dose modification guidelines for the ocular 
disorders.  
7. Use of prescreening and main study ICFs was clarified.  
8. Reference to QoL was changed to PRO, except when referring to the questionnaires. 
Amendment 8A Summary of Key Changes (North America only) 
The primary reason for amending the protocol was to add the possibility for the collection 
of urine samples pre-and 24-hours-post an infusion on Cycle 2, 3, or 4 from patients 
receiving IMGN853 at designated sites in North America.  
Amendment 9 Summary of Key Changes 


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The primary reason for amending the protocol was to allow patients who are receiving 
IMGN853 and experiencing clinical benefit the option to continue to receive IMGN853 
after the closure of the clinical database for the study. 
1. Updated cover page and study contact information. 
2. Language to this effect was added to the Protocol Synopsis and Section 4.1.1, 
Section 4.1.3, Section 5.6.1.9, Section 5.7.3, Section 5.8, Section 6.1, Section 6.2, 
Section 8.15.1, Section 9.1, Section 9.1.1.1, Section 9.2.1, Section 10, Section 12.1, 
and Section 13.9. 
3. A new Schedule of Assessments was added as Appendix D. 
4. A form for the Investigator’s declaration for continued treatment added as 
Appendix N. 
 




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representatives. Both the IDMC and SSC supported this assessment, and the SSC approved 
the decision to use 6 mg/kg AIBW Q3W for patients randomized to IMGN853 in this Phase 3 
study.  
Patients enrolled in Stage 1 of the Phase 2 study prior to the Sponsor decision will continue 
on the study on the respective dosing schedule to which they were assigned and follow the 
schedule of assessments as outlined in Appendix A (Schedule A) and Appendix B (Schedule 
B).  
 


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APPENDIX M. CRITERIA FOR CROSSOVER TO IMGN853 AFTER 
PROGRESSIVE DISEASE AS ASSESSED BY BIRC 
(PATIENTS ENROLLED TO AMENDMENT 6 ONLY) 
Patients who discontinue IC chemotherapy for BIRC-confirmed, RECIST-defined PD will be 
given the option to crossover to the IMGN853 arm (Arm 1). Patients are assigned to 
IMGN853 after meeting the following criteria: 
• ECOG performance status (PS) 0 or 1. 
• Patients must complete five half-lives or four weeks whichever is shorter after the 
last dose of IC chemotherapy. 
• Patients must have recovered from all toxicities related to reference chemotherapy 
to AEs Grade ≤ 1 or baseline values (CTCAE v 4.03). 
• Major surgery (not including placement of vascular access device or tumor 
biopsies) must be completed four weeks prior to Day 1. 
• Patients must have adequate hematologic, liver and kidney function and 
coagulation parameters (Section 3.1.1). 
• Patients must fulfill exclusion criteria #4 to #14 (Section 3.1.2) and must not have 
untreated CNS disease or symptomatic CNS metastasis. 
• Patients must crossover to the IMGN853 treatment within 56 days of BIRC-
confirmed PD. 
• Patients who receive non-protocol anticancer therapy after BIRC confirmed PD 
will not be eligible to crossover. 
• Patients must complete EOT visit before crossing over to Arm 1. 
A Crossover End of Treatment (CO-EOT) visit will be performed when the patients 
discontinue IMGN853. 
 


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APPENDIX N. INVESTIGATOR’S DECLARATION FOR CONTINUED 
TREATMENT 
 
 
Investigator’s Declaration for Continued Treatment 
 
To be completed by the treating investigator every 3 months in order to continue to provide 
IMGN853 access to a patient that is deriving clinical benefit from IMGN853 treatment. 
 
Study:  IMGN853-0403 
 
Subject: ______________  
 
Restatement of Investigator’s Agreement 
I have received and read the Investigator Brochure for mirvetuximab soravtansine. I have 
read the ImmunoGen Protocol #0403 and agree to conduct the study as outlined and in 
conformance with Good Clinical Practice (GCP) and applicable regulatory requirements. I 
agree to maintain the confidentiality of all information received or developed in connection 
with this protocol. 
 
Statement of Investigator’s Agreement for Continued Treatment 
I agree to conduct the study as outlined for patients who continue to receive IMGN853 after 
the study is completed by the Sponsor. I agree to report all SAEs and AESIs as outlined in the 
protocol and to submit drug accountability logs every 3 months in order to continue to 
provide IMGN853 access to a patient that is deriving clinical benefit. 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 


Mirvetuximab Soravtansine (IMGN853) 
 
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Protocol Number IMGN853-0403 
 
 
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SAP_000.pdf: 
Page 1 of 62
ImmunoGen, Inc. 
Protocol #: 0403 
FORWARD 1:  A Randomized, Open Label Phase 3 Study to Evaluate the Safety and Efficacy of 
Mirvetuximab Soravtansine (IMGN853) Versus Investigator’s Choice of Chemotherapy in Women 
with Folate Receptor α−positive Advanced Epithelial Ovarian Cancer, Primary Peritoneal Cancer or 
Fallopian Tube Cancer 
Statistical Analysis Plan 
Version 4.0 
Document last saved: 3-Mar-2020 1:56 PM 
Prepared for: 
 
ImmunoGen, Inc. 
830 Winter Street 
Waltham, MA 02451 
Prepared by: 
 
Novella Clinical 
1700 Perimeter Park Dr. 
Morrisville, NC  27560 
Approvals 
NCT02631876


 
 
Page 2 of 62  
 
 
 
 
 
 ImmunoGen, Inc. 
 
 
Date 
 
 
 
 
 
 
 
 ImmunoGen, Inc.  
 
 
Date 
 
 
 
 
 
 
 
 Novella Clinical 
 
Date 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................... 7 
1. 
INTRODUCTION .................................................................................. 10 
1.1. 
Background ............................................................................................. 10 
2.1. 
Protocol Objectives ................................................................................. 13 
2.1.1. 
Primary Objective ................................................................................... 13 
2.1.2. 
Secondary Objectives ............................................................................. 13 
2.1.2.1. 
Key Secondary Objectives: ..................................................................... 13 
2.1.2.2. 
Other Secondary Objectives: .................................................................. 13 
2.1.3. 
Exploratory Objectives ........................................................................... 14 
2.2. 
Study Endpoints ...................................................................................... 14 
2.2.1. 
Primary Endpoint .................................................................................... 14 
2.2.2. 
Secondary Endpoints .............................................................................. 14 
2.2.2.1. 
Key Secondary Endpoints: ..................................................................... 14 
2.2.2.2. 
Other Secondary Endpoints: ................................................................... 14 
2.2.3. 
Exploratory Endpoints ............................................................................ 15 
2.3. 
Study Overview ...................................................................................... 15 
2.3.1. 
Study Population ..................................................................................... 17 
2.3.2. 
Power and Sample Size .......................................................................... 17 
2.3.2.1. 
Primary Endpoints .................................................................................. 17 
2.3.2.2. 
Power for Key Secondary Endpoints ...................................................... 18 
2.3.3. 
Treatment Randomization and Stratification .......................................... 18 
2.3.4. 
Blinding and the BIRC ........................................................................... 19 
2.3.4.1. 
BIRC ....................................................................................................... 19 
2.3.5. 
Assessment Schedule .............................................................................. 20 
2.4. 
Interventions ........................................................................................... 20 
2.4.1. 
Clinical Trial Material ............................................................................ 20 
3. 
GENERAL ANALYTICAL CONSIDERATIONS ............................... 21 
3.1. 
Data Sources ........................................................................................... 21 
3.2. 
Definition of Baseline ............................................................................. 21 
3.3. 
Missing Data ........................................................................................... 21 
3.4. 
Multiple Assessments for the Same Assessment Time Point ................. 22 


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3.5. 
Multiple Study Centers ........................................................................... 22 
3.6. 
Covariate Adjustment in Primary Analysis ............................................ 22 
3.7. 
Sample Size Reassessment ..................................................................... 22 
3.8. 
Interim Analyses ..................................................................................... 22 
3.9. 
Timing of Final Analysis ........................................................................ 23 
3.10. 
Test Sizes ................................................................................................ 23 
3.11. 
Hypothesis Testing and Multiple Comparisons ...................................... 23 
3.11.1. 
Primary Endpoints .................................................................................. 23 
3.11.2. 
Key Secondary Endpoints ....................................................................... 24 
3.12. 
Analysis Populations .............................................................................. 25 
3.12.1. 
Screened .................................................................................................. 25 
3.12.2. 
ITT Population ........................................................................................ 25 
3.12.3. 
Per Protocol Population .......................................................................... 26 
3.12.4. 
Response-Evaluable Population ............................................................. 26 
3.12.5. 
CA-125-Evaluable Population ................................................................ 26 
3.12.6. 
Safety Population .................................................................................... 26 
3.13. 
Data Display Characteristics ................................................................... 26 
4. 
PATIENT ACCOUNTABILITY ........................................................... 28 
4.1. 
Patient Characteristics ............................................................................ 28 
4.1.1. 
Demography ........................................................................................... 28 
4.1.2. 
Height and Baseline Weight, AIBW, and Body Surface Area ............... 28 
4.1.3. 
Medical History ...................................................................................... 28 
4.1.4. 
Disease Characteristics, Prior Therapy, and Gene Mutations ................ 29 
4.2. 
Patient Disposition .................................................................................. 29 
4.2.1. 
Screened and Enrolled Patients .............................................................. 29 
4.2.2. 
ITT, Safety Disposition .......................................................................... 29 
4.2.3. 
Protocol Deviations and Population Inclusions ...................................... 30 
5. 
EFFICACY ANALYSES ....................................................................... 31 
5.1. 
Efficacy Outcomes .................................................................................. 31 
5.1.1. 
Best Overall Response ............................................................................ 31 
5.1.2. 
CA-125 Response ................................................................................... 31 
5.1.3. 
DOR ........................................................................................................ 31 


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5.1.4. 
ORR ........................................................................................................ 32 
5.1.5. 
OS ........................................................................................................... 32 
5.1.6. 
PFS .......................................................................................................... 32 
5.1.7. 
RECIST-Related Endpoints – BIRC or Investigator’s Assessment ....... 33 
5.1.8. 
Time to Response ................................................................................... 33 
5.1.9. 
PFS2 ........................................................................................................ 33 
5.2. 
Primary Efficacy Outcome Analysis ...................................................... 34 
5.3. 
Secondary Efficacy Analyses ................................................................. 35 
5.4. 
Exploratory Efficacy Analyses ............................................................... 36 
5.5. 
Efficacy Analysis on Subgroups of Patients ........................................... 37 
5.6. 
Additional Sensitivity Analyses ............................................................. 37 
5.7. 
Strategies for Pooling Stratification Factors ........................................... 41 
5.7.1. 
Rationale for pooling approach .............................................................. 42 
5.8. 
Prognostic and Predictive Value of FRα Expression on PFSBIRC ........... 42 
5.9. 
Other Efficacy-related Summaries ......................................................... 42 
6. 
SAFETY ANALYSES ........................................................................... 44 
6.1. 
Exposure ................................................................................................. 44 
6.2. 
AEs ......................................................................................................... 45 
6.2.1. 
Fresh Biopsy Patient TEAE .................................................................... 48 
6.2.2. 
Infusion-related Reactions ...................................................................... 48 
6.3. 
Clinical Laboratory Results .................................................................... 48 
6.4. 
Vital Signs .............................................................................................. 49 
6.5. 
ECGs ....................................................................................................... 49 
6.6. 
Concomitant Medications ....................................................................... 50 
6.7. 
Concomitant Procedures ......................................................................... 51 
6.8. 
Ophthalmic Examinations ...................................................................... 51 
6.9. 
Ocular Symptom Assessments ............................................................... 51 
6.10. 
Corticosteriod and Lubricating Eye Drop Compliance .......................... 52 
6.11. 
Transfusions ............................................................................................ 52 
6.12. 
Physical Examination ............................................................................. 52 
6.13. 
Pulmonary Function Tests ...................................................................... 52 
6.14. 
Pulse Oximetry ....................................................................................... 52 


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6.15. 
ECOG PS ................................................................................................ 52 
6.16. 
ECHOCARDIOGRAM/MULTIPLE GATED ACQUISITION SCANS
 ................................................................................................................ 52 
7. 
PRO......................................................................................................... 53 
8. 
IMMUNOGENICITY ............................................................................ 54 
9. 
BIOMARKERS ...................................................................................... 55 
10. 
PHARMACOKINETICS ....................................................................... 56 
REFERENCES .......................................................................................................... 57 
APPENDIX 1:  TEMPLATE SAS® CODE .............................................................. 58 
APPENDIX 2: MONTE-CARLO SIMULATION REPORT ................................. 60 
 
LIST OF TABLES 
Table 1: 
History of Protocol Amendments ........................................................... 10 
Table 2: 
Dosing and Dosing Schedule for Phase 3 Portion .................................. 20 
Table 3: 
Analysis Populations .............................................................................. 25 
Table 4: 
PFS Definitionsa ..................................................................................... 32 
Table 5: 
PFSAINV Definitionsa .............................................................................. 38 
Table 6: 
PFSB BIRC Definitionsa ............................................................................ 39 
Table 7: 
PFSRBIRC Definitionsa ............................................................................. 40 
Table 8: 
Pooling of Stratification Factors ............................................................. 42 
Table 9: 
Summary of Monte-Carlo Simulations ................................................... 62 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema ............................................................................. 16 
Figure 2: 
Study Period Schema .............................................................................. 17 
Figure 3: 
Hochberg Procedure ............................................................................... 24 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation or 
Specialist Term  
Explanation  
ADA  
Anti-drug antibodies  
AE  
Adverse event  
AESI 
Adverse event of special interest 
AIBW  
Adjusted ideal body weight  
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BIRC 
Blinded Independent Review Committee 
BOR 
Best overall response 
BRCA  
Breast cancer susceptibility gene  
BSA  
Body surface area  
CA-125 
Cancer antigen 125 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel test 
CR  
Complete response 
CTCAE  
Common Terminology Criteria for Adverse Events  
DOR  
Duration of response  
ECG  
Electrocardiogram  
ECHO 
Echocardiogram 
ECOG PS  
Eastern Cooperative Oncology Group Performance Status 
eCRF  
Electronic case report form  
EOC  
Epithelial ovarian cancer  
EORTC 
European Organisation for Research and Treatment of Cancer 
FcγR  
Fc gamma receptor  
FRα  
Folate receptor alpha  
FOSI 
FACT-ovarian symptom index 
GCIG  
Gynecologic Cancer Intergroup  
IC  
Investigator’s choice/selected standard-of-care chemotherapy  
IDMC  
Independent Data Monitoring Committee  


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Abbreviation or 
Specialist Term  
Explanation  
IHC 
Immunohistochemistry 
IMGN  
ImmunoGen  
INV 
Investigator 
ITT  
Intent-to-treat  
MDR1 
Multi-drug resistant gene 
MedDRA  
Medical Dictionary for Regulatory Activities  
MTD 
Maximum tolerated dose 
MUGA 
Multigated acquisition scan  
ORR  
Objective response rate  
OS  
Overall survival  
Pac 
Paclitaxel 
PD  
Progressive disease  
PFS  
Progression-free survival  
PFS2 
Time to second disease progression 
PgP 
P-glycoprotein  
PK  
Pharmacokinetics  
PLD  
Pegylated liposomal doxorubicin  
PR  
Partial response  
PR interval 
Pulse rate interval 
PRO 
Patient reported outcomes 
PT 
Preferred term 
Q3W  
Every 3 weeks  
Q4W  
Every 4 weeks  
QoLP 
Primary endpoint for quality of life 
QRS 
Part of electrocardiographic wave representing ventricular depolarization 
QT 
The length of time it takes the electrical system in the heart to repolarize, 
adjusted for heart rate 
QTc 
Corrected QT interval 
QTcF 
Corrected QT using Fridericia’s formula 
RECIST  
Response Evaluation Criteria in Solid Tumors  
RMST 
Restricted mean survival time 


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Abbreviation or 
Specialist Term  
Explanation  
RR 
Respiratory rate 
SAE  
Serious adverse event  
SAP  
Statistical analysis plan  
SOC 
System organ class 
TBL 
Total bilirubin 
TEAE  
Treatment-emergent adverse event  
Topo 
Topotecan 
TTR 
Time to response 
ULN  
Upper limit of normal  
WHO Drug  
World Health Organization Drug Dictionary 


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1. 
INTRODUCTION 
1.1. 
Background 
The Forward 1 study IMGN853-0403 was initiated during the dose-expansion stage of study 
IMGN853-0401, a first-in-human study of single-agent mirvetuximab soravtansine (also 
known as IMGN853). 
During the dose-escalation stage of study IMGN853-0401, 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 [modified weekly]). Dose expansion began once the Schedule A 
maximum tolerated dose (MTD) was identified and a dose was selected for further 
exploration. Schedule B evaluation was stopped prior to identifying the MTD. 
Study IMGN853-0401 identified the recommended Phase 2 dose of single-agent 
mirvetuximab soravtansine in patients with epithelial ovarian cancer (EOC) and other folate 
receptor alpha (FRα)-positive tumors to be 6.0 mg/kg adjusted ideal body weight (AIBW) 
administered on Day 1 of a 21-day cycle. 
Study IMGN853-0403 was initially opened as a Phase 2 study to further evaluate the 2 
dosing schedules of mirvetuximab soravtansine (Q3W and Q4W). Following emerging data 
from study IMGN853-0401, IMGN853-0403 was placed on hold and redesigned to be a 
randomized, open-label, Phase 3 study to evaluate the safety and efficacy of mirvetuximab 
soravtansine (IMGN853) versus Investigator’s choice (IC) of chemotherapy in women with 
FRα−positive advanced EOC, primary peritoneal cancer, or fallopian tube cancer.  
The protocol for study IMGN853-0403 describes the general approach to the analysis of 
study data. This statistical analysis plan (SAP) describes the additional detail needed to 
complete such an analysis. Table, figure, and listing shells will be supplied in an 
accompanying document. 
This SAP is based on Amendment 8A of Protocol 0403.  
A brief history of protocol amendments is presented in Table 1. 
Table 1: 
History of Protocol Amendments 
Version 
Approval Date 
Salient Changes (if any)* 
Original Protocol 
18 August 2015 
 
Amendment 1 
01 September 2015 
Secondary objectives for Stage 1 were revised. 
Amendment 2 
23 September 2015 
No changes that require accommodation in this 
analysis plan. 
Amendment 3 
20 October 2015 
Modification of the CA-125 assessment schedule 
Amendment 4 
01 February 2016 
No changes that require accommodation in this 
analysis plan. 
Amendment 5 
17 August 2016 
The trial has been changed from a Phase 2 study 
to a Phase 3 study, and limited to women with 


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Version 
Approval Date 
Salient Changes (if any)* 
FRα-positive advanced EOC, primary peritoneal 
cancer, or fallopian tube cancer. The title of the 
study was revised to reflect these changes, and 
Exclusion Criterion 1 for male patients was 
added.  
Stage 1 of the study has been closed for 
enrollment. The dosing schedule for Arm 1 
(IMGN853) of Stage 2 was updated to 6mg/kg 
AIBW Q3W. 
Chemotherapy agents for the IC (Arm 2) 
chemotherapy were updated to include only Pac, 
PLD, and Topo. 
Randomization stratification factors have been 
revised to include number of prior lines of 
therapy, FRα levels, and IC chemotherapy, while 
BRCA mutation status has been excluded. 
Central radiology reviews by a BIRC were added 
to assess tumor response in addition to the 
Investigator’s radiology assessment. 
The primary endpoint for Stage 2 was revised. 
PFS as assessed by the BIRC is the primary 
endpoint. The sample size has been updated to 
reflect the change in the primary endpoint.  
An interim futility analysis has been added with 
rules for study termination. 
The secondary objectives for Stage 2 were 
updated to include ORR, DOR by BIRC and 
Investigator, and PFS as assessed by the 
Investigator. 
Soluable FRα level in blood was added as an 
exploratory endpoint. 
Patients on IC chemotherapy will have the option 
to cross over to the IMGN853 arm after 
BIRC-confirmed PD. 
A window for start of treatment from 
randomization was added; Cycle 1 Day 1 should 
be within 7 calendar days of randomization. 
PRO questionnaires to be used in the study have 
been revised to include EORTC QLQ-C30, 
EORTC QLQ-OV28, eight-item FOSI, and 
EQ-5D-5L questionnaires instead of the FACT-O 
questionnaire. 
Statistical tests for PROs were added. 


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Version 
Approval Date 
Salient Changes (if any)* 
Collection of TEAEs has been revised to events 
collected from the time of informed consent until 
30 days after the patient’s last study treatment. 
Pneumonitis was added as an AESI for 
IMGN853. 
Requirement for post-dose ECGs as well as 
triplicate ECGs were removed. 
Requirement for pulse oximetry assessment was 
removed. 
Amendment 6 
19 September 2016 
No changes that require accommodation in this 
analysis plan. 
Amendment 7 
04 November 2016 
Optional crossover from IC chemotherapy to 
IMGN853 after BIRC-confirmed PD was 
removed. 
PFS2 was added as an exploratory endpoint 
Amendment 8 
08 May 2017 
No changes that require accommodation in this 
analysis plan. 
Amendment 8A 
(North America) 
25 September 2017 
The protocol was amended to add the possibility 
for the collection of urine samples from patients 
receiving IMGN853 at designated sites in North 
America. The exploratory objectives of the 
protocol have been updated. However, the 
analysis of the urine samples will be conducted 
under the separate PK analysis plan. 
*Changes expected to require accommodation in analysis plan. 
AESI = adverse event of special interest; AIBW = adjusted ideal body weight; BIRC = Blinded Independent 
Review Committee; BRCA = breast cancer susceptibility gene; CA-125 = cancer antigen 125; DOR = duration 
of response; ECG = electrocardiogram; EOC = epithelial ovarian cancer; EORTC = European Organisation for 
Research and Treatment of Cancer; FOSI = FACT-ovarian symptom index; FRα = folate receptor alpha; 
IC = Investigator’s choice; ORR = overall response rate; Pac = paclitaxel; PD = progressive disease; 
PFS = progression-free survival; PFS2 = time to second disease progression; PK = pharmacokinetic(s); 
PLD = pegylated liposomal doxorubicin; PRO = patient-reported outcome; QLQ = Quality of Life 
Questionnaire; TEAE = treatment-emergent adverse event; Topo = topotecan. 
This SAP will govern the analysis of study data. The plan for the primary efficacy analysis 
may be modified until the time of the interim analysis. The plan for all other analyses may be 
modified until the time of database lock. Any deviations from the SAP will be documented as 
such in the study report.  
The Phase 3 portion of the study is the main focus of this SAP and will be refered to as 
‘study’, information included that specifically relates to a Stage 1 topic is designated as such.  


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2. 
STUDY DESIGN 
2.1. 
Protocol Objectives 
2.1.1. 
Primary Objective 
• To compare the progression-free survival (PFS) of patients randomized to 
IMGN853 versus selected standard-of-care chemotherapy (IC), as assessed by the 
Blinded Independent Review Committee (BIRC) in the Intent-to-treat (ITT) 
population (defined in Section 3.12.2) and in the high-FRα subgroup (≥ 75% of 
tumor staining at ≥ 2+ intensity). 
2.1.2. 
Secondary Objectives 
2.1.2.1. 
Key Secondary Objectives: 
• To compare the objective response rate (ORR) of patients randomized to 
IMGN853 versus selected standard-of-care chemotherapy (IC). 
− Primary analysis of ORR will be based on BIRC assessments. ORR based on 
Investigator’s assessment will be analyzed as sensitivity analysis. 
• To compare the overall survival (OS) of patients randomized to IMGN853 versus 
selected standard-of-care chemotherapy (IC). 
• To compare the primary patient reported outcomes (PRO) endpoint using 
QLQ-OV28 assessments from patients randomized to IMGN853 versus selected 
standard-of-care chemotherapy (IC) as described in Protocol Section 11.7.  
2.1.2.2. 
Other Secondary Objectives: 
• To compare the safety and tolerability of IMGN853 with that of selected 
standard-of-care chemotherapy (IC). 
• To compare the duration of response (DOR) of patients randomized to IMGN853 
versus selected standard-of-care chemotherapy (IC). 
− Primary analysis of DOR will be based on BIRC assessments. DOR based on 
Investigator’s assessment will be analyzed as sensitivity analysis. 
• To compare the cancer antigen 125 (CA-125) response rate per Gynecologic 
Cancer Intergroup (GCIG) CA-125 criteria of patients randomized to IMGN853 
versus selected standard-of-care chemotherapy (IC). 
• To compare the PFS of patients randomized to IMGN853 versus selected 
standard-of-care chemotherapy (IC), as assessed by the Investigator. 
• To evaluate the pharmacokinetics (PK) of IMGN853. 
• To assess the immunogenicity of IMGN853 (anti-drug antibodies, ADA). 
• To assess PRO using the European Organisation for Research and Treatment of 
Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30, EORTC 


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QLQ-OV28, EQ-5D-5L, and eight-item FACT-ovarian symptom index (FOSI) 
questionnaires.  
2.1.3. 
Exploratory Objectives 
• To evaluate potential biomarkers in blood and tumor tissue that might predict 
response to IMGN853.  
• To compare the time to second disease progression (PFS2) of patients randomized 
to IMGN853 versus selected standard-of-care chemotherapy (IC). 
• To identify DM4 metabolites in urine. 
2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoint 
• PFS: the time from the date of randomization until the time of death or 
progressive disease (PD), as assessed by the BIRC (PFSBIRC): 
− In all patients randomized to the study. 
− In patients with high FRα level (≥ 75% of tumor staining at ≥ 2+ intensity). 
2.2.2. 
Secondary Endpoints 
2.2.2.1. 
Key Secondary Endpoints: 
• ORR per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
criteria as assessed by BIRC. 
• OS: the time from date of randomization until the date of death. 
• Primary PRO endpoint using the QLQ-OV28 questionnaire as described in 
Protocol Section 11.7.  
2.2.2.2. 
Other Secondary Endpoints: 
• Treatment-emergent adverse events (TEAEs) and laboratory test results, physical 
examination, electrocardiograms (ECGs), or vital signs. 
• Gynolocologic Cancer Intergoup CA-125 criteria clinical response rate. 
• Time-to-event endpoints: 
− PFS as assessed by Investigator. 
− DOR: the time from first objective response (complete response[CR]/partial 
response[PR]) to the time of PD among those who have achieved a PR or 
CR), as assessed by BIRC.  
− DOR as assessed by the Investigator. 
• PK parameters of IMGN853.  


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• Immunogenicity of IMGN853: ADA. 
• Patient scores on EORTC QLQ-C30, EORTC QLQ-OV28, EQ-5D-5L, and 
8-item FOSI questionnaires. 
2.2.3. 
Exploratory Endpoints 
• Evaluate association of breast cancer susceptibility gene (BRCA) mutation status 
in tumor tissue and FRα expression level with anti-tumor activity of IMGN853. 
• Evaluate the association of anti-tumor activity and/or safety with the following: 
− Mutational status and other genomic alterations in tumor samples.  
− Activation status of oncogenic pathways in tumor samples.  
− Expression of drug transporters such as multi-drug resistant gene 1 (MDR1) 
(ie, P-glycoprotein [PgP]) as well as other proteins that may influence anti-
tumor activity or safety. 
− Blood-based biomarkers (such as soluble FRα). 
− Genotyping of Fc gamma receptor (FcγR). 
• PFS2, as assessed by the Investigator: the time from randomization to the time of 
second PD or death. 
• Qualitative analysis of DM4 metabolites in urine. 
2.3. 
Study Overview  
This study is designed to compare the efficacy of IMGN853 to that of selected 
standard-of-care chemotherapy (IC) in women with platinum-resistant advanced EOC, 
primary peritoneal cancer, or fallopian tube cancer.  
Patients will be stratified by number of prior lines of treatment (1 or 2 vs 3), FRα levels 
(≥ 75% tumor staining at ≥ 2+ intensity [high] vs ≥ 50% and < 75% tumor staining at > 2+ 
intensity [medium]), and IC chemotherapy (paclitaxel [Pac], pegylated liposomal 
doxorubicin (PLD), or topotecan [Topo]). Patients will be randomized 2:1 into 1 of 2 arms as 
follows (Figure 1):  
• Arm 1: IMGN853 6mg/kg AIBW Q3W.  
• Arm 2: IC chemotherapy (weekly paclitaxel every 4 weeks [Q4W], PLD 
administered once Q4W, or topotecan administered either on Days 1, 8, and 15 
Q4W or for 5 consecutive days Q3W).  


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Figure 1: 
Study Design Schema 
Arm 1: IMGN853
 6mg/kg
AIBW Q3W 
Arm 2: Investigator’s Choice 
Chemotherapy (Pac, PLD, or Topo)
Randomization
2:1
 assessed by BIRC
PD
PD
 
AIBW = adjusted ideal body weight; BIRC = Blinded Independent Review Committee; Pac = paclitaxel; 
PD = disease progression; PLD = pegylated liposomal doxorubicin; Q3W = every 3 weeks; Topo: topotecan. 
Patients will continue to receive study treatment until they present with PD per RECIST 
Version 1.1, (as assessed by the BIRC), develop unacceptable toxicity, or withdraw consent, 
whichever comes first, or until the Sponsor terminates the study.  
Tumor assessments, including radiological assessments by computerized tomography or 
magnetic resonance imaging scans, will be performed at screening and subsequently every 
6 weeks (± 1 week) for the first 36 weeks then every 12 weeks (± 1 week) until PD per 
RECIST Version 1.1, death, or the initiation of subsequent anti-cancer therapy, whichever 
occurs first. All patients will be followed every 3 months (± 2 weeks) for survival until death, 
patient is lost to follow-up, patient withdraws consent for survival, or until End of Study, 
whichever comes first. 
The study consists of a Screening period, a Treatment period, an End-of-Treatment visit, and 
a Follow-up period. See Figure 2. 
 


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Figure 2: 
Study Period Schema 
EOT = end of treatment; Pac = paclitaxel; PLD = pegylated liposomal doxorubicin; Q3W = every 3 weeks; 
Topo = topotecan. 
2.3.1. 
Study Population 
All patients must have 1 of the following pathologically documented, definitively diagnosed 
tumor types: advanced platinum-resistant EOC, primary peritoneal cancer, or fallopian tube 
cancer. Patients must also have the following: 
• At least 1 lesion that meets the definition of measurable according to RECIST 
Version 1.1.  
• Received at least 1 but no more than 3 prior systemic lines of anti-cancer therapy.  
• Confirmation of FRα positivity by immunohistochemistry (IHC) (≥ 50% of tumor 
staining at ≥ 2+ intensity) in archival or fresh biopsy tumor sample.  
See Section 3.1 of the protocol for a complete list of the inclusion/exclusion criteria. 
Patients who have consented to the study and have been randomized are considered enrolled. 
Patients who are issued a patient number, but who do not successfully complete the screening 
process and who do not get randomized will be considered screen failures. Patient numbers 
assigned to patients who screen fail will not be re-issued. 
2.3.2. 
Power and Sample Size  
2.3.2.1. 
Primary Endpoints 
The study has 2 primary endpoints, PFS as assessed by BIRC in all randomized patients and 
PFS as assessed by BIRC in the FRα high-expression subgroup. The study is designed to test 
the null hypothesis that the survival function for PFS is the same between the IMGN853 arm 
and the IC chemotherapy arm versus the alternative hypothesis that the survival function for 
PFS is different between the IMGN853 and IC chemotherapy arms. The Hochberg procedure 
will be used to control the overall type I error (see Section 3.11 Hypothesis Testing and 
Multiple Comparisons for further details).  
Approximately 333 patients will be randomized 2:1 (222 to the IMGN853 arm and 111 to the 
IC arm) over a period of approximately 21 months across approximately 130 study centers 
globally. The final analysis will be conducted when at least 236 PFS events are observed.  


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An interim futility analysis will be conducted when at least 80 PFS events have been 
observed. The study will be terminated for futility at interim analysis if the observed hazard 
ratio [IMGN853 to IC chemotherapy] is greater than 1 in all randomized patients and in the 
FRα high-expression subgroup.  
The study will have 91% power to detect a hazard ratio of 0.583 in the FRα high-expression 
subgroup and 96% power in all randomized patients at a study-wise alpha level of 5%; the 
study will have a 39% probability of stopping for futility at interim analysis under the null 
hypothesis.  
Sample size and power were determined by simulations using SAS® software with the 
following assumptions:  
• Median PFS for the IC arm is 3.5 months. 
• Median PFS for the IMGN853 arm is 6 months. 
• Exponential distribution for both event and censoring processes. 
• Ratio of FRα high to FRα medium is 2:1.  
• Annual censoring rate is 20% in both arms. 
2.3.2.2. 
Power for Key Secondary Endpoints 
ORR as assessed by BIRC  
With a sample size of 333 (222 in the IMGN853 arm and 111 in the IC chemotherapy arm), 
the study will have a power of 89% to detect a 17% difference in ORR (35% in IMGN853 vs 
18% in IC chemotherapy). 
OS 
At the final analysis of PFS, the study will have 29% power to detect an OS hazard ratio of 
0.778, assuming the median OS for IC chemotherapy is 14 months. 
Primary PRO endpoint  
Number of patients achieving at least a 15% improvement on the QLQ-OV28 
abdominal/gastointestinal symptom subscale [Items 31-36] at the Week 8/9 assessment): This 
endpoint will be analyzed using a responder approach. Assuming a 90% compliance rate in 
the PRO endpoint, the study will have a power of 86% to detect a 15% difference in response 
rate for the primary PRO endpoint (25% in IMGN853 versus 10% in IC chemotherapy).  
2.3.3. 
Treatment Randomization and Stratification 
The treatment randomization schedule was developed by Y Prime. Patients will be 
randomized 2:1 into 2 groups, as follows: 
• Arm 1: IMGN853 six mg/kg AIBW Q3W.  
• Arm 2: IC chemotherapy (weekly Pac Q4W, PLD Q4W, or Topo administered 
either on Days 1, 8, and 15 Q4W or for 5 consecutive days Q3W  


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Randomization will be stratified as follows: 
• Number of prior lines of therapy (1 or 2 vs 3). 
• FRα levels (high, defined as ≥ 75% of tumor staining at ≥ 2+ intensity vs medium, 
defined as ≥ 50% and < 75% at ≥ 2+ intensity).  
• IC chemotherapy (Pac, PLD, or Topo). 
The required FRα expression level is ≥ 50% of tumor staining at ≥ 2+ intensity. A 
stratification cutoff of ≥ 75% at ≥ 2+ will also be implemented to evaluate anti-tumor activity 
of IMGN853 based on higher levels of FRα expression. 
Cycle 1 Day 1 should occur within 7 calendar days from randomization. 
2.3.4. 
Blinding and the BIRC 
This is an open-label study. Treatment assignment will not be blinded. A BIRC will be used 
to provide an independent assessment of radiographic tumor assessments. The BIRC will be 
blinded to the treatment assignment.  
The Sponsor has also decided to blind certain members of the study team to the efficacy 
endpoints. Specifically, clinical scientists, medical monitors, study statisticians, and study 
statistical programmers will not have access to the RECIST tumor assessments for either the 
Investigator’s assessment captured in the EDC system or the BIRC data. Data managers and 
clinical trial managers will have access to the tumor assessment data.  
Please see the Data Access Plan for this study for detailed information regarding the blinding 
of efficacy endpoints. 
2.3.4.1. 
BIRC 
Copies of all imaging scans must be obtained and sent to a central imaging vendor designated 
by ImmunoGen as outlined in the Imaging Manual. The central imaging vendor will assess 
the quality of the images. The imaging vendor will be responsible for the formation and 
management of the BIRC.  
Tumor response will be assessed by the Investigator and by the BIRC using RECIST 
Version 1.1. Response as determined by the Investigator will be recorded in the electronic 
case report forms (eCRFs). The BIRC assessment will be used for the primary endpoint 
analysis.  
All time points other than the Investigator-determined PD will be assessed by BIRC in a non-
expedited manner. Results of these assessments will not be communicated to the sites.  
For time points with Investigator-determined PD, the BIRC will perform an expedited 
review. While the images are assessed by the BIRC, the patient should continue on the study 
treatment as planned if it is clinically acceptable to do so. If the BIRC confirms PD, the 
patient must discontinue study treatment. If the BIRC does not confirm PD, the patient 
should continue receiving the study treatment unless there is a medical need (ie, rapid PD or 
clinical deterioration) that requires an immediate change in therapy. Although disease 
progression may be determined by the Investigator based upon clinical deterioration, every 


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effort should be made to document PD using radiographic methods. The basis for 
determination of disease progression per clinical deterioration should be documented in the 
eCRFs. 
The central imaging vendor will ensure that the central radiologists remain blinded to the 
local assessment from the Investigator and other unblinding information. This and all other 
imaging procedures will be documented in an independent review charter agreed upon 
between ImmunoGen and the imaging vendor before initiation of any BIRC reviews. BIRC 
assessment of PD will be used for the primary endpoint analysis.  
2.3.5. 
Assessment Schedule 
See protocol Appendix A, Appendix B, and Appendix C for study schedules of assessments. 
2.4. 
Interventions 
2.4.1. 
Clinical Trial Material 
The dose levels and dosing schedule is provided in Table 2. 
Table 2: 
Dosing and Dosing Schedule for Phase 3 Portion 
Phase 3 (Randomization 2:1) 
Group 
Drug 
Dose 
Dosing Schedule 
Arm 1 
IMGN853 
6 mg/kg AIBW 
Day 1 of a 3-week cycle  
Arm 2 
Paclitaxel 
80 mg/m2 
Days 1, 8, 15, and 22 of a 4-week 
cycle 
PLD 
40 mg/m2  
Day 1 of a 4-week cycle 
Topotecan 
(4-week cycle) 
4 mg/m2 
Days 1, 8, and 15 of a 4-week cycle 
Topotecan 
(3-week cycle) 
1.25 mg/m2  
Days 1 through 5 of a 3-week cycle  
AIBW = adjusted ideal body weight; PLD = pegylated liposomal doxorubicin. 
The protocol provides additional details in Section 4.1.2. 


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3. 
GENERAL ANALYTICAL CONSIDERATIONS 
3.1. 
Data Sources 
Data are recorded on eCRFs. Central laboratory data will be provided via electronic data 
transfers. Section 12 of the protocol provides additional details regarding data recording and 
handling. Patient entry into the eCRF system and randomization are completed through the 
Y Prime system. The data are then automatically mapped into the eCRF system, and will be 
available through the eCRF data extract. 
3.2. 
Definition of Baseline 
Study Day 1 (ie, Cycle 1 Day 1) will be designated as the first day a patient receives study 
drug. The baseline value is defined as the last non-missing value on or before the date of first 
dose of study drug.  
3.3. 
Missing Data 
Partial dates are allowed on the eCRF for adverse event (AE) onset and resolution dates, 
concomitant medication start and stop dates, and concomitant procedure, procedure dates. An 
entry for the year is required in the eCRF system for each of these dates. Only the month and 
day may be entered as unknown. Dates from these forms will be reported in listings as 
collected. Every effort will be made to query missing dates.  
For records with missing AE onset date, the following procedure will be employed for use in 
determining whether the AE is treatment emergent: 
• AE onset dates with missing day and non-missing month will be assumed to occur 
on the first day of the non-missing month, except for AEs occurring in the first 
month of dosing, in which case the date will be the first day of dosing. 
• AE onset dates with missing month will be assumed to occur on the first day of 
the non-missing year (ie, January 1), except for AEs occurring in the first year of 
dosing, in which case the date will be the first day of dosing.  
For records with a missing medication start and/or stop date, the following procedure will be 
employed for use in determining whether the medication is prior or concomitant: 
• Medication start dates with a missing day and non-missing month will be assumed 
to occur on the first day of the non-missing month, except for medications 
occurring in the first month of dosing, in which case the date will be the first day 
of dosing. 
• Medication start dates with missing month will be assumed to occur on the first 
day of the non-missing year (ie, January 1), except for medications occurring in 
the first year of dosing, in which case the date will be the first day of dosing.  
• Medications that are not ongoing and have a medication stop date with a missing 
day and non-missing month will be assumed to occur on the last day of the non-
missing month. 


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• Medications that are not ongoing and have a medication stop date with a missing 
month will be assumed to occur on the last day of the non-missing year 
(ie, December 31). 
For records with a missing procedure date, the following procedure will be employed for use 
in determining whether the procedure is prior or concomitant: 
• Procedure dates with a missing day and non-missing month will be assumed to 
occur on the first day of the non-missing month, except for procedures occurring 
in the first month of dosing, in which case the date will be the first day of dosing. 
• Procedure dates with missing month will be assumed to occur on the first day of 
the non-missing year (ie, January 1), except for procedures occurring in the first 
year 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 unless otherwise stated in this document.  
3.4. 
Multiple Assessments for the Same Assessment Time Point 
In the case of multiple observations at a specific visit, the first non-missing measurement will 
be used for analysis, unless multiple study assessments are expected (eg, pre-dose vs post-
dose). When multiple study assessments are expected, the first non-missing measurement for 
the visit and assessment time point will be used for analysis. 
3.5. 
Multiple Study Centers 
No adjustment for study center is planned.  
3.6. 
Covariate Adjustment in Primary Analysis 
In the primary efficacy analysis, no covariate adjustment will be made. A stratified analysis 
using randomization stratification factors will used for primary inference. The details are 
described in Section 5.2. 
3.7. 
Sample Size Reassessment 
Not applicable. 
3.8. 
Interim Analyses 
An interim futility analysis will be conducted when at least 80 PFS events as assessed by 
BIRC have occurred. The study will be terminated for futility at interim analysis if the 
observed hazard ratio [IMGN853 to IC chemotherapy] is greater than 1 in all randomized 
patients as well as in the FRα high-expression subgroup. No alpha spending is planned for 
this futility.  
Under the enrollment assumptions (see Appendix 2: Monte-Carlo Simulation Report), the 
interim analysis will occur when approximately 160-180 patients have been randomized. 
This is expected to occur approximately 1 year after the first patient is randomized. 


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The interim analysis of efficacy endpoints will follow the analysis methods described in the 
interim analysis plan.  
Additionally, there will be ongoing analysis of safety data by the Independent Data 
Monitoring Committee (IDMC) as described in the IDMC charter.  
3.9. 
Timing of Final Analysis 
If the study continues to a minimum of 333 patients for full enrollment (ie, the study is not 
stopped for futility at the interim analysis), the final analysis will be conducted when at least 
236 PFS events have been observed in the ITT population (as determined by the BIRC). 
3.10. 
Test Sizes 
Any tested hypotheses will be tested against 2-sided alternatives, using procedures that 
provide an expected probability of Type I error (α) of 0.05. 
3.11. 
Hypothesis Testing and Multiple Comparisons 
3.11.1. 
Primary Endpoints 
The 2 null hypotheses for primary endpoints are: 
• H01: the survival function for PFSBIRC is the same between the IMGN853 arm and 
the IC chemotherapy arm in the ITT population, and  
• H02: the survival function for PFSBIRC is the same between the IMGN853 arm and 
the IC chemotherapy arm in the FRα high-expression subgroup.  
And the alternative hypotheses are: 
• Ha1: the survival function for PFSBIRC is different between the IMGN853 arm and 
the IC chemotherapy arm in the ITT population, and  
• Ha2: the survival function for PFSBIRC is different between the IMGN853 arm and 
the IC chemotherapy arm in the FRα high-expression subgroup.  
The Hochberg procedure will be used to control the overall type I error. Assume the log-rank 
p-values for the 2 primary endpoints are P(1) and P(2) (P(1) ≤ P(2)). Let H0(1) be the null 
hypothesis corresponding to P(1) and H0(2) the hypothesis corresponding to P(2). The 
Hochberg will first test P(2) against 0.05.  
• If P(2) ≤ 0.05, then reject both H01 and H02 and claim statistical significance in both 
endpoints.  
• If P(2) > 0.05, then P(1) will be tested against 0.025.  
− If P(1) ≤ 0.025, then reject H0(1) and claim statistical significance for that 
endpoint.  
− If P(1) > 0.025, then no null hypothesis will be rejected.  
This Hochberg procedure is illustrated in Figure 3.  


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Figure 3: 
Hochberg Procedure 
P(2)  ≤ 0.05 
No Null hypothesis 
is rejected
Reject H0(1)
STOP
& 
 reject both H01 & H02 
NO
YES
P(1)  ≤ 0.025
NO
YES
 
3.11.2. 
Key Secondary Endpoints 
For the 3 key secondary endpoints, a hierarchical testing procedure will be applied to control 
the overall type I error only if both null hypotheses for the primary endpoints are rejected 
using the Hochberg method. The order of the hierarchical testing is as follows: 
• ORRBIRC 
• OS 
• Primary PRO endpoint as described in Protocol Section 11.7 (primary endpoint 
for quality of life [QoLP]) 
The null hypothesis for ORRBIRC is as follows: 
• H03: the ORRBIRC is the same between the IMGN853 arm and the IC 
chemotherapy arm in the ITT population.  
And the alternative hypothesis is as follows: 
• Ha3: the ORRBIRC is different between IMGN853 arm and the IC chemotherapy 
arm in the ITT population.  
The null hypothesis for OS is as follows: 
• H04: the survival function for OS is the same between the IMGN853 arm and the 
IC chemotherapy arm in the ITT population.  
And the alternative hypothesis is as follows: 
• Ha4: the survival function for OS is different between the IMGN853 arm and the 
IC chemothearpy arm in the ITT population.  


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The null hypothesis for QoLP is as follows: 
• H05: the QoLP is the same between the IMGN853 arm and the IC chemotherapy 
arm in the ITT population.  
And the alternative hypothesis is as follows: 
• Ha5: the QoLP is different between the IMGN853 arm and the IC chemotherapy 
arm in the ITT population.  
This procedure first tests H03 at a 2-sided alpha level of 0.05. If H03 is rejected favoring the 
IMGN853 arm, statistical significance will be claimed for ORRBIRC, and H04 will be tested at 
a 2-sided alpha level of 0.05. If H04 is rejected favoring the IMGN853 arm, statistical 
significance will be claimed for OS, and H05 will be tested at a 2-sided alpha level of 0.05. 
The procedure will stop at the first test not significant at a 2-side alpha level of 0.05 and no 
claims will be made for that endpoint and subsequent endpoints. 
3.12. 
Analysis Populations  
Five analysis populations will be defined for use with various analyses. Table 3 illustrates the 
relationship between each population and the analyses for which the data from the population 
will be used. 
Table 3: 
Analysis Populations 
Analysis 
Population 
Analysis 
Baseline 
Patient Disposition 
Efficacy 
Safety 
Screened 
X 
 
 
 
ITT 
X 
X 
X 
 
Per Protocol  
 
 
X 
 
Response 
Evaluable  
 
 
ORR only 
 
CA-125 Evaluable  
 
 
CA-125 only 
 
Safety 
 
 
 
X 
CA-125 = cancer intigen 125; ITT = intent-to-treat; ORR = objective response rate. 
3.12.1. 
Screened 
The Screened population includes all patients entered into the eCRF system who have signed 
an informed consent.  
3.12.2. 
ITT Population 
The ITT population is defined as all patients randomized in the Phase 3 portion of the study 
(Amendment 6 and onwards).  


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3.12.3. 
Per Protocol Population 
Per Protocol Population is defined as all patients randomized in the Phase 3 portion of the 
study who have received at least 1 dose of the study drug, excluding patients with protocol 
deviations in the following categories: patients - 
• whose tumors have FRα low expression (<50% tumor staining at ≥ 2+ intensity), 
and/or  
• who have received four (4) or more prior lines of cancer therapy, and/or  
• who are not secondary platinum resistant.  
3.12.4. 
Response-Evaluable Population 
The Response-Evaluable population is defined as all patients randomized in the Phase 3 
portion of study who have received at least 1 dose of study drug, undergone baseline and at 
least 1 post-baseline tumor assessment, or who died within 105 days of randomization.  
3.12.5. 
CA-125-Evaluable Population 
The CA-125-Evaluable population is defined as all patients randomized in the Phase 3 
portion of the study whose pretreatment sample is ≥ 2.0 times the upper limit of normal 
(ULN), within 2 weeks prior to randomization, and who have at least 1 post-baseline CA-125 
evaluation.  
3.12.6. 
Safety Population 
All enrolled patients who received at least 1 dose of IMGN853 or IC chemotherapy will be 
included in the Safety population. 
 
3.13. 
Data Display Characteristics 
Data displays produced for this study will include summary tables, data listings, and figures. 
Data listings will be produced for all recorded data as described in Section 4, Section 5, 
Section 6, and Section 8.  Summary tables will be produced as specified in Section 4, 
Section 5, Section 6, and Section 8. 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 Section 4, Section 5, and Section 6. 
Stage 1 data will be provided in listings only. As there are only 4 patients in Stage 1, no 
tables or figures will be provided. Tables, listings, and figures will be provided for the 
Phase 3 portion of the study. Stage 1 and Phase 3 data will be presented separately. 
Data listings will report the data recorded on the eCRF or derived for each patient. Data will 
be ordered by treatment, patient number, and date/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 treatment groups, 
unless described otherwise in Section 4, Section 5, and Section 6, and Section 8. For safety 


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analyses, the columns of the summary tables will be IMGN853 6mg/kg Q3W, Pac, PLD, 
Topo Q3W or Q4W, and Total Investigator’s Choice. For efficacy analyses, the columns of 
the summary tables will be Arm 1: IMGN853 6mg/kg Q3W and Arm 2: Investigator’s 
Choice.  
The summary statistics displayed will be a function of the type of data associated with the 
summarized assessment. Unless stated otherwise in relevant sections, Section 4, Section 5, 
and Section 6, continuous data will be summarized with the number of non-missing values, 
mean, standard deviation, minimum, median, and maximum. Categorical data will be 
summarized with the number of non-missing values and the numbers of values equal to each 
of the possible values. Percentages of patients with each of the possible values will be 
calculated from the number of patients in the corresponding analysis population, unless 
stated otherwise. Some continuous variables may also be grouped into categorical levels and 
evaluated in frequency tables. 


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4. 
PATIENT ACCOUNTABILITY 
4.1. 
Patient Characteristics 
Patient characteristics will be summarized and listed for the ITT population by the treatment 
to which they were randomized (planned treatment). For Stage 1, listings of the following 
information will be provided for the Safety population by the treatment actually received 
(actual treatment). 
If the primary efficacy endpoint (PFSBIRC) is only statistically significant in patients with 
FRα high expression but not in the ITT, the following subgroup tables will be prepared for 
patients with FRα high expression.   
• Demographics and baseline disease characteristics 
• Prior cancer therapy 
4.1.1. 
Demography 
Data collected about the following patient characteristics at the screening visit will be 
summarized as follows: 
• Age is collected in the Y Prime system at the time of patient registration. As this 
is a global study, there are certain regions where local regulations prohibit the 
collection of a complete date of birth. Therefore, age will not be recalculated for 
analysis purposes. The collected age will be used for summarization. 
• Sex and childbearing potential yes/no 
• Ethnicity 
• Race 
All demography data, including informed consent date, will be listed. 
4.1.2. 
Height and Baseline Weight, AIBW, and Body Surface Area 
Height and baseline weight, AIBW, and body surface area (BSA) will be summarized by 
treatment group and presented in a listing. Note that AIBW and BSA are collected depending 
on the treatment group to which a patient is assigned. Thus, baseline AIBW and BSA will 
only be summarized for the treatment groups for which this data is available. 
4.1.3. 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Affairs (MedDRA) 
(Version 18.1 or later), associating lower-level terms with preferred terms (PTs) and system 
organ classes (SOCs) by the primary hierarchy. Medical histories will be summarized as the 
number and percentage of patients who reported at least 1 medical history event; and number 
and percentage of patients who reported at least 1 medical history event in each SOC. Within 
each SOC, tables will display the number and percentage of patients reporting at least 
1 medical history event as designated by PT. All medical history information will also be 
listed. 


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4.1.4. 
Disease Characteristics, Prior Therapy, and Gene Mutations 
Listings of all collected data related to disease characteristics and prior therapy will be 
provided. A summary of the following elements will also be provided: 
• Primary diagnosis (epithelial ovarian cancer, fallopian tube cancer, primary 
peritoneal cancer, other). 
• FRα status 
• Histology 
• Disease stage at initial diagnosis 
• Histologic grade 
• Prior radiotherapy (yes/no) 
• Prior systemic therapy  
− The number of prior systemic therapies is defined as the number of distinct 
treatment regimens 
 Adjuvant ± Neoadjuvant will be considered 1 regimen 
 Maintenance therapy will be considered part of the preceding regimen 
 PARP inhibitor therapy will be considered a prior treatment unless 
given as maintenance therapy 
 
Hormonal therapy will not be considered prior systemic treatment (included 
in this category are tamoxifen, anastrozole, exemestane, megasterol, and 
letrozole) 
• Prior surgery (yes/no) 
• Prior exposure to bevacizumab (yes/no) 
• Any BRCA mutations mutations (yes[BRCA1, BRCA2]/no) 
4.2. 
Patient Disposition 
4.2.1. 
Screened and Enrolled Patients   
The number and percentage of patients who were screened and enrolled (randomized) will be 
summarized by overall, geographic region (North America and Europe), country, and site.   
4.2.2. 
ITT, Safety Disposition  
A summary of patient disposition will summarize, for the ITT population, the number of 
patients randomized and the reason for treatment and study discontinuation. This summary 
will also be produced for the Safety population if more than 5% of patients in the ITT 
population are excluded from the Safety population. 
Percentage of patients who withdrew for each reason on the End-of-Treatment and 
End-of-Study forms will be calculated using all members of the relevant population in the 
relevant treatment group for the denominator. 


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A listing of End-of-Treatment and End-of-Study information will be provided for the ITT 
population. For Stage 1, a listing of End-of-Treatment and End-of-Study information will be 
provided for the Safety population. 
A hierarchical table of the populations in which screened patients were included will 
summarize the relationship to the analysis populations. The number of screened patients will 
be provided in the Total column. Given population definitions, the ITT population will be 
treated as the starting, parent population. The number and percentage of ITT patients 
included in the Safety population and Per-protocol population will be presented for each 
treatment group. This table will be produced for all patients at all sites, pooled. 
4.2.3. 
Protocol Deviations and Population Inclusions 
Protocol deviations will be captured in a protocol deviation log. A summary of the number of 
patients with any protocol deviation will be provided by treatment group for the ITT 
population.  
Protocol deviations will also be summarized by the following categories, as collected in the 
protocol deviation log: 
• Those who entered the study even though they did not satisfy the entry criteria. 
• Those who developed withdrawal criteria during the study but were not 
withdrawn. 
• Those who received the wrong treatment or incorrect dose. 
• Those who received an excluded concomitant treatment. 
The summary will be grouped first by deviation categories and then by site within each 
deviation category. 
A listing from the protocol deviation log will be provided, grouped by site for the ITT 
population. The Stage 1 listing will use the Safety population. 


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5. 
EFFICACY ANALYSES  
The main efficacy analyses will use data from the ITT population. Patients will be analyzed 
by the treatment to which they were randomized (planned treatment).  
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 
either the BIRC or the Investigator, depending on the analysis) recorded between the date of 
randomization and the date of objectively documented PD per RECIST Version 1.1, the date 
of the start of new anti-cancer therapy, or the date of study discontinuation, whichever occurs 
first. When an analysis cutoff date is implemented, only radiological assessments occurring 
on or prior to the cutoff date will be used for analysis.  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. When stable disease is the best overall response, it 
must meet the minimum duration of 35 days (6 weeks – 1 week window = 35 days from the 
date of randomisation). The confirmatory scan is valid following treatment discontinuation as 
long as the patient has not started a new anti-cancer therapy.  
5.1.2. 
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 CA-125 response will 
be conducted using the CA-125-Evaluable population. 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 
include the number (percentage) of patients in the CA-125-Evaluable population, and that 
sample size will then be used as the denominator for CA-125 response rate. 
5.1.3. 
DOR 
DOR is defined as the time from the date of the first response (CR or PR), whichever occurs 
first, to the date of PD or death from any cause, whichever occurs first. DOR is only defined 
for patients who have a best overall response of CR or PR.  
Per the BOR definition, patients with an overall response of CR or PR must have a repeat 
tumor assessment performed no less than 4 weeks 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. 
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. 
Patients who did not have PD or death will be censored at the date of their last radiological 
assessment. Patients who had PD or death after missing 2 or more consecutive radiological 
assessments (PD or death date - last radiological assessment date +1 ≥ 105 days) will be 
censored at the date of their last radiological assessment. When an analysis cutoff date is 
implemented, only data (deaths or radiological assessments) occurring on or before the cutoff 
date will be used for analysis. 


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5.1.4. 
ORR 
The ORR will be calculated as the number of patients with a BOR of CR or PR divided by 
the number of patients in the ITT population. Patients without at least 1 post-baseline 
RECIST assessment will be treated as non-responders (ie, these patients will contribute to the 
denominator, but not the numerator). 
5.1.5. 
OS 
OS is defined as the time from the date of randomization until the date of death from any 
cause.  
Patients who are alive or lost to follow-up at the analysis are censored at the last known date 
at which they were known to be alive. When an analysis cutoff date is implemented, only 
deaths occurring on or before the cutoff date are counted as OS events. Patients whose date 
of death or the last date at which the patient was known to be alive (eg, after the data cutoff 
date) will be censored at the analysis cutoff date.  
5.1.6. 
PFS 
PFS is defined as the time from the date of randomization until the date of PD or death from 
any cause, whichever occurs first. PFS is defined based on radiological assessments and 
determined by the BIRC or the Investigator (depending on the analysis). Clinical progression 
is not considered a progression endpoint.  
 
Table 4 summarizes the rules to be used for PFS. 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. 
 
Table 4: 
PFS Definitionsa  
Situation 
Date of PFS Event or Censoring 
Outcome 
No baseline tumor assessments 
or post-baseline radiological 
assessments, and patient did 
not die within 105 days of 
randomization 
Date of randomization  
Censored 
No baseline tumor assessments 
or post-baseline radiological 
assessments, and patient died 
within 105 days of 
randomization 
Date of death 
Death 
Death 
Date of death 
Death 
Radiological Progression 
Date of first radiological 
assessment indicating progression 
(ie, OR = PD). 
Progression 


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Situation 
Date of PFS Event or Censoring 
Outcome 
New anti-cancer therapy prior 
to PD or death (including 
palliative radiotherapy during 
study treatment) 
Date of last radiological 
assessment prior to the start of the 
new anticancer therapy 
Censored 
No death or PD 
Date of last radiological 
assessment 
Censored 
PD or death after missing 2 or 
more consecutive radiological 
assessments (PD or death date 
- last radiological assessment 
date +1 ≥ 105 days) 
Date of last adequate radiological 
assessment showing no PD 
Censored 
a Includes radiographic progression only - PFSBIRC is based on BIRC assessment; PFSINV is based on the 
Investigator’s assessment. 
OR = overall response; PD = disease progression; PFS = progression-free survival.  
5.1.7. 
RECIST-Related Endpoints – BIRC or Investigator’s Assessment 
The primary analyses will use endpoints based on the BIRC assessment of response. The 
Investigator assessment of response will be used for sensitivity analyses. A subscript of 
BIRC or INV (Investigator) will indicate which assessment of response is used for the 
calculation of the endpoint. For example, BORBIRC and PFSBIRC will be used to denote BOR 
and PFS based on the BIRC assessment of response. BORINV and PFSINV will be used to 
denote the BOR and PFS based on the Investigator’s assessment of response. 
5.1.8. 
Time to Response 
Time to response (TTR) is defined as the time from the date of randomization until the date 
of the first observed CR or PR. TTR is only defined for patients who have confirmed CR or 
PR. 
5.1.9. 
PFS2 
PFS2 is defined as time from randomization to second PD or death. Specifically, for the 
purposes of the PFS2 analysis, the date of event was defined as the following, whichever 
occurred first:  
• Date the patient experienced an event of radiological or clinical progression 
reported on the long-term follow-up form.  
• Date of death.  
• Date of end of next-line treatment.  
− For next-line treatment, any therapy other than radiotherapy will be 
considered.  
• Any event of PD reported during the long-term follow-up evaluation will be 
considered, including PD in patients who did not receive subsequent next-line 
treatment.  


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• Patients who did not experience PD (BIRC) during the study period but who had 
PD documented on the follow-up form will also be considered as having an event 
of PFS2.  
− For patients who did not receive subsequent therapy, nor experience PD or 
death during long-term follow-up, the data will be censored at the time of the 
last follow-up contact.  
− Data from patients lost to follow-up after at least 1 follow-up assessment will 
be included in the analysis as censored observations on the date the patient 
was last known to be alive.  
− Patients who did not have follow-up contacts will be censored on the date of 
study discontinuation. 
5.2. 
Primary Efficacy Outcome Analysis 
The protocol specifies the following primary efficacy endpoint: 
• PFS as assessed by the BIRC 
− In all patients randomized on the study (ie, PFSBIRC,All) 
− In patients with high FRα level (≥ 75% of tumor staining at ≥ 2+ intensity) 
(ie, PFSBIRC,High). 
The distribution of PFSBIRC,All and PFSBIRC,High will be summarized using the Kaplan-Meier 
method. PFS rates will be reported at 3-month intervals (eg, 3 months, 6 months, etc.). 
Median times will be estimated for each treatment from the 50th percentile of the 
corresponding Kaplan-Meier estimates. 95% confidence intervals (CI) for the 3-month 
intervals and median times will also be provided. The primary comparison between 
treatments will use the log-rank test stratified by the randomization stratification factors. 
Stratified analysis using values collected on the eCRFs will be conducted as sensitivity 
analysis. As a sensitivity analysis, the results from an unstratified analysis will also be 
provided. The chi-square p-values from the log-rank tests will be reported. 
Additionally, the restricted mean survival time (RMST) for PFSBIRC,All and PFSBIRC,High will 
also be reported at 3 month intervals (eg, 3 months, 6 months, etc.). The RMST will be 
compared between treatments stratified by the randomization stratification factors (Zucker 
DM 1998). As a sensitivity analysis, the RMST from an unstratified analysis will also be 
provided. Stratified analysis using values collected on the eCRFs will be conducted as 
sensitivity analysis. 
For PFSBIRC,All, the strata will be FRα expression level (high vs medium), IC chemotherapy 
(Pac vs PLD vs Topo), and the number of prior lines of therapy (1 or 2 vs 3). For 
PFSBIRC,High, the strata will be IC chemotherapy (Pac vs PLD vs Topo), and the number of 
prior lines of therapy (1 or 2 vs 3). 
The hazard ratio for PFSBIRC,All and PFSBIRC,High treatment comparisons will be estimated 
using a stratified Cox proportional hazards model. As a sensitivity analysis, the hazard ratio 
from an unstratified Cox proportional hazards model will also be provided. 


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The hazard ratio (IMGN853 arm vs IC chemotherapy arm) will be reported using the 
maximum likelihood estimate along with 95% CI. The IC chemotherapy arm will be used as 
the reference treatment (ie, denominator of the hazard ratio). A time-to-event hazard ratio 
less than 1.0 would indicate an IMGN853 benefit over IC chemotherapy. 
Kaplan-Meier estimates of PFS and RMST for PFS at 3, 6, 9, and 12 months will also be 
compared between the IMGN853 and IC chemotherapy arms. 
As a sensitivity analysis, PFSBIRC will also be analyzed in the Per-protocol population.  
Patients will be analyzed by the actual treatment they received. 
For diagnostic purposes, the proportional hazard assumption will be checked using 
appropriate approaches; including comparing the hazard ratios from stratified and unstratified 
Cox models, as well as checking graphs (ie, Kaplan-Meier plots: plot of ln(-ln(s(time))) vs 
time or ln(time), and plots of Scheonfeld residuals vs time). A summary of these checks will 
be provided to the Sponsor. 
5.3. 
Secondary Efficacy Analyses 
The protocol describes the following key secondary efficacy endpoints: 
• ORR per RECIST Version 1.1 criteria based on the BIRC assessment (ORRBIRC). 
• OS. 
• Primary PRO endpoint as described in the PRO analysis appendix. 
Additionally, the following efficacy endpoints will also be analyzed: 
• PFS as assessed by the Investigator (PFSINV). 
• ORR per RECIST Version 1.1 as assessed by the Investigator (ORRINV). 
• DOR based on BIRC assessment (DORBIRC). 
• DOR based on Investigator’s assessment (DORINV). 
• GCIG CA-125 criteria clinical response rate. 
• TTR based on BIRC assessment (TTRBIRC). 
• TTR based on Investigator’s assessment (TTRINV). 
Unless noted otherwise, all analyses of secondary endpoints will be based on the ITT 
population. In addition, ORR will also be summarized using the Response-Evaluable 
population. 
As a sensitivity analysis, ORRBIRC and OS will also be summarized on the Per-protocol 
population. 
GCIG CA-125 response will be summarized using the CA-125 Response-Evaluable 
population only. 
DOR will be summarized in patients with confirmed CR or PR only. 


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ORR and GCIG CA-125 response will be analyzed using a Cochran-Mantel-Haenszel 
(CMH) test stratified by the randomization stratification factors to test for differences 
between the IMGN853 arm and the IC chemotherapy arm. P-value and 95% CIs for the 
proportion of patients with ORR or GCIG CA-125 clinical response will be provided.  
The distribution of time-to-event variables (PFS, DOR, and OS) will be summarized using 
the Kaplan-Meier method. PFS, DOR, and OS will be reported at 3 month intervals (eg, 
3 months, 6 months, etc.). Median times will be estimated for each treatment from the 50th 
percentile of the corresponding Kaplan-Meier estimates. 95% CIs for the 3-month intervals 
and median times will also be provided. The primary comparison between treatments will use 
the log-rank test stratified by the randomization stratification factors. Stratified analysis using 
values collected on the eCRFs will be conducted as sensitivity analysis. As a sensitivity 
analysis, the results from an unstratified analysis will also be provided. The chi-square p-
values from the log-rank tests will be reported.  
The hazard ratio for the time-to-event variables (PFS, DOR, and OS) treatment comparisons 
will be estimated using a stratified Cox proportional hazards model. As a sensitivity analysis, 
the hazard ratio from an unstratified Cox proportional hazards model will also be provided. 
The hazard ratio (IMGN853 arm vs IC chemotherapy arm) will be reported using the 
maximum likelihood estimate along with 95% CI. The IC chemotherapy arm will be used as 
the reference treatment (ie, denominator of the hazard ratio). A time-to-event hazard ratio 
less than 1.0 would indicate an IMGN853 benefit over IC chemotherapy. 
For diagnostic purposes, the proportional hazard assumption will be checked using 
appropriate approaches; including comparing the hazard ratios from stratified and unstratified 
Cox models, as well as checking graphs (ie, Kaplan-Meier plots: plot of ln(-ln(s(time))) vs 
time or ln(time), and plots of Scheonfeld residuals vs time). A summary of these checks will 
be provided to the Sponsor. 
TTR will be summarized using descriptive statistics for patients who achieved a confirmed 
response of CR or PR as assessed by BIRC or the Investigator (TTRBIRC and TTRINV).  
The analysis of the primary PRO endpoint will be described in a separate document to the 
SAP.  
The median follow up time and its 95% CI will be estimated using reverse Kaplan-Meier 
method on OS. 
5.4. 
Exploratory Efficacy Analyses 
The protocol describes the following exploratory efficacy analyses: 
• Evaluate association of BRCA mutation status and FRα expression level with 
anti-tumor activity of IMGN853.  
• Evaluate the association of anti-tumor activity and/or safety with the following:  
− Mutational status and other genomic alterations in tumor samples.  
− Activation status of oncogenic pathways in tumor samples.  


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− Expression and polymorphism of drug transporters such as MDR1 (ie, PgP) 
and other proteins that may influence anti-tumor activity or safety.  
− Soluble FRα level in blood samples. 
− Genotyping of FcγR.  
• Evaluate PFS2. PFS2 analysis will be conducted using the same method as in PFS 
analysis. 
5.5. 
Efficacy Analysis on Subgroups of Patients 
PFSBIRC, PFSINV, ORRBIRC, ORRINV, and OS  will be analyzed with the following subgroups 
of patients: 
• BRCA status (positive vs negative/unknown).  
• FRα levels (≥ 75% tumor staining at ≥ 2+ intensity vs < 75% tumor staining at 
≥ 2+ intensity). 
• Age (< 65 year vs ≥ 65 years). 
• Baseline Eastern Cooperative Oncology Group Performance State (ECOG PS) 
(0 vs 1). 
• Prior exposure to bevacizumab (yes vs no). 
• Number of prior lines of therapy (1 or 2 vs 3). 
• Type of IC chemotherapy. 
• Location of metastasis (visceral vs non-visceral). 
• Race (white vs non-white). 
The summaries for time to event variables include the number and percentage of events, 
median and its 95% CI, 2-sided P-value, and hazard ratio (IMGN853 to IC chemo) and its 
95% CI. 
The forest plot of time to event variables will display the number of subjects, events, hazard 
ratio (IMGN853 to IC chemo) and its 95% CI.   
The summaries for ORR include the ORR and its 95% CI, and difference in ORR (IMGN853 
– IC chemo) and its 95% CI. 
The forest plot of ORR will display the number of subjects, difference in ORR (IMGN853 – 
IC chemo) and its 95% CI.   
5.6. 
Additional Sensitivity Analyses 
As additional sensitivity analyses, PFSBIRC,All will also be analyzed by:  
• Stratifying only by FRα level. 
• Stratifying by FRα level, and using the number of prior therapies and IC 
chemotherapy as covariates. 


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As additional sensitivity analyses, PFSBIRC,High will also be analyzed by: 
• Using the number of prior therapies and IC chemotherapy as covariates. 
The primary analyses for PFS are based on the BIRC assessment of radiological assessments 
only. A sensitivity analysis of PFS based on the Investigator assessment (PFSINV) is 
described Section 5.3  As an additional sensitivity analysis, PFS will be re-assessed by using 
the Investigator’s radiological and clinical assessments (PFSAINV). In this analysis, PFSAINV 
will be defined as the time from the date of the randomization until the date of PD by 
radiological or clinical assessment or death from any cause, whichever occurs first, as 
determined by the Investigator. If PD is noted in both clinical and radiological assessments, 
the first date where PD is noted will be used for analysis.   
Table 5: 
PFSAINV Definitionsa  
Situation 
Date of PFS Event or Censoring 
Outcome 
No baseline tumor assessments 
or post-baseline tumor 
assessments, and patient did 
not die within 105 days of 
randomization and no clinical 
progression noted 
Date of randomization  
Censored 
No baseline tumor assessments 
or post-baseline tumor 
assessments, and patient died 
within 105 days of 
randomization and no clinical 
progression noted 
Date of death 
Death 
Death 
Date of death 
Death 
Radiological or clinical 
progression 
The earliest of: 
Date of first radiological 
assessment indicating progression 
(ie, OR = PD on RECIST 
response eCRF), or 
Date of first instance of clinical 
progression (ie, on RECIST 
response eCRF, the earliest date 
of clinical progression). 
Progression 
New anti-cancer therapy prior 
to progression or death 
(including palliative 
radiotherapy during study 
treatment) 
Date of last radiological 
assessment prior to the start of the 
new anticancer therapy 
Censored 
No death or progression 
Date of last radiological 
assessment 
Censored 


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a Includes Investigator assessed radiological and clinical progression. 
eCRF = electronic case report form; OR = overall response; PD = disease progression; PFS = progression-free 
survival; RECIST = Response Evaluation Criteria in Solid Tumors. 
 
Additionally, for PFSBIRC, rather than censoring patients who progressed or died after 
missing 2 or more consecutive radiological assessments, the date of the PFS event will be 
backdated to the date of first missed assessment. This analysis will be called PFSBBIRC. 
Table 6 provides the rules for PFSBBIRC. 
Table 6: 
PFSB BIRC Definitionsa  
Situation 
Date of PFS Event or Censoring 
Outcome 
No baseline tumor assessments 
or post-baseline radiological 
assessments, and patient did 
not die within 105 days of 
randomization 
Date of randomization 
Censored 
No baseline tumor assessments 
or post-baseline radiological 
assessments, and patient died 
within 105 days of 
randomization 
Date of death 
Death 
Death 
Date of death 
Death 
Progression 
Date of first radiological 
assessment indicating progression 
(ie, OR = PD). 
Progression 
New anti-cancer therapy prior 
to PD or death (including 
palliative radiotherapy during 
study treatment) 
Date of last radiological 
assessment prior to the start  of 
the new anticancer therapy 
Censored 
No death or progression 
Date of last radiological 
assessment 
Censored 
PD or death after missing 2 or 
more consecutive radiological 
assessments (PD or death date 
- last radiological assessment 
date +1 ≥ 105 days). 
Date of first missed radiological 
assessment (ie, date of the last 
adequate assessment + 42 days 
[ie, 6 weeks]). 
Progression 
a Includes BIRC assessed radiographic progression only. 
Progression (radiological or 
clinical) or death after missing 
2 or more consecutive 
radiological assessments  
(PD or death date - last 
radiological assessment 
date + 1 ≥ 105 days) 
Date of last RECIST assessment 
Censored 


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OR = overall response; PD = disease progression; PFS = progression-free survival. 
Additionally, PFSRBIRC will be analyzed by not censoring patients receiving palliative 
radiotherapy during study treatment while everything else is identical to PFSBIRC. Table 7 
provides the rules for PFSRBIRC. 
Table 7: 
PFSRBIRC Definitionsa  
Situation 
Date of PFS Event or Censoring 
Outcome 
No baseline tumor assessments 
or post-baseline radiological 
assessments, and patient did 
not die within 105 days of 
randomization 
Date of randomization  
Censored 
No baseline tumor assessments 
or post-baseline radiological 
assessments, and patient died 
within 105 days of 
randomization 
Date of death 
Death 
Death 
Date of death 
Death 
Radiological progression 
Date of first radiological 
assessment indicating progression 
(ie, OR = PD) 
Progression 
New anti-cancer therapy prior 
to PD or death (not including 
palliative radiotherapy during 
study treatment) 
Date of last radiological 
assessment prior to the start of the 
new anticancer therapy 
Censored 
No death or progression 
Date of last radiological 
assessment 
Censored 
PD or death after missing 2 or 
more consecutive radiological 
assessments (PD or death date 
- last radiological assessment 
date + 1 ≥ 105 days) 
Date of last adequate radiological 
assessment showing no PD 
Censored 
a Includes radiographic progression only. 
OR = overall response; PD = progressive disease or disease progression; PFS = progression-free survival. 
 
The following sensitivity analyses will also be performed: 
• The concordance/discordance rate between the PFS outcomes for the BIRC 
assessment and the INV assessment will be summarized. 
• The concordance/discordance rate between the BIRC Best Overall Response and 
the INV Best Overall Response will be summarized. 
• In cases where the BIRC and INV assessment are different, PFS will be re-
calculated using several methods of censoring: 


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− Method 1 (PFSC): INV PFS of patients with at least 1 scan submitted for 
BIRC review.  
 
The rules for PFSC are the same as those described in Table 4  
 
except only patients with at least 1 scan submitted for BIRC review are 
included in the analysis. 
− Method 2 (PFSD): If PFSBIRC was censored but PFSINV had an event, replace 
PFSBIRC with PFSINV.  
 
Table 4 describes the rules for PFSBIRC and PFSINV.  
 
PFSBIRC and PFSINV will be calculated prior to calculating PFSD.   
 
PFSD will be equal to PFSBIRC except in cases where PFSBIRC is censored, but 
PFSINV shows an event. In those cases, PFS4 will be equal to PFSINV. 
− Method 3 (PFSE): If both PFSBIRC and PFSINV had an event, but the INV date 
is earlier than the BIRC date, replace BIRC PFS date with INV PFS date. 
 
Table 4  describes the rules for PFSBIRC and PFSINV.  
 
PFSBIRC and PFSINV will be calculated prior to calculating PFSE. 
 
PFSE will be equal to PFSBIRC except in cases where PFSBIRC and PFSINV both 
indicate an event and the PFSINV event date is earlier than the PFSBIRC event 
date. In those cases, PFSE will be equal to PFSINV. 
5.7. 
Strategies for Pooling Stratification Factors 
This study uses 3 factors to stratify patients for randomization, with a total of 12 stratification 
levels. At the final analysis, levels may have a small number of patients in 1 or more of the 
stratification levels. The following strategy for pooling stratification levels will be used if 1 
or more of the stratification levels contains fewer than 12 patients (Table 8)  
After pooling, each stratum is expected to have at least 1 event at the final analysis.  


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Table 8: 
Pooling of Stratification Factors 
FRα 
Priors 
IC Chemotherapy 
If n < 12 Pool With 
high 
1,2 
PLD 
Next stratum 
high 
1,2 
Pac 
Previous stratum 
high 
1,2 
Topo 
Previous stratum 
high 
3 
PLD 
Next stratum 
high 
3 
Pac 
Previous stratum 
high 
3 
Topo 
Previous stratum 
medium 
1,2 
PLD 
Next stratum 
medium 
1,2 
Pac 
Previous stratum 
medium 
1,2 
Topo 
Previous stratum 
medium 
3 
PLD 
Next stratum 
medium 
3 
Pac 
Previous stratum 
medium 
3 
Topo 
Previous stratum 
FRα = folate receptor alpha; IC = Investigator’s choice; Pac = paclitaxel; PLD = pegylated liposomal 
doxorubicin; Topo = topotecan. 
5.7.1. 
Rationale for pooling approach  
The FRα levels will not be pooled, and the number of prior lines of therapy is an important 
prognostic indicator. Therefore, the approach above is to pool patients by the type of IC 
chemotherapy in consideration prior to randomization. 
5.8. 
Prognostic and Predictive Value of FRα Expression on PFSBIRC 
Prognostic value of FRα expression on PFSBIRC will be analyzed for patients in the IC chemo 
arm.  Hazard ratio (FRα high to FRα medium) and its 95% CI will be reported. 
Predictive value of FRα expression on PFSBIRC will be analyzed for the ITT population using 
a Cox proportional hazard regression model with treatment, FRα expression, and their 
interaction as covariates.  The hazard ratio (IMGN853 to IC chemo) will be reported for  
patients with FRα high expression and FRα medium expression separately.  The interaction 
hazard ratio and its 95% CI will also be reported.  The null hypothesis that the hazard ratio 
(IMGN853 to IC chemo) is the same between patients with FRα high expression and patients 
with FRα medium expression will be tested using the interaction term. 
5.9. 
Other Efficacy-related Summaries 
New anti-cancer therapy data will be summarized for the ITT population by randomized arm 
as follows: 
• Number and percentage of patients receiving new anti-cancer therapy. 
• Type of new anti-cancer therapy. 


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Listings of efficacy-related data for will include the following: 
• All lesion assessments (target lesion, non-target lesion, new lesion). 
• New anti-cancer therapy. 
• BIRC RECIST assessments. 
• Investigator’s RECIST assessments. 
• CA-125 results. 
• Derived parameters for CA-125 response, BOR, PFS, DOR, TTR, and OS. 
• Censoring for time-to-event variables. 
Listings of efficacy-related data for Stage 1 will be presented using the Safety population and 
actual treatment received, as follows: 
• All lesion assessments (target lesion, non-target lesion, new lesion). 
• New anti-cancer therapy. 
• Investigator’s RECIST assessments. 
• CA-125 results. 


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6. 
SAFETY ANALYSES 
The main safety summary tables will use data from the Safety population. Patients will be 
analyzed according to the actual study drug received.  
If the primary efficacy endpoint (PFSBIRC) is only statistically significant in patients with 
FRα high expression but not in the ITT, the following subgroup tables will also be prepared 
for patients with FRα high expression.   
• Exposure 
• Treatment-emergent adverse events (TEAEs) 
• Serious TEAEs 
• Lab shift tables 
• Clinically significant values in liver function tests 
Listings will be provided for patients in the Safety population. The actual study drug received 
will be displayed on the listing. 
 
6.1. 
Exposure 
Summary tables will be provided with the following information. 
Exposure to IMGN853, paclitaxel, topotecan, and PLD will be summarized in tables with 
descriptive statistics for the number of doses received, the number of cycles received, 
duration of dosing (weeks), total cumulative dose ( mg), absolute dose intensity (mg/kg/dose 
for IMGN853, calculated as total cumulative dose [mg])/number of valid drug administration 
records (performed infusions or held infusions)/AIBW (kg); mg/m2/dose for remaining 
investigational products, calculated as total cumulative dose (mg)/number of valid drug 
administration records (performed infusions or held infusions)/BSA (m2), and relative dose 
intensity (percentage of planned, calculated as [absolute dose intensity/6] × 100 for 
IMGN853, [absolute dose intensity/80] × 100 for paclitaxel, [absolute dose intensity/40] × 
100 for PLD, [absolute dose intensity/1.25] × 100 for topotecan 1.25 mg/m2, [absolute dose 
intensity/4] × 100 for topotecan 4 mg/m2). 
The number of infusions with dose decreased, infusions interrupted, and dose delayed will 
also be summarized by study drug. The number of infusions with the rate of infusion 
decreased will also be summarized for the IMGN853 study-drug groups. 
The number of patients who received IMGN853 pivotal lots,  non-pivotal lots, and different  
lot numbers will be summarized. 
A listing will be provided with the information from all study drug administration eCRFs 
over the treatment period.  
For Stage 1, a separate listing will be provided with the information from all study drug 
administration eCRFs.  


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6.2. 
AEs 
AEs will be documented on the AE eCRF and monitored continuously throughout the study 
from the time of informed consent until 30 days after the patient’s last study drug or until the 
event has resolved, stabilized, or returned to baseline. AEs attributed to study procedures, 
including those events that occur prior to the first dose, should also be documented on the AE 
eCRF.  
AE data are available to ImmunoGen from 2 sources, the eCRFs and the serious adverse 
event (SAE) forms. While reconciliation will be performed, the production of data 
summaries and listings will be based on the data collected on the eCRF.  
Pre-treatment AEs are defined as AEs with an onset date prior to the first dose of study drug. 
TEAEs are defined as AEs with an onset date on or after the first dose of study drug, and 
within 30 days of the last dose of study drug or prior to the start of a new anti-cancer 
treatment, whichever occurs first. Medical history conditions that exist before the initiation of 
study drug but worsen in severity during the study will also be recorded on the AE eCRF as 
an AE and will be included as treatment-emergent in the summary tables and listings.  
The adverse events will be coded using MedDRA (Version 18.1 or later), associating 
lower-level terms with PT and SOC by the primary hierarchy. The tables will display the 
counts and percentages of patients who reported at least 1 TEAE in each SOC represented in 
the AE data. Within each SOC, the tables will display the counts and percentages of patients 
reporting at least 1 TEAE as designated by the PT. 
AEs are graded using Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.03. AE summaries may include summaries for all AEs and by the maximum 
CTCAE grade for the item being summarized (ie, SOC or PT). In these cases, the outputs 
will include a row for All Grades as well as rows for the 5 potential CTCAE grades, Grade 1 
(Mild), Grade 2 (Moderate), Grade 3 (Severe), Grade 4 (Life threatening or disabling), or 
Grade 5 (Death). AEs missing a severity grade will not be included in the Grade 1-5 rows of 
the tables. An AE reported by a patient more than once will be represented in the most severe 
category. 
The following AE summary tables will be produced:   
• An overall summary of safety will summarize the numbers of patients with 
TEAEs of each grade and the number of patients who died during the study or 
within 30 days of last dose. 
• All TEAE.s 
• Serious TEAEs. 
• Non-Serious TEAEs (ie, TEAEs excluding SAEs). 
• Grade 3 or higher TEAEs. 
• TEAEs leading to drug withdrawal. This subset includes TEAEs with an action 
taken of drug permanently discontinued. 


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• TEAEs related to study drug. This table will include TEAEs with a drug 
relationship of possibly related, probably related, or definitely related. The table 
will include TEAEs with missing drug relationships. An AE reported by a patient 
more than once will be included in this table if at least 1 of the drug association 
grades is 1 of the grades listed here. 
• Serious, related TEAES. This subset includes all serious TEAEs with a drug 
relationship of possibly related, probably related, or definitely related. The table 
will 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 1 of the drug 
association grades is 1 of the grades listed here. 
• Deaths on study or within 30 days of the last dose. 
The following AE listings will be produced:  
• All pre-treatment AEs will be listed. 
• All AEs, sorted chronologically by patient. This listing includes SOC, PT, onset 
and end dates, and other relevant information. 
• Serious TEAEs, sorted 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, probably related, or definitely related. This listing 
will 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, probably related, or definitely related. 
This listing will include serious TEAEs with missing drug relationships.  
• TEAEs resulting in death. This listing includes TEAEs with a CTCAE grade of 
Grade 5 (death) or TEAEs with an outcome of fatal. 
• All deaths, with an indication of whether the death occurred on study or within 
30 days of the last dose. 
The following groupings of TEAEs will be generated as part of the focused analysis of 
safety: 
• Ocular TEAEs 
− A list of PTs for ocular AEs will be provided and finalized by the Sponsor 
before the final database lock. 
• Peripheral neuropathy TEAES 
− A list of PTs for peripheral neuropathy AEs will be provided and finalized by 
the Sponsor before the final database lock. 
• Pneumonitis  


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For each of the focused safety analysis groups, the following summary tables will be 
produced: 
• TEAEs by SOC, PT, and maximum CTCAE grade. 
• Related TEAEs by SOC, PT, and maximum CTCAE grade. 
• Serious TEAEs by SOC, PT, and maximum CTCAE grade. 
• Related serious TEAEs by SOC, PT, and maximum CTCAE grade. 
Additionally, a table will be produced which contains the following for each of the focused 
safety analysis groups: 
• The number of patients with at least 1 TEAE in each group, presented by 
treatment arm. 
• Time to first onset of each group of TEAEs. 
• Action taken with study drug with respect to each group of TEAEs. 
For the focused safety analysis, the following listings will be produced: 
• Ocular TEAEs. 
• Peripheral neuropathy TEAEs. 
• Pneumonitits TEAE. 
For Stage 1, the following AE listings will be produced: 
• All pre-treatment AEs. 
• All AEs, sorted chronologically within patient. This listing includes SOC, PT, 
onset and end dates, and other relevant information. 
• Serious TEAEs, sorted 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, probably related, or definitely related. The listing 
will 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, probably related, or definitely related. 
This listing will include serious TEAEs with missing drug relationships.  
• TEAEs resulting in death. This listing includes TEAEs with CTCAE Grade 5 
(death) or TEAEs with an outcome of fatal. 
• All deaths. 
 


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6.2.1. 
Fresh Biopsy Patient TEAE 
Summary of adverse events, not necessarily TEAEs, experienced within 7 days of biopsy 
will be generated by SOC, PT and CTCAE grade.  A listing of AEs experienced within 7 
days of biopsy will also be generated. 
6.2.2. 
Infusion-related Reactions 
A summary table of infusion-related reactions, occurring 1 day or within 3 days of any 
infusion  will be generated by SOC, PT,  and CTCAE grade.  A listing of infusion-related 
reactions occurring within 3 days after any infusion will also be generated.  A list of the PTs 
for infusion related reactions will be determined by the Sponsor prior to final database lock. 
6.3. 
Clinical Laboratory Results 
Laboratory test results (including hematology, coagulation, serum chemistry, and urinalysis) 
and abnormal laboratory values will be presented in data listings.  
CTCAE Version 4.03 laboratory grades will also be presented. 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 laboratory grades will be 
provided for laboratory parameters graded according to CTCAE Version 4.03. Grade 3 or 
higher laboratory values will be summarized based on the worst grade observed on study.  
Clinically significant values in liver function tests will be summarized by the following 
categories, using the maximum value while on study drug. The denominator for the 
summaries will be the number of patients who had at least 1 non-missing value during 
treatment. The categories for each test are not mutually exclusive: 
• Aspartate aminotransferase (AST) 
− > 3 × ULN 
− > 5 × ULN 
− > 10 × ULN 
− > 20 × ULN 
• Alanine Aminotransferase (ALT) 
− > 3 × ULN 
− > 5 × ULN 
− > 10 × ULN 
− > 20 × ULN 
• AST or ALT 
− > 3 × ULN 
− > 5 × ULN 


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− > 10 × ULN 
− > 20 × ULN 
• Total bilirubin (TBL) 
− > ULN 
− > 2 × ULN 
• Alkaline phosphatase (ALP) 
− > 1.5 × ULN 
• (AST or ALT) and TBL (concurrent) 
− AST or ALT > 3 × ULN and TBL > 1.5 × ULN 
− AST or ALT > 3 × ULN and TBL > 2 × ULN 
• (AST or ALT) and ALP and TBL (concurrent) 
− AST or ALT > 3 × ULN and ALP < 2 × ULN and TBL > 2 × ULN 
Results from pregnancy tests will be provided in listings.  
6.4. 
Vital Signs 
Vital signs (including temperature, pulse rate, systolic blood pressure, diastolic blood 
pressure, respiratory rate, and weight) will be presented in data listings.  
Summaries of actual values and changes from baseline will be presented by treatment group 
for each assessment time point, beginning with the Cycle 1 Day 1 Completion of Infusion 
time point. 
6.5. 
ECGs 
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 be reported in the listing for that patient with 
QTcF.  
The number and percentage 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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For the purpose of QTc analysis, derived values using QT and RR will be used if QTcF or 
QTcB are not collected on the eCRF:   
𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄= 𝑄𝑄𝑄𝑄
√𝑅𝑅𝑅𝑅
3
 
𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄= 𝑄𝑄𝑄𝑄
√𝑅𝑅𝑅𝑅
 
6.6. 
Concomitant Medications 
All medications and supportive therapy taken within 4 weeks prior to Cycle 1 Day 1 and 
through 30 days after last study treatment must be recorded on the appropriate eCRF. The 
identity of all medications, dosage, route of administration, frequency, duration of 
administration, and indication for use will be recorded in the appropriate sections of the 
eCRF. 
Prior medications are defined as medications with a stop date prior to the first dose of study 
drug.  
Concomitant medications are defined as medications which are taken during the course of 
study treatment and within 30 days of the last dose of study drug, as follows:  
• For Stage 1, medications started after the first dose of study drug and within 
30 days of the last dose of study drug are considered concomitant medications.  
• Medications started before the first dose of study drug, but with a stop date after 
the first dose of study drug and within 30 days of the last dose of study drug will 
be considered concomitant medications.  
• Medications started before the first dose of study drug that are ongoing will be 
considered concomitant medications. 
• Medications started after the first dose of study drug and within 30 days of the last 
dose of study drug or before the start of a new anti-cancer treatment, whichever 
occurs first, are considered concomitant medications.  
• Medications started before the first dose of study drug, but with a stop date after 
the first dose of study drug and within 30 days of the last dose of study drug or 
prior to the start of a new anti-cancer treatment, whichever occurs first, will be 
considered concomitant medications.  
• Medications started before the first dose of study drug that are ongoing will be 
considered concomitant medications. 
Prior and concomitant medications will be coded using the September 2015 or later version 
of World Health Organization drug dictionary (WHO Drug). 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 number and 


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percentage of patients who reported using at least 1 medication in each represented 
pharmacological subgroup. If a patient has more than 1 medication in the subgroup, the 
patient will be counted only once. 
A complete listing of medications will be generated by patient. The listing will indicate 
which medications are prior and which are concomitant. The listing will display entries from 
the concomitant medications form, ordered within patient by start date. The listing will 
display the recorded term from the eCRF and the WHO Drug anatomical main class (ATC 
Level 1 term) and pharmacological subgroup (ATC Level 3 term). 
6.7. 
Concomitant Procedures 
All procedures within 4 weeks of Cycle 1 Day 1 and through 30 days after last study 
treatment must be recorded on the appropriate eCRF.  
Prior procedures are defined as occurring before the first dose of study drug (by procedure 
date).  
Concomitant procedures are defined as procedures with a procedure date on or after the first 
dose of study drug, and within 30 days of the last dose of study drug, as follows:  
• For Stage 1, procedures occurring on or after the first dose of study drug, and 
within 30 days of the last dose of study drug (by procedure date).  
• Procedures are defined as concomitant procedures with a procedure date on or 
after the first dose of study drug, and within 30 days of the last dose of study drug 
or prior to the start of a new anti-cancer treatment, whichever occurs first.  
Prior and concomitant procedures will be coded using MedDRA (Version 18.1 or later), 
associating lower-level terms with PT and SOC by the primary hierarchy. Summary tables 
will be provided for prior and concomitant procedures. The tables will display number and 
percentage of patients who reported at least 1 procedure in each SOC represented in the 
eCRF data. Within each SOC, the tables will display number and percentage of patients 
reporting at least 1 concomitant procedure as designated by PT. 
A complete listing of procedures will be generated. The listing will indicate which 
procedures are prior and which are concomitant. The listing will display entries from the 
concomitant procedures form, ordered within patient by date of procedure. The listing will 
display the recorded term from the eCRF and the SOC and PT.  
6.8. 
Ophthalmic Examinations  
Ophthalmic Examinations are collected at the Screening, End-of-Treatment, and 
30-Day Follow-up Visits. Results of the ophthalmic examinations will be presented in data 
listings.  
A summary table will be provided of the overall exam result (within normal limits, abnormal, 
not clinically significant, and abnormal, clinically significant) by treatment group and visit. 
6.9. 
Ocular Symptom Assessments 
Results of the acular assessments will be presented in data listings.  


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A summary table will be provided of the ocular symptom assessment (within normal limits, 
abnormal, not clinically significant, and abnormal, clinically significant) by treatment group 
and visit. 
6.10. 
Corticosteriod and Lubricating Eye Drop Compliance 
All compliance information collected on the eCRF will be presented in data listings. 
6.11. 
Transfusions 
All transfusions recorded on the eCRF will be presented in data listings. Transfusions will be 
coded using MedDRA Version 18.1 or later.  
6.12. 
Physical Examination 
Physical examination results will be presented in data listings.  
6.13. 
Pulmonary Function Tests   
Pulmonary function test results will be presented in data listings.  
6.14. 
Pulse Oximetry 
Pulse oximetry data were collected only for patients in Stage 1, and will be presented in a 
data listing. 
6.15. 
ECOG PS 
ECOG PS results will be presented in data listings.  
6.16. 
ECHOCARDIOGRAM/MULTIPLE GATED ACQUISITION 
SCANS 
Echocardiogram (ECHO)/multiple gated acquisition (MUGA) scans are taken only for 
patients receiving PLD. All ECHO/MUGA results will be presented in data listings. 
Summaries of actual values and changes from baseline will be presented for the PLD 
treatment group for each assessment time point, beginning with Cycle 4 Day 1.  
 
 
 


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7. 
PRO 
Analyses for PRO, including quality of life and healthcare resource utilization, will be 
covered by a separate, independent analysis plan by the PRO vendor, in collaboration with 
ImmunoGen. 


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8. 
IMMUNOGENICITY 
The ADA analyses, including the impact of immunogenicity on PK, will be covered by a 
separate, independent analysis plan (see Section 10).  
Impact of immunogenicity on safety and efficacy will be explored. A by patient TEAE listing 
for those patients determined seropositive for IMGN853 antibodies will be produced. 
Summary of TEAEs experienced within 1 and 3 days of ADA+ will be generated for those 
patients who sero-convert following the first dose of mirvetuximab soravtansine.  Efficacy 
will be analysed by seroconversion status for patients treated with IMGN853. 


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9. 
BIOMARKERS 
The exploratory biomarker analyses for this study will be covered by a separate, independent 
analysis plan.  


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10. 
PHARMACOKINETICS 
The PK analyses will be covered by a separate, independent analysis plan. The PK analyses 
will be performed using the plasma collected for PK purposes. 


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REFERENCES 
Zucker DM, Restricted mean life with covariates: modification and extenstion of a useful survival 
analysis method, J Am Stat Assoc 93: 702-709, 1998 


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APPENDIX 1:  TEMPLATE SAS® CODE 
This appendix provides template SAS® code (Version 9.3 or higher) that will be used for 
analysis.  
Template code for the ORR, DCR, and GCIG CA-125 response estimates along with the 95% 
CIs: 
proc freq data=AD_RESP; 
by TRTP; 
tables AVAL / binomial alpha=0.05; 
run; 
Template code for the stratified CMH test: 
proc freq data=AD_RESP; 
tables STRATUM*TRTP*AVAL / cmh; 
run; 
Template code for the unstratified chi-squared test: 
proc freq data=AD_RESP; 
tables TRTP*AVAL / chisq; 
run; 
Template code for median time-to-event estimates along with 95% confidence intervals: 
proc lifetest data=AD_TTE; 
time AVAL*CNSR(1); 
strata TRTP; 
run; 
Template code for the stratified log-rank test: 
proc lifetest data=AD_TTE; 
time AVAL*CNSR(1); 
strata STRATUM / group=TRTP; 
run; 
Template code for the unstratified log-rank test: 
proc lifetest data=AD_TTE; 
time AVAL*CNSR(1); 
strata TRTP; 
run; 


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Template code for the stratified Cox proportional hazards model: 
proc phreg data=AD_TTE; 
 
class trtp; 
model AVAL*CNSR(1) = TRTP / risklimits; 
strata STRATUM; 
run; 
Template code for the unstratified Cox proportional hazards model: 
proc phreg data=AD_TTE; 
model AVAL*CNSR(1) = TRTP / risklimits; 
run; 
where: 
AD_RESP is the name of the ADaM dataset used for response analysis 
AD_TTE is the name of the ADaM dataset used for time-to-event analysis 
TRTP is a variable containing the treatment used for analysis.  
AVAL is a variable containing the value for analysis (eg, objective response or time to death)  
CNSR is a variable indicating whether the AVAL is censored (1=censored, 0=non-censored) 
STRATUM is a variable containing all levels of the randomization stratification factors 
 
 


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APPENDIX 2: 
MONTE-CARLO SIMULATION REPORT 
This appendix describes the assumptions, algorithms, and results of Monte-Carlo simulation 
studies evaluating the type I error and power of this study under different scenarios. 
Randomization and Stratification 
The study will randomize 333 patients over a period of 21 months with a randomization ratio 
of 2:1 (222 to the IMGN853 arm and 111 to the IC chemotherapy arm). The randomization 
will be stratified by the following factors: 
• FRα expression level by IHC (≥ 75% tumor staining at ≥ 2+ intensity vs ≥ 50% 
and < 75% tumor staining at > 2+ intensity). 
• Number of prior lines of therapy (1 or 2 vs 3). 
• IC chemotherapy (Pac, PLD or Topo). 
Interim Futility Analysis 
The study will have an interim futility analysis when 80 PFS events have occurred in the ITT 
population. If the hazard ratio (HR, IMGN853 relative to IC chemotherapy) estimate for PFS 
is greater than 1 in both the ITT population and the FRα high expression subgroup, the study 
will be stopped for futility. Otherwise, the study will continue to full enrollment of 
333 patients in the ITT population.  
Primary Efficacy Endpoints 
The final analysis will occur when at least 236 PFS events have occurred in the ITT 
population and 2 primary efficacy endpoints will be analyzed as follows: 
• PFS in the ITT population. 
• PFS in the FRα high-expression subgroup. 
Hypothesis Testing 
The null hypotheses are as follows: 
• H01: the survival function for PFS is the same between the IMGN853 arm and the 
IC chemotherapy arm in the ITT population, and  
• H02: the survival function for PFS is the same between the IMGN853 arm and the 
IC chemotherapy arm in the FRα high-expression subgroup.  
And the alternative hypotheses are as follows: 
• Ha1: the survival function for PFS is different between the IMGN853 arm and the 
IC chemotherapy arm in the ITT population, and  
• Ha2: the survival function for PFS is different between the IMGN853 arm and the 
IC chemotherapy arm in the FRα high-expression subgroup.  
Each endpoint will be tested using a stratified log-rank test (stratified by the stratification 
factors used in randomization).  


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Multiple Testing Procedure 
The Hochberg procedure will be used to control the study-wise type I error. Assume the 
log-rank p-values for the 2 endpoints are P(1) and P(2) (P(1) ≤ P(2)). Let H0(1) be the null 
hypothesis corresponding to P(1) and H0(2) the hypothesis corresponding to P(2). The 
Hochberg will first test P(2) against 0.05.  
• If P(2) ≤ 0.05, then reject both H01 and H02 and claim statistical significance in both 
endpoints.  
• If P(2) > 0.05, then P(1) will be tested against 0.025.  
− If P(1) ≤ 0.025, then reject H0(1) and claim statistical significance for that 
endpoint.  
− If P(1) > 0.025, then no null hypothesis will be rejected.  
This Hochberg procedure is illustrated as follows: 
 
P(2)  ≤ 0.05 
No Null hypothesis 
is rejected
Reject H0(1)
STOP
& 
 reject both H01 & H02 
NO
YES
P(1)  ≤ 0.025
NO
YES
  
 
Simulation Assumptions 
The following assumptions are used in the Monte-Carlo simulation studies. 
• Monthly enrollment rate increases linearly during first 6 months, followed by 
uniform enrollment during months 7-21. 
• PFS follows exponential distribution for the IC chemotherapy arm, 
FRα medium-expression subgroup in the IMGN853 arm, and 
FRα high-expression subgroup in the IMGN853 arm, respectively.  
• Censoring process follows an exponential distribution with 1-year censoring rate 
of 20% for both arms. 


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• Ratio of number of patients between FRα high expression and medium expression 
is 2:1 or 1:1. 
• Median PFS for the IC chemotherapy arm is 3.5 months. 
− Number of trials under each scenario is 10000. 
Simulation Results 
Under different scenarios, the probability of stopping for futility at interim and the 
probability of rejecting H01 (for the ITT population) and H02 (for FRα high-expression 
subgroup) are summarized in Table 9.  If the FRα high/medium ratio is 2:1, there is 39% 
probability of stopping for futility at interim if both null hypotheses H01 and H02 are true and 
the overall type I error is controlled at 4.0%. Using the Hochberg procedure, the study will 
have a 96% and 91% power to detect a median PFS of 6.0 months in the IMGN853 arm 
(HR = 0.583) in the ITT population and FRα high-expression subgroup, respectively. If the 
FRα high/medium ratio is 1:1, there is 37% probability of stopping for futility at interim if 
both null hypotheses H01 and H02 are true and the overall type I error is controlled at 3.6%. 
Using the Hochberg procedure, the study will have a 96% and 81% power to detect a median 
PFS of 6.0 months in the IMGN853 arm (HR = 0.583) in the ITT population and 
FRα high-expression subgroup, respectively. 
Table 9: 
Summary of Monte-Carlo Simulations 
True Median PFS (months) 
FRα High/ 
Medium 
Ratio 
Probability of 
Stopping for 
Futility at 
Interim 
Analysis 
Probability of 
Rejecting 
IC 
Chemo 
IMGN853 
(FRα medium) 
IMGN853 
(FRα high) 
H01 
H02 
3.5 
3.5 
3.5 
2:1 
39% 
2.1% 
1.9% 
3.5 
3.5 
6.0 
2:1 
2.1% 
75% 
85% 
3.5 
4.5 
6.0 
2:1 
1.2% 
89% 
89% 
3.5 
5.0 
6.0 
2:1 
0.8% 
93% 
90% 
3.5 
5.5 
6.0 
2:1 
0.6% 
95% 
90% 
3.5 
6.0 
6.0 
2:1 
0.5% 
96% 
91% 
3.5 
3.5 
3.5 
1:1 
37% 
1.9% 
1.7% 
3.5 
3.5 
6.0 
1:1 
3.4% 
51% 
72% 
3.5 
4.5 
6.0 
1:1 
1.8% 
80% 
77% 
3.5 
5.0 
6.0 
1:1 
1.2% 
88% 
79% 
3.5 
5.5 
6.0 
1:1 
0.8% 
93% 
80% 
3.5 
6.0 
6.0 
1:1 
0.5% 
96% 
81% 
Chemo = chemotherapy; FRα = folate receptor alpha; IC = Investigator’s choice; PFS = progression-free 
survival.