Women's Triple-Negative First-Line Study: A Phase II Trial of Mirvetuximab Soravtansine in Patients With Localized Triple-Negative Breast Cancer (TNBC) With Tumors Predicted Insensitive to Standard Neoadjuvant Chemotherapy (NACT), Including a Lead-In Cohort to Establish Activity in Patients With Metastatic TNBC
Phase: PHASE2
Conditions: Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage IIA Breast Cancer AJCC v8, Anatomic Stage IIB Breast Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IIIA Breast Cancer AJCC v8, Anatomic Stage IIIB Breast Cancer AJCC v8, Anatomic Stage IIIC Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Estrogen Receptor Negative, Folate Receptor Alpha Positive, HER2/Neu Negative, Progesterone Receptor Negative, Prognostic Stage II Breast Cancer AJCC v8, Prognostic Stage IIA Breast Cancer AJCC v8, Prognostic Stage IIB Breast Cancer AJCC v8, Prognostic Stage III Breast Cancer AJCC v8, Prognostic Stage IIIA Breast Cancer AJCC v8, Prognostic Stage IIIB Breast Cancer AJCC v8, Prognostic Stage IIIC Breast Cancer AJCC v8, Prognostic Stage IV Breast Cancer AJCC v8, Triple-Negative Breast Carcinoma
Sponsor: M.D. Anderson Cancer Center

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Women’s Triple-Negative First-Line Study: A Phase II Trial of Mirvetuximab 
Soravtansine is Patients with Localized Triple-Negative Breast Cancer (TNBC) 
with Tumors Predicted Insensitive to Standard Neoadjuvant Chemotherapy 
(NACT) Including a Lead-in Cohort to Establish Activity in Patients with 
Metastatic TNBC. 
 
 
Principal Investigator:           Stacy Moulder, MD, MSCI   
 
Co-principal investigators:   Senthil Damodaran, MD; W. Fraser Symmans, MD 
 
Collaborating Statistician:     
 
Clinical Collaborators: 
 
 
 
 
 
 
 
Department:                 Breast Medical Oncology 
Phone:                          713-792-2817 
Fax:                               713-794-4385 
Research Nurse:         Alyson Clayborn 
 
Protocol Type:             Standard Protocol 
Protocol Phase:           Phase II 
Version Status:            07 

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LIST OF ABBREVIATIONS 
Abbreviation or 
Specialist Term 
Explanation 
ADA 
Anti-drug antibody 
ADC 
Antibody drug conjugate 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
AE 
Adverse event 
AIBW 
Adjusted ideal body weight 
ALT 
Alanine aminotransferase (SGPT) 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
ASCO 
American Society of Clinical  Oncology 
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the time-concentration curve 
BUN 
Blood urea nitrogen 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
CR 
Complete response/remission 
CRC 
Cohort Review Committee 
CRF 
Case report form 
CT 
Computed Tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
DLT 
Dose limiting toxicity 
DM4 
N2’-[4-[(3-carboxypropyl)dithio]-4-methyl-1-oxo-2-sulfopentyl]-N2’-
deacetylmaytansine 
DM4-Me 
Methylated-N2’-[4-[(3-carboxypropyl)dithio]-4-methyl-1-oxo-2-
sulfopentyl]-N2’-deacetylmaytansine 
DOR 
Duration of response 
DTR 
Deep tendon reflex 
EC 
Endometrial Cancer 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EOC 
Epithelial ovarian cancer 

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Abbreviation or 
Specialist Term 
Explanation 
FRα 
Folate receptor α 
GCIG 
Gynecologic cancer intergroup  
GCP 
Good clinical practice 
GI 
Gastrointestinal 
GOG 
Gynecologic oncology group 
HFS 
Hand-foot syndrome 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest non-severely toxic dose 
IBW 
Ideal body weight 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
IEC 
Independent ethics committee 
IHC 
Immunohistochemistry 
IMGN 
ImmunoGen 
IMGN853 
Mirvetuximab soravtansine 
IND 
Investigational new drug  
INR 
International normalized ratio 
IRB 
Institutional review board 
IV 
Intravenous 
LBW 
Lean body weight 
LDH 
Lactic acid dehydrogenase 
LFT 
Liver function test 
Mab 
Monoclonal antibody 
MAD 
Maximum administered dose 
MedDRA 
Medical dictionary for regulatory activities 
MRI 
Magnetic resonance imaging 
MRSD 
Maximum recommended starting dose 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 

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Abbreviation or 
Specialist Term 
Explanation 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PET 
Positron emission testing 
PFS 
Progression-free survival 
PFT 
Pulmonary function tests 
PGP 
p-glycoprotein 
PK 
Pharmacokinetics 
PLD 
Pegylated liposomal doxorubicin 
PO 
Per orem (by mouth) 
PR 
Partial response/remission 
PRES 
Posterior reversible encephalopathy syndrome 
PS 
Performance status 
PT 
Prothrombin time 
RBC 
Red blood cell (count) 
RNA 
Ribonucleic acid 
RP2D 
Recommended phase 2 dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
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 
STD 
Severely toxic dose 
SUSAR 
Suspected unexpected serious adverse reaction 
t1/2 
Half-life 
Tmax 
Maximum time 
TBW 
Total body weight 
TTP 
Time to progression 
ULN 
Upper limit of normal 

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Abbreviation or 
Specialist Term 
Explanation 
UPC 
Urine protein creatinine ratio 
US 
United States 
VHL 
Von Hippel Lindau 
VSS 
Volume of distribution at steady state 
WBC 
White blood cell (count) 
WCBP 
Woman of child bearing potential 
WHO 
World Health Organization 
WHO-DD 
World Health Organization –Drug Dictionary 
 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................2 
TABLE OF CONTENTS .................................................................................................................6 
1. 
INTRODUCTION ......................................................................................................14 
1.1. 
Target Background .....................................................................................................14 
1.2. 
IMGN853 ....................................................................................................................14 
1.3. 
Triple Negative Breast Cancer (TNBC) .....................................................................16 
1.3.1. 
Neoadjuvant Treatment of TNBC ..............................................................................16 
1.3.2. 
Folate receptor  expression in TNBC .......................................................................17 
1.4. 
Non-Clinical Studies of IMGN853 .............................................................................17 
1.4.1. 
Pharmacology .............................................................................................................17 
1.4.2. 
Pharmacokinetics ........................................................................................................18 
1.4.3. 
Toxicology ..................................................................................................................19 
1.5. 
Clinical Studies of IMGN853 .....................................................................................19 
1.5.1. 
First-in-Human Phase 1 Study: Study 0401 ...............................................................19 
1.6. 
Rationale for the starting dose ....................................................................................20 
1.6.1. 
IMGN853 ....................................................................................................................20 
1.7. 
Rationale for the Study Plan .......................................................................................20 
2. 
TRIAL OBJECTIVES AND ENDPOINTS ...............................................................22 
2.1. 
Primary Objectives .....................................................................................................22 
2.2. 
Primary Endpoints ......................................................................................................22 
2.3. 
Secondary Objectives .................................................................................................22 
2.4. 
Secondary Endpoints ..................................................................................................22 
2.5. 
Exploratory Objectives (Cohort B only).....................................................................23 
2.6. 
Exploratory Endpoints ................................................................................................23 
3. 
STUDY POPULATION .............................................................................................24 
3.1. 
Criteria for Selection of Patient Population ................................................................24 
3.1.1. 
Diagnosis, allowable prior therapy and disease measurability: ..................................24 
3.1.2. 
Inclusion Criteria ........................................................................................................24 
3.1.2.1. 
Inclusion Criteria for Cohort A: .................................................................................24 
3.1.2.2        Inclusion Criteria for Cohort B:……………………………………………………. 25 
3.1.3. 
Exclusion Criteria .....................................................................................................277 

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3.1.3.1. 
Exclusion Criteria for Cohort A : .............................................................................277 
3.1.3.2        Exclusion Criteria for Cohort B:…………………………………………………….29 
4. 
INVESTIGATIONAL PLAN .....................................................................................31 
4.1. 
Study Design ...............................................................................................................31 
4.1.1. 
Overview and Schema ................................................................................................31 
4.1.1.1. 
Dose ............................................................................................................................31 
4.1.2. 
Definition: Toxicity Requiring Dose Reduction .........................................................32 
5.                Study Treatment……………………………………………………………………..31 
5.1.             Description of Study Treatment……………………………………………………..31 
5.2.             IMGN853 Packaging………………………………………………………………..31 
5.3.            Storage, Handling and Compatibility………………………………………………..31 
5.4        Study Treatment Compliance ...........................................................................................35 
5.5 
Assignment of Patient Number ...................................................................................35 
5.5.1 
Enrolled Patient Definition .........................................................................................35 
5.6.             Blinding……………………………………………………………………………..32 
5.7.            Study Treatment Administration…………………………………………………….32 
5.8.            Drug Preparation and Administration………………………………………………..33 
5.8.1.         Premedication for Study Treatment………………………………………………….33 
5.8.2.         Preparation and Administration of IMGN853……………………………………….33 
5.8.2.1.      Calculation for Adjusted ideal Body Weight (AIBW)………………………………33 
5.8.2.2.      Preparation…………………………………………………………………………...34 
5.8.2.3.      Administration……………………………………………………………………….34 
5.9 
Monitoring and Management of Adverse Events .......................................................38 
5.9.1.         Potential Infusion-related Reactions ............................................................................34 
5.9.2.         Monitoring and Management of Treatment-emergent Ocular Disorders……………36 
5.9.2.1.      Monitoring - Potential Ocular Disorders…………………………………………….36 
5.9.2.2.      Management Guidelines for Ocular Disorders………………………………………38 
5.9.3.         Monitoring of Non-Infectious Pneumonitis following the Administration of Study 
Treatment………………………………………………………………………………………...39 
5.9.4.        Monitoring and Management of Diarrhea Following the Administration of Study 
Treatment………………………………………………………………………………………..40 

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5.9.5.       Monitoring and Management of Nausea and Vomiting Following the Administration of 
Study Treatment………………………………………………………………………………….40 
5.9.5.1.    Management of Electrolyte Imbalance………………………………………………..41 
5.10.           Treatment Guidelines……………………………………………………………….41 
5.10.1.        Re-Treatment Criteria……………………………………………………………….41 
5.10.1.1.     To Begin a New Cycle of Treatment or to Continue Treatment within a Cycle…....41 
5.10.2.        Follow-up for AEs Leading to Discontinuation……………………………………..42 
5.10.3.        Criteria for Re-Initiation of Study Treatment Following Occurrence of a Toxicity 
Requiring Dose Modification……………………………………………………………………42 
5.10.4.        Dose Modification Guidelines………………………………………………………43 
5.10.4.1.     IMGN853 Dose Reduction Following a Toxicity Requiring Dose Modification…..43 
5.10.5.        Discontinuation of Study Treatment Due to Adverse Events……………………….43 
5.11.           Removal of Patient from Study or from Study Drug Administration……………….44 
5.11.1.       Replacement of Patients who are withdrawn Prior to the End of Cycle 1……….…..44 
5.12.         Period of Observation……………………………………………………………..….44 
5.13.         Concomitant Medications and Procedures……………………………………………45 
5.13.1.      Lubricating Artificial Tears…………………………………………………………..45 
5.13.2.      Antiemetic and Antidiarrheal Medications…………………………………………...45 
5.13.3.      Folate-Containing Vitamins…………………………………………………………..45 
5.13.4.      Antineoplastic Therapy……………………………………………………………….45 
5.13.5.      Hematopoietic Growth Factors……………………………………………………….45 
5.13.6.      Other Concomitant Medications……………………………………………………...45 
5.13.7.      Medication Metabolized Through Cytochrome P450 (CYP3A)……………………..46 
5.14.         Overdose and Medication Error………………………………………………………46 
6. 
TRANSLATIONAL RESEARCH STUDIES (COHORT B ONLY) ........................50 
6.1. 
Correlation between FRα Expression and IMGN853 anti-tumor activity ..................51 
6.1.1. 
Evaluation of FRα Expression in Tumor Tissue ........................................................51 
6.2. 
Exploratory Biomarker Studies (Cohort B Only) .......................................................52 
7. 
STUDY PROCEDURES ............................................................................................53 
7.1. 
Informed Consent .......................................................................................................53 
7.2. 
Inclusion and Exclusion Criteria ................................................................................53 
7.3. 
Confirmation of Disease Diagnosis ............................................................................53 

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7.4. 
Demographic/Medical History ...................................................................................53 
7.5. 
Physical Examination, Weight and Height .................................................................53 
7.6. 
Vital Signs ..................................................................................................................54 
7.7. 
Laboratory Assessments .............................................................................................54 
7.7.1. 
Clinical Laboratory Panels .........................................................................................55 
7.8. 
Pregnancy Screen and Prevention ..............................................................................49 
7.9. 
Eastern Cooperative Oncology Group Performance Status ........................................50 
7.10. 
Radiologic Imaging ....................................................................................................50 
7.11. 
Tumor Response Assessment .....................................................................................50 
7.11.1. 
RECIST.......................................................................................................................50 
7.12. 
Eligibility Based on FRα Expression ..........................................................................50 
7.13. 
Recording Adverse Events and Serious Adverse Events ...........................................58 
7.13.1. 
Definition of Adverse Events .....................................................................................51 
7.13.1.1. 
Adverse Event (AE) ....................................................................................................58 
7.13.1.2. 
Serious Adverse Event (SAE) ....................................................................................59 
7.13.1.3. 
Adverse Events of Special Interest (AESI) ................................................................61 
7.13.2. 
Classification of Adverse Events ................................................................................61 
7.14. 
Adverse Events ...........................................................................................................62 
7.14.1. 
Reporting Serious Adverse Events .............................................................................62 
7.14.2. 
Reporting Adverse Events of Special Interest ............................................................64 
7.14.3. 
Reporting a Pregnancy ................................................................................................64 
8. 
STUDY ACTIVITIES ................................................................................................65 
8.1. 
Screening Visit ............................................................................................................65 
8.1.1. 
Standard of Care Assessments ....................................................................................65 
8.2. 
End of Treatment Visit ...............................................................................................65 
8.3. 
Follow-up Assessments ..............................................................................................65 
8.3.1. 
Safety Follow-up ........................................................................................................65 
8.3.2. 
Response Follow-up ...................................................................................................65 
9. 
STATISTICAL METHODS .......................................................................................58 
9.1. 
Quality control and assurance .....................................................................................60 
10. 
ADMINISTRATIVE CONSIDERATIONS, STUDY MONITORING AND 
DATA MANAGEMENT ...........................................................................................69 

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10.1. 
Investigators and Study Administrative Structure ......................................................69 
10.2. 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval .....................................................................................................................69 
10.3. 
Ethical Conduct of the Study ......................................................................................69 
10.4. 
Patient Information and Consent ................................................................................69 
10.5. 
Patient Confidentiality ................................................................................................70 
10.6. 
Study Monitoring ........................................................................................................70 
10.7. 
Grantor Case Report Forms and Study Reports .........................................................70 
10.8. 
Critical Documents .....................................................................................................71 
10.9. 
Protocol Violations/Deviations ...................................................................................71 
10.10. 
End of Study ...............................................................................................................72 
10.11. 
Study termination ........................................................................................................72 
10.11.1. 
Study Termination ......................................................................................................72 
10.11.2. 
Site Termination .........................................................................................................72 
10.12. 
Access to Source Documentation ...............................................................................72 
10.13. 
Data Generation and Analysis ....................................................................................72 
10.14. 
Retention of Data ........................................................................................................73 
10.15. 
Financial Disclosure ...................................................................................................73 
10.16. 
Publication and Disclosure Policy ..............................................................................73 
SUPPORTER MAY PUBLISH THE RESULTS OF OR SUBMIT ABSTRACTS OF 
THE STUDIES AFTER REVIEW BY NCCN AND GRANTOR. SHOULD 
THE RESULTS OF A STUDY OR STUDIES BE DERIVED FROM A 
MULTICENTER STUDY, NEITHER NCCN, NOR ANY MEMBER 
INSTITUTION(S) SHALL PUBLISH ITS OWN INDIVIDUAL RESULTS, 
BUT RATHER, ALL SHALL PARTICIPATE IN A JOINT, 
MULTICENTER PUBLICATION OF THE STUDY RESULTS. NCCN 
SHALL CONTRACTUALLY REQUIRE EACH MEMBER 
INSTITUTION TO AGREE TO (A) PROVIDE GRANTOR A COPY OF 
ANY MANUSCRIPT OR ABSTRACT RELATING TO A STUDY, (B) 
NOT PUBLISH ANY MANUSCRIPT OR ABSTRACT RELATING TO A 
STUDY UNTIL GRANTOR HAS HAD AN OPPORTUNITY TO 
REVIEW IT, (C), UPON THE WRITTEN REQUEST OF GRANTOR, 
DELAY THE PUBLICATION AND DISCLOSURE OF SUCH 
MANUSCRIPT OR ABSTRACT TO ANY THIRD PARTY FOR UP TO 
AN ADDITIONAL SIXTY (60) DAYS SO THAT GRANTOR MAY SEEK 
PATENT PROTECTION OF INTELLECTUAL PROPERTY RIGHTS, (D) 
DELETE FROM ANY MANUSCRIPT OR ABSTRACT ANY 
INFORMATION THAT GRANTOR REQUESTS AND BELIEVES IS ITS 

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CONFIDENTIAL INFORMATION, (E) ACKNOWLEDGE GRANTOR 
AS THE SUPPLIER OF THE STUDY DRUG AND (F) NOT ISSUE A 
PRESS RELEASE THAT REFERENCES THE STUDIES OR RESULTS 
WITH GRANTOR’S NAME OR TRADEMARKS WITHOUT THE PRIOR 
WRITTEN CONSENT OF GRANTOR.  NCCN SHALL 
CONTRACTUALLY REQUIRE EACH MEMBER INSTITUTION TO 
PROVIDE A FINAL REPORT OR MANUSCRIPT FOR PUBLICATION 
FOR REVIEW WITHIN NINE (9) MONTHS OF THE CONCLUSION OF 
THE APPLICABLE STUDY .....................................................................................74 
11. 
LIST OF  REFERENCES: ..........................................................................................75 
APPENDIX A. SCHEDULE OF CLINICAL ASSESSMENTS – (IMGN853 ) .......................77 
APPENDIX B.   ECOG PERFORMANCE SCALE…………………………………………….78 
APPENDIX C.   RESPONSE DEFINITION (RECIST 1.1) .........................................................84 
APPENDIX D.   CTCAE VER.4.03 GRADING FOR SELECTED AE'S……………………...80 
APPENDIX E.    CYP3A SUBSTRATES FOR IMGN853……………………………………..81 
 

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LIST OF TABLES 
 
Table 1: 
Planned Dose Levels ...................................................................................................32 
Table 2: 
DLT Definitions ..........................................................................................................33 
Table 3:      Management Guidelines for Potential Infusion-Related Reactions………..38 
Table 4: 
Schedule for Ophthalmic Assessments……………………………………40 
Table 5: 
Management of Ocular Disorders ...............................................................................41 
Table 6: 
Management of Non-Infectious Pneumonitis .............................................................42 
Table 7: 
Management of Nausea and Vomiting .......................................................................44 
Table 8: 
IMGN853 Dose Modification Guidelines ..................................................................46 
Table 9: 
Vital Sign Measurements ............................................................................................54 
Table 10: Clinical Laboratory Tests ...........................................................................................55 
Table 11: Adverse Event Recording Guidlines ..........................................................................58 
Table 12:    Adverse Event Severity……………………………………………………………..60 
Table 12: Adverse Event Causal Relatedness .............................................................................60 
Table 13:    Probability of protocol Success……………………………………………………..65 
 
 
 
List of Figures 
Figure 1: 
IMGN853 Structure …………………………………………………………. 15 
Figure 2:         Molecular Results Driven Decision Diagram…………………………………....16 
Figure 3:         ATREMIS Study Design…………………………………………………….…..17 
Figure 4: 
Study Design Schema ………………………………………………………….....31 
 
 
 
 
 
 

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1. 
INTRODUCTION 
1.1. 
Target Background 
Folate receptor α (FRα) is a glycosyl phosphatidylinositol-anchored cell surface protein encoded 
by the FOLR1A gene. FRα binds and internalizes folate, which is an essential co-factor for one 
carbon transfer reactions that are required for DNA and RNA synthesis, cell growth and 
proliferation. Marked upregulation 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 (FRβ), reduced folate carrier and proton-coupled folate transporter for 
folate uptake (Weitman 1992, Markman 2000, Mantovani 1994, Elnakat 2004, Kelemen 2006, 
and Investigator’s Brochure).  
TNBC accounts for 15-20% of all breast cancers and has been associated with younger age at 
diagnosis as well as a higher incidence in minority populations. Treatment of TNBC relies 
exclusively on chemotherapy and this approach is associated with limitations including poor 
bioavailability and off target effects in healthy cells. Nanotechnology has resulted in more 
precise drug delivery systems and several therapeutic nanocarriers have been FDA approved for 
the delivery of potent cytotoxic agents in a number of tumor types, including breast cancer. 
Targeting tumors with nanotechnology requires both the rational design of nanocarriers as well 
as an understanding of underlying tumor biology, including surface antigen expression. Clinical 
and preclinical data have suggested evidence of activity for using nanocarriers to target folate 
receptors for treatment of TNBC. FR is a membrane bound protein with a high affinity for 
binding and transporting folate into cells. Not surprisingly, overexpression of FR confers a 
growth advantage by increasing uptake of folate and activating alternate cell signaling pathways. 
FR expression is also notably higher in epithelial malignancies compared to normal cells, 
including ovarian, lung and breast cancers. FR expression is common in TNBC with 67% of 
these tumors demonstrating tumor cell membrane staining and nearly 40% expressing high levels 
of FR. [9]  
Importantly, nanoparticle delivery of potent maytansinoids using antibody conjugates has also 
demonstrated feasibility with diminished toxicity in breast cancers that express high levels of 
surface HER2. In HER2+ early stage breast cancer, the ADAPT trial reported a pCR rate of 
~29% for single agent T-DM1 (Gluz, et al. J Clin Oncol 33, 2015; suppl; abstr 506) and pCR 
rates of 57% have also been reported when combined with docetaxel, though toxicity rates were 
much higher with doublet therapy (Martin, et al. SABCS, 2013). It is anticipated that 
mirvetuximab soravtansine will have similar rates of excellent pathologic response given the 
similar maytansinoid conjugate and high expression of surface FR in nearly 40% of TNBCs. 
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 antibody drug conjugate (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 

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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).  
 
Figure 1:     IMGN853 Structure 
 
DM4 is ~2% by weight relative to monoclonal antibody. 
Due to the nature of the conjugation process, the number of DM4 molecules attached to the 
monoclonal antibody ranges from 1 to 7 molecules per antibody, with an average of 3 or 4 DM4 
molecules per antibody. Conjugation of the maytansinoid to the tumor-targeting antibody ensures 
that the cytotoxic component remains inactive in the circulation. Release of the cytotoxic 
payload requires binding, internalization, and degradation of the antibody. The released payload 
then kills the cell by inducing G2-M arrest and cell death. Cellular processing of maytansinoid 
conjugates can also generate lipophilic catabolites that cross cell membranes and kill neighboring 
cells (Erickson 2006).  
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 FRα. Cytotoxic 
effects of IMGN853 in vitro is correlated to level of cell-surface expression of FRα. IMGN853 
additionally demonstrates significant activity against FRα -positive xenografts, with partial and 
complete remissions observed in ovarian models (Ab 2015). Together with the selective 
upregulation of FRα in solid tumors, these results provide the rationale for exploring the clinical 
utility of IMGN853. 
 
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1.3. 
Triple Negative Breast Cancer (TNBC) 
The study will enroll patients with advanced/metastatic TNBC and chemotherapy insensitive 
non-metastatic TNBC undergoing neoadjuvant therapy while enrolled in the ARTEMIS trial 
(MDA protocol 2014-0185).  
1.3.1. 
Neoadjuvant Treatment of TNBC 
Patients with localized TNBC are preferably treated with systemic chemotherapy (usually 
sequential anthracyclinetaxane) in the neoadjuvant setting (NACT). Pathologic response to 
NACT can be determined by measuring the amount of residual cancer remaining in the breast 
and draining lymph nodes and is such a powerful indicator of prognosis that the Food and Drug 
Administration (FDA) has recognized significant improvement in complete response to 
neoadjuvant therapy as a pathway to drug approval. Investigators at MD Anderson have 
developed and validated a scoring system known as the Residual Cancer Burden (RCB) to 
quantify the extent of disease remaining after NACT.[1] Approximately 50% of TNBC patients 
treated with standard NACT will have either pathologic compete response (pCR/RCB-0) or 
minimal residual disease (RCB-I) at the time of surgical resection and those patients have 
identical and exceptionally good long-term prognosis (less than 10% risk of developing distant 
metastatic disease within 5 years). Unfortunately, those with more extensive disease (RCB-II or 
RCB-III) have a much worse prognosis, with 50%-80% of patients developing distant metastatic 
disease within 3 years of initial diagnosis.[2] Clinical trials of NACT in breast cancer have also 
demonstrated that patients without response to their first chemotherapeutic regimen have very 
low chance (5%) of achieving pCR after their second neoadjuvant course of chemotherapy.[3] 
However, this has not been the case with targeted regimens such as trastuzumab in HER2+ 
tumors, suggesting that intrinsic resistance to chemotherapy can be overcome with appropriate 
targeted therapy.[4] Though several targeted agents have been tested for treatment in TNBC, so 
far none have been successful. The underlying causes of this failure are commonly attributed to 
the molecular heterogeneity of tumors classified within the ‘catch all’ category of TNBC as well 
as the dilution effects of chemotherapy sensitive disease. Recent advances in molecular 
characterization have identified subgroups of TNBC with distinct molecular features that, if 
appropriately selected, may be more responsive to targeted therapy, leading to rapid 
improvement of outcomes in 
this high-risk breast cancer 
population. [5-9]  
Our platform consists of a 
clinical trial to identify and 
characterize chemotherapy 
insensitive TNBC 
(ARTEMIS: A Robust 
TNBC Evaluation 
FraMework to Improve 
Survival.  (PI: Moulder, 
Figure 2) as well as a diverse 
portfolio of phase II therapeutic trials to treat chemoinsensitive TNBC. In the ARTEMIS trial, 
Figure 2: M.D. Anderson Neoadjuvant Research Platform for TNBC 

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treatment naïve patients (n=360) with newly diagnosed, localized TNBC undergo a pretreatment 
biopsy and then immediately start their initial phase of anthracycline-based chemotherapy. As 
such, the results of the molecular characterization are used in combination with response 
assessment after initial chemotherapy (clinical exam/diagnostic imaging) to identify 
chemotherapy insensitive disease and inform the second phase of neoadjuvant therapy based 
upon the patient’s tumor characteristics, thus using a ‘second hit’ strategy in the middle of       
neoadjuvant chemotherapy to 
overcome drug resistance. 
Patients enrolled onto 
ARTEMIS will use imaging 
assessment of response to 
predict chemosensitivity. All 
patients are treated the same 
(Figure 3). 
  
1.3.2. 
Folate receptor 
 expression in 
TNBC 
Moderate to high 
expression of folate receptor alpha (FR) has been associated with a worse prognosis in women 
with breast cancer independent of tumor size, nodal status or receptor status. Though an 
independent prognostic factor, FR expression most often occurs in TNBC with 67% of these 
tumors demonstrating tumor cell membrane staining and nearly 40% expressing high levels of 
FR (3+ in greater than 50% of cells).[9] 
Preclinical data also suggest that using nanocarriers to target FR for the treatment of TNBC is 
also feasible. For example, vintafolide, a small molecule drug conjugate consisting of folate 
linked to a potent vinca alkaloid demonstrated 80% complete response rates in mice bearing 
MDA-MB-231 xenografts (SABCS, 2013).  Also, folic acid conjugation of micellar 
nanoparticles were able to successfully deliver the fatty acid synthase inhibitor orlistat which 
resulted in improved intracellular drug delivery and cytotoxicity compared to free orlistat in 
TNBC cell lines. Our group has also led vaccine trials targeting folate receptors as adjuvant 
therapy for patients with high risk breast cancer, many of who had residual disease after NACT. 
 
1.4. 
Non-Clinical Studies of IMGN853 
1.4.1. 
Pharmacology 
Results of nonclinical pharmacology studies demonstrate the following: 
Figure 3: ARTEMIS uses imaging assessment of response to predict chemosensitivity. 
Notably, molecular profiling using IHC is an integral biomarker in the study design as it is 
used to select a therapeutic trial from the BMO research portfolio. 

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 FRα (gene name FOLR1) has limited normal tissue expression and marked expression in 
epithelial tumors, particularly serous and endometrioid ovarian cancers and serous 
endometrial cancers, as assessed by IHC (Investigator’s 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 and a second catabolite, S-
methyl-DM4, then 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).   
 IMGN853 shows significant in vivo efficacy against ovarian (IGROV-1, OVCAR-3 and OV-
90 models) and NSCLC (NCI-H2110 model) tumor xenografts.  
 Combination IMGN853 + BEV is more efficacious than either agent administered as 
a monotherapy in ovarian (OV90 and IGROV-1) tumor xenografts as well as in an 
ovarian cancer patient derived xenograft model (ST088).  In the patient derived 
xenograft model, the IMGN853 + BEV combination is more efficacious than 
combination therapy consisting of paclitaxel + BEV. 
 Combination IMGN853 + carboplatin is more efficacious than either agent 
administered as a monotherapy in the OV90 ovarian tumor xenograft 
model.  Combination IMGN853 + carboplatin is more efficacious than carboplatin + 
paclitaxel in the model.  
 Combination IMGN853 + PLD is more efficacious than either agent administered as 
a monotherapy in the ST088 ovarian cancer patient derived xenograft model. 
Pharmacology studies are further detailed in the IMGN853 Investigator’s Brochure. 
 
1.4.2. 
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 

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with free DM4 was conducted in monkey. PK studies demonstrated the stability of IMGN853 in 
circulation, showed clearance via a distribution phase lasting about 24 hours followed by a 
slower terminal elimination phase after intravenous administration, and suggested linear PK.  
These studies are further detailed in the IMGN853 Investigator’s Brochure.  
1.4.3. 
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-in-
human (FIH) trial 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 IMGN853 Investigator’s Brochure. 
 
1.5. 
Clinical Studies of IMGN853 
1.5.1. 
First-in-Human Phase 1 Study: Study 0401 
Study 0401 is a Phase 1, FIH, study designed to establish the maximum tolerated dose (MTD) 
and determine the recommended Phase 2 dose (RP2D) of IMGN853 when administered 
intravenously as a single agent in adult patients with FRα-positive solid tumors who have 
relapsed or are refractory to standard therapies.  The study is comprised of two stages, dose 
escalation and dose expansion, and two dosing schedules, Schedule A (IMGN853 on Day 1 
every 21 days) and Schedule B (IMGN853 on Days 1, 8, and 15, every 28 days).  
The primary aim of the dose-escalation phase is to evaluate the safety and tolerability of 
IMGN853, to identify the MTD, and to characterize the PK profile of IMGN853 for each of the 
two dosing schedules. NCI CTCAE version 4.03 is used to grade the severity of treatment-
emergent adverse events. Dose escalation is complete for both schedules.  
For Schedule B, the starting dose of IMGN853 was 1.1 mg/kg, which was 1/3 the 3.3 mg/kg 
dose level, which was deemed clinically safe in nine patients on a Q3W schedule.  IMGN853 
was administered on Days 1, 8, and 15, with cycles repeating every 28 days. All doses were 
calculated according to adjusted ideal body weight (AIBW).  Patients were enrolled in cohorts of 
3 to 6 patients. The starting dose of IMGN853 for Schedule B was 1.1 mg/kg, which is 1/3 of the 
3.3 mg/kg dose level, a dose level which was well tolerated in the nine patients dosed on the 
Q3W schedule. Twenty-five patients were enrolled to the following dose levels: 1.1, 1.8, 2.0 and 
2.5 mg/kg (AIBW). The MTD was determined to be 2.0 mg/kg (AIBW).  The cohort review 
committee (CRC) convened to review safety, PK and efficacy data from the dose escalation 
cohorts, as well as available data from patients dosed on Schedule A.  These findings were 
presented at the ASCO annual meeting (Borghaei, 2015). 
The modified weekly schedule did not provide any apparent safety or efficacy advantage. Based 
on safety and overall response data collected through May 2015, the CRC determined that all 

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new patients will receive IMGN853 treatment according to Schedule A (Q3W) only. Patients 
currently enrolling in the trial are receiving IMGN853 at the MTD of 6 mg/kg once every three 
weeks. Of note, the safety data available to date indicate that the MTD is equal to the RP2D. 
As of January 31, 2016, 176 patients have been dosed. At least one treatment-emergent adverse 
event (TEAE) was reported by 171 patients (97%).  Treatment-emergent adverse events of  
Grade 1 or 2 were most common (100 patients, 57%), 58 patients (33%) reported Grade 3 
TEAEs, eight patients (5%) reported Grade 4 and five patients (3%) experienced a Grade 5 
TEAE.  
The most common TEAEs, reported in ≥ 20% of patients included diarrhea (75 patients, 43%); 
nausea (68 patients, 39%); fatigue (65 patients, 37%); vision blurred (49 patients, 28%); 
headache (44 patients, 25%); vomiting (43 patients, 24%); neuropathy peripheral (42 patients, 
24%); aspartate aminotransferase (AST) increased (40 patients, 23%); and abdominal pain (38 
patients, 22%). Please refer to the Investigators’ Brochure for detailed safety information. 
1.6. 
Rationale for the starting dose  
1.6.1. 
IMGN853 
Mirvetuximab soravtansine has demonstrated activity (objective response rate of 53%) as a 
single agent in heavily pretreated, FR expressing tumors such as epithelial ovarian carcinoma 
(Borghaei, et al. J Clin Oncol 33, 2015-suppl; abstr 5558) with acceptable toxicities of diarrhea, 
fatigue, punctate keratitis, blurred vision and nausea.  The maximum tolerated dose (MTD) of 6 
mg/kg IV has been established for a q 3 week schedule. No patients with TNBC were enrolled on 
this initial phase I trial, but it is anticipated that mirvetuximab soravtansine will have similar 
efficacy in metastatic TNBC and may overcome chemotherapy insensitive disease in the 
neoadjuvant setting in select TNBCs that express high levels of FR. 
1.7. 
Rationale for the Study Plan 
Given the challenges of neoadjuvant trials for drug development in TNBC, the multi-disciplinary 
program at MD Anderson has designed an innovative drug development strategy that identifies 
and molecularly characterizes chemotherapy insensitive TNBC and determines the effect of a 
subtype-specific targeted agent (either alone or in combination with chemotherapy) to induce 
excellent pathologic response (pCR/RCB-0 or I). This strategy uses a minimal number of 
patients (n=37) to give a go/no go signal for further development of a targeted agent in the 
neoadjuvant setting and provides the preliminary data needed to inform the design of larger, 
randomized trials. Because chemoinsensitive disease is associated with such a dismal prognosis 
in TNBC, exploring novel agents that show preliminary evidence of activity in the metastatic 
setting is a viable strategy as potentially curative chemotherapy is not compromised in this high 
risk patient population. Taken together, the activity of mirvetuximab soravtansine in advanced, 
heavily pretreated ovarian cancer and the common expression of high levels of FR in TNBCs 
support the rationale to determine the activity of mirvetuximab soravtansine for the neoadjuvant 
treatment of high risk, chemotherapy insensitive TNBC. As such, we propose using a lead-in 
cohort of 20 patients with metastatic TNBC who have received no more than 2 prior therapies for 
metastatic disease to determine the response rate of mirvetuximab soravtansine in TNBC. If 2 

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patients develop response to therapy, the neoadjuvant portion of the trial will be activated to 
determine the pathologic response rate in chemotherapy insensitive, localized TNBC. 

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2. 
TRIAL OBJECTIVES AND ENDPOINTS 
2.1. 
Primary Objectives  
 Determine if mirvetuximab soravtansine as a single agent is likely to induce response 
in at least 20% of patients with metastatic FR+ TNBC.  
 Determine if mirvetuximab soravtansine, as a single agent, in the neoadjuvant setting 
will improve rates of excellent pathologic response (pCR/RCB-0 or RCB-I) from 5% 
to 20% in patients with high risk, chemotherapy insensitive, FR+ TNBC. 
2.2. 
Primary Endpoints  
 Response rate as measured by RECIST 
 Pathologic response as measured by RCB after completion of neoadjuvant therapy 
2.3. 
Secondary Objectives 
 Determine the radiographic response rate as measured by ultrasound and/or MRI 
(partial response + complete clinical response) for mirvetuximab soravtansine in 
chemotherapy insensitive, FR+ localized TNBC or using RECIST criteria in 
patients with FR+ advanced TNBC. 
 Determine toxicity of 4 cycles of mirvetuximab soravtansine given in the neoadjuvant 
setting following anthracycline based therapy (cohort B) and unrestricted cycles in 
patients receiving therapy in the advanced/metastatic setting (cohort A).  
 Determine disease free survival (DFS) at 3 years for patients treated with 
mirvetuximab soravtansine given in the neoadjuvant setting; progression free survival 
(PFS), duration of response (DOR) and overall survival at 3 years (OS at 3 years) in 
patients receiving therapy for advanced/metastatic TNBC.   
 Compare disease response (as measured by pCR/RCB-I) in patients with FR+ 
chemotherapy resistant disease treated on clinical trial with mirvetuximab 
soravtansine in the neoadjuvant setting to those with similar molecular features who 
receive standard taxane-based chemotherapy as the second phase of their NACT.  
2.4. 
Secondary Endpoints 
 Volumetric change of the primary tumor as measured by ultrasound and/or MRI  
 Treatment-emergent adverse events and clinically significant ≥ Grade 3 changes in 
laboratory test results, physical examination or vital signs 
 DFS, PFS, DOR, OS  
 Pathologic response as measured by RCB after completion of neoadjuvant therapy in 
patients with chemotherapy insensitive FR+ TNBC treated with mirvetuximab 
soravtansine compared to those treated with standard taxane based therapy 

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2.5. 
Exploratory Objectives (Cohort B only) 
 Correlate response to mirvetuximab soravtansine with expression of FR/FOLR1 in 
primary tumors. 
 Determine if treatment with the antibody drug conjugate mirvetuximab soravtansine 
alters the tumor microenvironment of TNBC making the tumors more susceptible to 
treatment with antibodies targeting the T cell inhibitory molecule PD-1 or its ligand PD-
L1. 
 
2.6. 
Exploratory Endpoints 
 RCB status will be correlated with FR as measured by immunohistochemistry and 
expression of FOLR1 using RNAseq. 
 Changes in microenvironment will be studied using multiplex immunofluorescence for T 
cell and NK cell markers performed on pre- and post-treatment specimens. 
 
 

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3. 
STUDY POPULATION 
3.1. 
Criteria for Selection of Patient Population 
Patients with advanced breast cancer or localized, chemotherapy insensitive TNBC that express 
low levels of FR will be enrolled onto this study. For purposes of study entry, low FRα 
expression on the cell surface will be defined as >25% of cells with ≥ 1+ expression. TNBC will 
be defined as estrogen receptor (ER) <10%, progesterone receptor (PR) <10% and HER2 0-2+ 
using standard immunohistochemistry (IHC). Tumors that are HER2 2+ by IHC must 
demonstrate non-amplification (ratio <2) by standard in situ hybridization techniques (CISH or 
FISH). 
 
3.1.1. 
Diagnosis, allowable prior therapy and disease measurability: 
This study will accrue two cohorts of patients those with advanced/metastatic TNBC (cohort A) 
and those with Patients with localized, chemotherapy insensitive TNBC (cohort B). Patients in 
cohort A will have no limit on prior treatment regimens for metastatic disease and patients in 
cohort B will have received no more than 4 cycles of Adriamycin-based neoadjuvant therapy as 
per the ARTEMIS trial. Patients enrolled in cohort A must have disease measurable using 
RECIST criteria and those enrolled in cohort B must have tumors >1.0 cm in size post 
Adriamycin-based neoadjuvant therapy. Patients receiving neoadjuvant paclitaxel in the control 
arm of 2014-0185 who meet the following criteria will be chosen for this analysis: 
Tumor expression of vimentin is >50% and  
 Develops clinical or radiographic progression on AC chemotherapy 
 Has less than 10% reduction in the volumetric size of the primary tumor 
 Predicted chemotherapy insensitive and has a <80% reduction in the size of the 
primary tumor 
 
3.1.2. 
Inclusion Criteria  
3.1.2.1. 
Inclusion Criteria for Patients Enrolled into Cohort A: 
1. Age ≥ 18 years. 
2. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 
3. Confirmed invasive triple-negative breast cancer defined as ER<10%; PR<10% by IHC 
and HER2 0-1+ by IHC or 2+, FISH < 2, gene copy number < 4.  
4. Archived tissue available pre-screening to confirm FRα+ breast cancer.  
5. Confirmed FR breast cancer pre-screening defined as low FRα expression: >25% of 
cells having >1+ expression. 
6. Measureable disease by RECIST. 

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7. No limit to prior therapies for metastatic disease. Relapse of disease within 6 months of 
adjuvant or neoadjuvant chemotherapy is considered 1 line of therapy for metastatic 
disease.  
8. Adequate bone marrow function as shown by:  
 ANC >1.5x109 /L,  
 Platelets >100x109 /L,  
 Hb >9 G/dL. 
9. Adequate organ function as shown by: 
 Total serum bilirubin <2.0 mg/dL, 
 ALT and AST <2.5x ULN (<5x ULN in patients with liver metastases), 
 INR< 2; 
 Serum creatinine <1.5x ULN; 
 Serum albumin >2. 
10. Signed informed consent obtained prior to any screening procedures. 
11. Time from prior therapy: 
a. Systemic anti-neoplastic therapy: five half-lives or four weeks, whichever is shorter.  
Hormonal therapy is not considered anti-neoplastic therapy. 
b. Radiotherapy: wide-field radiotherapy (e.g. > 30% of marrow-bearing bones) 
completed at least four weeks, or focal radiation completed at least two weeks, prior 
to starting study treatment 
12. Patients must have resolution of toxic effect(s) of the most recent prior chemotherapy to 
Grade 1 or less (except alopecia). 
13. WCBP must have a negative pregnancy test within 3 days prior to the first dose of study 
treatment. 
 
3.1.2.2. 
Inclusion Criterial for Patients Enrolled into Cohort B: 
14. Age ≥ 18 years. 
15. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 
16. Confirmed invasive triple-negative breast cancer defined as ER<10%; PR<10% by IHC 
and HER2 0-1+ by IHC or 2+, FISH < 2, gene copy number < 4.  
17. Confirmed FRα+ breast cancer defined as low FRα expression: >25% of cells having >1+ 
expression. 

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18. Clinical or radiologic primary tumor size of at least 1.5cm prior to enrollment onto 
protocol 2014-0185 (ARTEMIS). Primary tumor size of at least 1.0 cm or evidence of 
continued lymph node involvement by imaging (ultrasound or MRI) after Adriamycin-
based neoadjuvant therapy. 
19. Primary tumor sample collected before NACT started (on ARTEMIS) and underwent 
molecular testing for integral biomarkers including immunohistochemical assessment of 
FRα.  
20. Received at least one dose of an anthracycline-based NACT. Patients are eligible if 
therapy was discontinued due to disease progression or therapy intolerance. Patients with 
disease progression on anthracycline-based therapy should be evaluated by the surgical 
team. If the patient is deemed inoperable at the time of evaluation, the patient may 
continue to undergo protocol therapy with a goal of reduction in tumor size to become 
operable. If the patient is deemed at high risk of becoming inoperable by the surgical 
team based upon tumor size or location, the patient will be considered ineligible for study 
and will be recommended to go to surgery.   
21.  Primary tumor size of at least 1.0 cm by imaging (ultrasound or MRI) or evidence of 
continued lymph node involvement by imaging (ultrasound or MRI) after Adriamycin-
based neoadjuvant therapy. 
 
22. Baseline MUGA or echocardiogram showing LVEF ≥ 50% within 6 weeks prior to 
initiation of NACT.  
23. Adequate bone marrow function as shown by:  
 ANC >1.5x109 /L,  
 Platelets >100x109 /L,  
 Hb >9 G/dL. 
24. Adequate organ function as shown by: 
 Total serum bilirubin <2.0 mg/dL, 
 ALT and AST <2.5x ULN (<5x ULN in patients with liver metastases), 
 INR< 2; 
 Serum creatinine <1.5x ULN; 
 Serum albumin >2. 
25. Signed informed consent obtained prior to any screening procedures. 
26. Patients must have at least 3 and no more than 5 weeks between anthracycline-based 
therapy and start of treatment with mirvetuximab soravtansine. 
27. Patients must have resolution of toxic effect(s) of the most recent prior chemotherapy to 
Grade 1 or less (except alopecia). 

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28. WCBP must have a negative pregnancy test within 3 days prior to the first dose of study 
treatment. 
 
3.1.3. 
Exclusion Criteria 
3.1.3.1. 
Exclusion Criteria for Patients in Cohort A: 
1. Pregnant or lactating women. 
2. Patients with a history of non-compliance to medical regimens or who are considered 
potentially unreliable or will not be able to complete the entire study 
3. Women of childbearing potential (WCBP), defined as all women physiologically 
capable of becoming pregnant, must use highly effective methods of contraception 
during the study and 12 weeks after. Highly effective contraception methods include 
a combination of any two of the following: 
 Placement of an intrauterine device (IUD) or intrauterine system (IUS); 
 Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal 
suppository; 
 Total abstinence or; 
 Male/ female sterilization. 
Women are considered post-menopausal and not of child-bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy) or tubal ligation at least six weeks prior to study entry. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment is she considered not of childbearing potential. 
4. Male patients whose sexual partner(s) are WCBP who are not willing to use adequate 
contraception, during the study and for 12 weeks after the end of treatment. 
5. Patients with >  Grade 1 peripheral neuropathy 
6. Active or chronic corneal disorder, including but not limited to the following: 
Sjögren’s syndrome, Fuchs corneal dystrophy (requiring treatment), history of 
corneal transplantation, active herpetic keratitis, and also active ocular conditions 
requiring on-going treatment/monitoring such as wet age-related macular 
degeneration requiring intravitreal injections, active diabetic retinopathy with macular 
edema, presence of papilledema, and acquired monocular vision.   
7. Serious concurrent illness or clinically-relevant active infection, including, but not 
limited to the following: 
 Known active hepatitis B or C  

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 Known Human Immunodeficiency Virus (HIV) infection 
 Varicella-zoster virus (shingles)  
 Cytomegalovirus infection  
 Any other known concurrent infectious disease, requiring IV antibiotics 
within 2 weeks of study enrollment 
8. Clinically- significant cardiac disease: 
 Recent myocardial infarction (<6 months prior to day 1), 
 Unstable angina pectoris, 
 Uncontrolled congestive heart failure (New York Heart Association > class II), 
 Uncontrolled hypertension (> CTCAE v4.03 Grade 3), 
 Prior history of hypertensive crisis or hypertensive encephalopathy, 
 Uncontrolled cardiac arrhythmias, 
 Clinically-significant vascular disease (e.g. aortic aneurysm, or dissecting 
aneurysm), 
 Severe aortic stenosis, 
 Clinically significant peripheral vascular disease, 
 > Grade 3 cardiac toxicity following prior chemotherapy 
 QTc >470 for females and >450 for males 
9. History of neurological conditions that would confound assessment of treatment-
emergent neuropathy. 
10. History of hemorrhagic or ischemic stroke within the last 6 months  
11. History of cirrhotic liver disease 
12. Previous clinical diagnosis of non-infectious pneumonitis or non-infectious interstitial 
lung disease. 
13. Prior hypersensitivity to monoclonal antibodies 
14. Patients who have a history of another primary malignancy, with the exceptions of: 
non-melanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast from 
which the patient has been disease free for ≥3 years 
15. Carcinomatous meningitis, untreated central nervous system (CNS) disease or 
symptomatic CNS metastasis. Patients with previously treated CNS metastasis 
(excluding carcinomatous meningitis) may participate if they are stable (without 
evidence of progression by imaging, using identical imaging modality at each 
assessment, for at least 4 weeks prior to first dose of study treatment), have no 
evidence of new or emerging CNS metastasis, and are not using steroids for at least 7 
days prior to first dose of study treatment. 

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16. History or evidence of thrombotic or hemorrhagic disorders within 6 months before 
first study treatment 
17. Required used of folate-containing supplements (e.g. folate deficiency) 
 
3.1.3.2. 
Exclusion Criteria for Patients in Cohort B: 
18. Pregnant or lactating women. 
19. Presence of metastatic disease or prior radiation therapy of the primary breast 
carcinoma or axillary lymph nodes. 
20. Patients with a history of non-compliance to medical regimens or who are considered 
potentially unreliable or will not be able to complete the entire study 
21. Women of childbearing potential (WCBP), defined as all women physiologically 
capable of becoming pregnant, must use highly effective methods of contraception 
during the study and 12 weeks after. Highly effective contraception methods include 
a combination of any two of the following: 
 Placement of an intrauterine device (IUD) or intrauterine system (IUS); 
 Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal 
suppository; 
 Total abstinence or; 
 Male/ female sterilization. 
Women are considered post-menopausal and not of child-bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six 
weeks prior to study entry. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of childbearing potential. 
22. Male patients whose sexual partner(s) are WCBP who are not willing to use adequate 
contraception, during the study and for 12 weeks after the end of treatment. 
23. Patients with >  Grade 1 peripheral neuropathy 
24. Active or chronic corneal disorder, including but not limited to the following: 
Sjögren’s syndrome, Fuchs corneal dystrophy (requiring treatment), history of 
corneal transplantation, active herpetic keratitis, and also active ocular conditions 
requiring on-going treatment/monitoring such as wet age-related macular 
degeneration requiring intravitreal injections, active diabetic retinopathy with macular 
edema, presence of papilledema, and acquired monocular vision.   

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25. Serious concurrent illness or clinically-relevant active infection, including, but not 
limited to the following: 
 Known active hepatitis B or C  
 Known Human Immunodeficiency Virus (HIV) infection 
 Varicella-zoster virus (shingles)  
 Cytomegalovirus infection  
 Any other known concurrent infectious disease, requiring IV antibiotics 
within 2 weeks of study enrollment 
26. Clinically- significant cardiac disease: 
 Recent myocardial infarction (<6 months prior to day 1), 
 Unstable angina pectoris, 
 Uncontrolled congestive heart failure (New York Heart Association > class II), 
 Uncontrolled hypertension (> CTCAE v4.03 Grade 3), 
 Prior history of hypertensive crisis or hypertensive encephalopathy, 
 Uncontrolled cardiac arrhythmias, 
 Clinically-significant vascular disease (e.g. aortic aneurysm, or dissecting 
aneurysm), 
 Severe aortic stenosis, 
 Clinically significant peripheral vascular disease, 
 > Grade 3 cardiac toxicity following prior chemotherapy 
 QTc >470 for females and >450 for males 
27. History of neurological conditions that would confound assessment of treatment-
emergent neuropathy. 
28. History of hemorrhagic or ischemic stroke within the last 6 months  
29. History of cirrhotic liver disease 
30. Previous clinical diagnosis of non-infectious pneumonitis or non-infectious interstitial 
lung disease. 
31. Prior hypersensitivity to monoclonal antibodies 
32. Patients who have a history of another primary malignancy, with the exceptions of: 
non-melanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast from 
which the patient has been disease free for ≥3 years 
33. History or evidence of thrombotic or hemorrhagic disorders within 6 months before 
first study treatment 
34. Required used of folate-containing supplements (e.g. folate deficiency) 
 

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4. 
INVESTIGATIONAL PLAN 
4.1. 
Study Design 
4.1.1. 
Overview and Schema 
This study will accrue two cohorts of patients. All patients will receive mirvetuximab 
soravtansine IV on day 1 of a 21-day cycle. Patients with advanced/metastatic TNBC (Cohort A) 
will receive therapy until disease progression, unacceptable toxicity or withdrawal of informed 
consent. Patients with localized, chemotherapy insensitive TNBC (Cohort B) will receive a 
maximum number of 4 cycles prior to undergoing surgical resection of their disease. Patients 
with clinical disease progression at any point during neoadjuvant therapy will be allowed to 
proceed with surgical resection. Surgery will occur no sooner than 4 weeks after day 1 of the last 
cycle of therapy administered. 
 
Figure 4:       Study Design Schema 
 
 
 
4.1.1.1. 
Dose  
The starting dose of IMGN853 will be 6 mg/kg for all patients treated, with the dose calculated 
using AIBW.  All IMGN853 doses will be calculated according to AIBW.   
Patients who experience toxicity requiring dose reduction as described in section 4.1.2 will be 
dosed at level -1 or -2 for subsequent cycles as per guidelines in section 5.10.4.1. Patients who 
continue to have toxicity that meets requirements for dose reduction past dose levels -2 will 

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discontinue protocol therapy. Those treated in the neoadjuvant cohort (cohort B) will proceed 
with surgical resection once toxicity has returned to <grade 1 or baseline.  
 
Table 1:           Dose Modification Levels 
Dose Level  
IMGN8531 
(mg/kg, IVq3W) 
Cohort A 
1 
6 
-1 
5 
-2 
4 
No further treatment; patient will discontinue protocol therapy. 
Cohort B 
1 
6 
-1 
5 
-2 
4 
No further treatment. Patient will be recommended to go to surgery. 
1IMGN853 dose calculated using adjusted ideal body weight (AIBW). Maximum 
allowable dose is 6 mg/kg AIBW. All patients begin at Dose Level 1 for Day 1, Cycle 1. 
 
4.1.2. 
Definition: Toxicity Requiring Dose Reduction 
Toxicity requiring dose reduction will be defined as a TEAE or abnormal laboratory value 
related to IMGN853 (i.e., assessed as unrelated to disease, intercurrent illness, or concomitant 
medications), including those TEAEs and abnormal laboratory values that result in a failure to 
meet the criteria for re-treatment (Section 5.10.1.1.). Toxicity will be considered related to the 
study treatment unless there is clear evidence of an alternative explanation.  
If a patient experiences a toxicity requiring dose reduction any point during study treatment as 
outlined in (Table 2), the study treatment must be stopped and the toxicity(ies) in question must 
be followed until resolution or stabilization. If treatment is to be resumed, then re-treatment 
criteria must be met (Section 5.10.3.) and administration of IMGN853 must be resumed at a 
lower dose per dose modification guidelines (Section 5.10.4.1.). 
 
 
 

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Table 2:      Toxicity Requiring Dose Reduction 
TOXICITY 
CRITERIA REQUIRING DOSE REDUCTION 
Dose delays 
Failure to meet re-treatment criteria within the 
specified timeframe (Section 5.10.1.1) 
Severity Grade (CTCAE v4.03) 
Dose Modifications for IMGN853 
Hematological 
Neutropenia 
Grade 2 and Grade 3 
Hold drug until ANC is >1.0x109/L (1000/µL) then 
resume at the same dose level. 
Grade 4 
Hold drug until ANC is >1.5x109/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 >1.0x109/L (1000/µL) and 
then resume at a lower dose level. 
Thrombocytopenia 
Grade 2 and Grade 3 
Hold drug until platelet count is >75x109/L 
(75,000/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 >75x109/L 
(75,000/µL) and then resume at a lower dose level 
Non-hematological 
Nausea and Vomiting 
Grade 3 (that persists for 72 hours despite use of 
optimal anti-emetics) 
Hold drug until resolved to < Grade 1, then 
resume at lower level 
Grade 4 (that persists for 24 hours despite use of 
optimal anti-emetics) 
Permanently discontinue 
Diarrhea 
Grade 3 (that persists for 72 hours despite use of 
optimal anti-diarrheal treatment) 
Hold drug until resolved to < Grade 1, then 
resume at a lower dose level 

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Grade 4 (that persists for 24 hours despite use of 
optimal anti-diarrheal treatment) 
Permanently discontinue 
Ocular Disorders 
Refer to Section 5.9.2 
Non-infectious Pneumonitis 
Refer to Section 5.9.3 
Infusion Related Reactions 
Refer to Section 5.9.1 
All Other Non-hematological Toxicities 
(except AEs related to underlying disease, Grade 3 fatigue, isolated symptomatic Grade 3 biochemical 
laboratory abnormalities that last for <7 days including electrolyte abnormalities that respond to 
medical intervention) 
Grade 3 
Hold drug until resolved to < Grade 1, then 
resume at lower dose. 
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 Event 
Permanently discontinue 
Grade 4 non-hematological toxicities 
Permanently discontinue 
Abbreviation: Common Terminology Criteria for Adverse Events (CTCAE) 
For any dose limiting hepatic toxicity, evaluations should be performed to determine the underlying 
etiology and rule out drug-induced liver injury (Hy’s Law) 
 
5. STUDY TREATMENT 
5.1. Description of Study Treatment 
The investigational study drug, IMGN853, will be provided by ImmunoGen, Inc. at a protein 
concentration of 5.0 mg/mL in an aqueous pH 5.0 buffered solution. IMGN853 will be available 
in a 20 mL glass vial with 20 mL deliverable volume. IMGN853 should be stored upright at 2-
8°C. Refer to the Pharmacy Manual for more information. 
5.2. IMGN853 Packaging  
IMGN853 will be provided in a 20 mL Type I glass vial. The container closure for the Type I 
glass vials will consist of a 20 mm ETFE-coated serum stopper (Flurotec®) on the top and 
product contact surface with a 20 mm aluminum TruEdge® seal with blue Flip-off® top. Refer 
to the Pharmacy Manual for labeling information. 

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5.3. Storage, Handling and Compatibility 
Specific details regarding storage and handling can be found in the Pharmacy Manual. 
Accountability and shipping documents for all drugs supplied by the Grantor must be maintained 
by the Principal Investigator or designee (e.g., the study pharmacist). The Investigator or 
designee must maintain an accurate record of the receipt and dispensing of IMGN853 study 
drugs in a drug accountability log or equivalent. These records must always be available for 
inspection, and a copy will be supplied to ImmunoGen, Inc., on request. Information recorded on 
these accountability and shipping documents will include quantities received, dates and amount 
dispensed, the recorder’s initials, patient number and initials to whom administered, lot number 
of drug administered, and drug lost, damaged or destroyed.  
Upon completion of the study, all study drug dispatched to a site must be accounted for and 
unused supplies returned to ImmunoGen Inc., 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 electronic case report 
form (eCRF) should also record details of IMGN853 study drug administration such as date and 
time of administration. 
Drug accountability should be monitored regularly. 
5.4        Study Treatment Compliance 
The IMGN853 and combination drugs supplied for the study (if any) 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 (i.e., 
hospital pharmacy, satellite pharmacy), it is the responsibility of the Principal Investigator to 
ensure that all study drug is maintained in the manner described. 
 
5.5           Assignment of Patient Number 
Patient numbers are assigned in sequential order as patients sign informed consent to participate.  
The Investigator will certify that the patient satisfies all eligibility criteria at screening and 
continues to satisfy all inclusion and exclusion criteria on Cycle 1, Day 1 prior to dosing.  
5.5.1        Enrolled Patient Definition 
Patients who have consented to the study and who have received at least one dose of study 
treatment will be considered enrolled. Patients who are issued a patient number, but who do not 

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successfully complete the screening process and who do not receive a dose of IMGN853 will be 
considered a screen failure. Patient numbers for patients who screen fail will not be re-issued. 
 
5.5.2. Patient Assignment to Dosing Regimens 
5.6. Blinding 
Not applicable as this is an open-label study. 
5.7. Study Treatment Administration 
5.7.1. Study Treatment Overview and Schedule 
IMGN853 is an experimental anticancer drug, and, as with other potentially toxic compounds, 
caution should be exercised when handling this compound. It is recommended that gloves and 
protective garments be worn during preparation. Refer to the Pharmacy Manual and package 
inserts for more information. 
For logistical reasons such as holidays, delays in the scheduled study treatment for up to 3 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. 
5.8. Drug Preparation and Administration 
5.8.1. Premedication for Study Treatment 
All patients must receive 325-650 mg of acetaminophen/paracetamol (PO or IV), 10 mg IV 
dexamethasone, and 25-50 mg diphenhydramine (PO or IV) (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. 
5.8.2.  Preparation and Administration of IMGN853 
5.8.2.1. Calculation for Adjusted Ideal Body Weight (AIBW) 
In the on-going phase 1 study with IMGN853, the use of AIBW to calculate the dose of 
IMGN853 reduced the intra-cohort variability in Cmax and AUC0-∞ values, thereby improving 
the safety profile of IMGN853.  
The total dose of drug will be calculated based on each patient’s adjusted body weight using the 
following formula: 
 
Adjusted Ideal Body Weight (AIBW)  
1. IBW1 + 0.4 (Actual weight – IBW1) 
Where: 

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Ideal Body Weight (IBW)  
1. IBW1 (male) = 0.9H1-88 
2. IBW1 (female) = 0.9H1-92 
 
(1H=height in cm; W=weight in kg) 
 
The weight used for calculation should be obtained prior to 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). 
5.8.2.2. Preparation  
The desired amount should be withdrawn from the vial(s) and diluted using 5% dextrose to a 
final concentration as outlined in the Pharmacy Manual. Note: IMGN853 is incompatible with 
saline (0.9% sodium chloride). Therefore, dilutions must be made using 5% dextrose. Infusion 
bags must be labeled with the protocol number, patient number, storage temperature, dose, and 
volume of IMGN853 filtered into the bag, or according to institutional protocol. Once the 
solution is prepared, the infusion bag must not be left in direct sunlight, and the infusion must be 
completed within 8 hours of preparation. 
 
Study drug from two different drug lots cannot be mixed in a single dose administration. 
5.8.2.3. Administration 
The starting dose level of IMGN853 will be 6 mg/kg using AIBW for IMGN853 will be 
administered as an IV infusion following preparation as outlined in the Pharmacy Manual. An IV 
tubing administration set with a 0.22 micron in-line filter must be used for infusion. For patients 
who have not been administered IMGN853 as a prior anti-cancer therapy, IMGN853 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 5mg/min. Subsequent infusions may be delivered at the tolerated rate. Therefore, the 
overall length of infusion will vary depending on dose and patient tolerability. Following 
infusion, the IV line should be flushed with 5% dextrose as needed to ensure delivery of the full 
dose.  
Patients will be carefully observed during each infusion and vital signs taken as outlined in the 
Schedule of Clinical Assessments (Appendix A and Table 9). They will remain in the clinic 
under observation for 4 hours after the completion of the first infusion of IMGN853, and for at 
least 1 hour after each subsequent infusion.  

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5.9          Monitoring and Management of Adverse Events 
5.9.1.         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 (e.g. 
epinephrine, inhaled beta agonists, antihistamines, and corticosteroids), and other required 
resources to treat anaphylaxis must be readily available. In general, Investigators should manage 
acute 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 3. 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. 
 
 
 
 
 
Table 3:            Management Guidelines for Potential Infusion-related Reaction 
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 for nausea (or 
equivalent) 
 
Diphenhydramine (or equivalent) 25-50 mg PO or IV prn   
 
Methylprednisolone 125 mg (or equivalent) IV prn 

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Infusion Reaction CTCAE v4.03 
Severity Grade 
Management 
Grade 2: Moderate  
 
Interrupt infusion and disconnect infusion tubing from patient 
 
Promethazine (or equivalent) 150 mg PO per day for nausea 
 
Diphenhydramine (or equivalent) 25-50 mg PO or IV prn 
 
Acetaminophen (or equivalent) 650 mg PO prn 
 
Methylprednisolone 125 mg (or equivalent) IV prn 
 
After recovery from symptoms, resume the infusion at 50% of the 
previous rate and if no further symptoms appear, gradually increase rate 
until infusion is completed. 
 
For subsequent dosing in future cycles, 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 subject 
 
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 7.14.1) 
 
Permanently discontinue study medication treatment 
5.9.2. Monitoring and Management of Treatment-emergent Ocular Disorders 
5.9.2.1. Monitoring - Potential Ocular Disorders 
Changes in visual acuity resulting from corneal epithelium disorders have been reported in other 
studies of DM4-containing immunoconjugates that use the SPDB linker (Younes, 2012). Due to 
the observation of ocular disorders in patients treated with IMGN853 Q3W at dose levels > 3.3 
mg/kg, patients will be carefully monitored for ocular symptoms. Complete ophthalmologic 
exams and ocular symptom assessments will be performed in all symptomatic patients as 
described in the following schedule: 

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Table 4:       Schedule for Ophthalmic Assessments 
Assessment1 
Screening 
Day 1 (All 
Cycles) 
Prior to 
Day 1 Dose 
(Every 
other 
Cycle)2 
End of 
Study 
Visit 
30-Day 
Follow 
Up Safety 
Visit 
Ophthalmologic history – patients 
will be asked about ocular 
symptoms such as history of dry 
eye, and contact lens use 
X 
 
 
 
 
Complete Exam: 
- 
Visual acuity 
- 
Indirect fundoscopy 
- 
Slit lamp examination 
under dilatation 
- 
Intraocular pressure 
measurement 
- 
Corneal photography 
(optional) 
 
 
Patients who 
report 
treatment-
emergent 
changes in 
vision 
X 
X 
Schirmer’s test3 
 
 
Patients who 
report 
treatment-
emergent 
changes in 
vision 
 
 
Ocular symptom assessment 
(blurred vision, ocular 
discomfort, etc.) 
X 
X 
 
X 
X 
1 Performed by a board-certified ophthalmologist 
2 Within 1 week prior to Day 1 dose of every other cycle, required for patients who have experienced signs or 
symptoms of ocular toxicity and for those with blurred vision but normal eye exams. 
3 For patients experiencing ocular symptoms, the Schirmer’s test will be repeated at the first ophthalmology exam 
and subsequent ophthalmologic exams if clinically indicated. 
 
If a Patient develops ocular symptoms of any grade, the patient is required to have a complete 
examination by an ophthalmologist. If the patient develops > CTCAE grade 1 ocular symptoms 
(Appendix C) treatment with IMGN853 will be interrupted. Therapy may resume if ocular 

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disorders improve to Grade 1 or baseline within one cycle; a complete ocular examination will 
be required in every other cycle going forward, and at either the end of treatment or 30-day 
follow-up safety visit. 
5.9.2.2. Management Guidelines for Ocular Disorders 
In order to prevent dry eye, which may predispose a patient to corneal irritation, patients will be 
required to regularly use preservative-free, lubricating artificial tears on a daily basis (as directed 
by the product label or the treating physician) for the duration of their IMGN853 treatment. 
Patients should also be firmly advised to avoid using contact lenses while on study. Baby 
shampoo and a soft cloth should be used to clean the eyes, and a warm compress at bedtime may 
be used to decrease any possible inflammation on the eyelid’s surface. The use of UVA/UVB 
sunglasses is recommended for use outside in full daylight during the course of the study. The 
use of punctal plugs to increase lubrication of the eyes is also recommended. 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.  
Patients who have experienced study drug-related changes in vision, such as blurred vision, will 
have a complete ophthalmic examination performed prior to the start of every other cycle and at 
the end of study or 30-day follow up visit following end of treatment, even if the results of the 
patient’s ocular exam is normal. Management of treatment emergent ocular disorders with 
inflammatory characteristics should include corticosteroid eye drops and/or other measures as 
indicated by an ophthalmologist. 
Table 5:        Management of Ocular Disorders 
Severity Grade 
(CTCAE v4.03 
Grade)1 
Management 
Guidelines for IMGN853 
Dose Modifications 
Grade 1 
 
Complete eye exam as outlined in Table 4. 
 
Monitor for worsening symptoms 
 
Patient may use steroid eye drops to treat 
corneal keratopathy per ophthalmologist 
recommendation 
 
Continue IMGN853 
dosing 
Grade 2 
 
Complete eye exam by an ophthalmologist as 
outlined in Table 4. Repeat complete exam as 
clinically indicated. 
 
Patients may use steroid eye drops to treat 
corneal keratopathy per ophthalmologist 
recommendation 
 
Patients should have weekly symptomatic 
ocular assessments until the symptoms resolve 
to grade 1 or baseline (Section 5.10.3) or are 
deemed to be irreversible by the investigator 
 
Hold IMGN853 dosing. 
 
Patients with ocular disorders less 
than 14 days may be allowed to 
resume therapy at the same dose 
level. 
 
Patients with ocular disorders 
who experience dosing delays>14 
days, may resume treatment at a 
reduced dose level (see Table 8) 

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Grade 3 
 
Complete eye exam as outlined in Table 4. 
Repeat complete exam as clinically indicated. 
 
Patients may use steroid eye drops to treat 
corneal keratopathy per ophthalmologist 
recommendation 
 
Patients should have weekly symptomatic 
ocular assessments until the symptoms resolve 
to grade 1 or baseline (Section 5.10.3) or are 
deemed to be irreversible by the investigator. 
 
Hold IMGN853 dosing 
 
Patients may be allowed to 
resume therapy at a lower dose 
than the one they were receiving 
when the symptoms began (see 
Table 8). 
Grade 4 
 
Complete eye exam as outlines in Table 4. 
Repeat complete exam as clinically indicated. 
 
Patients may use steroid eye drops to treat 
corneal keratopathy per ophthalmologist 
recommendation 
 
Patients should have weekly symptomatic 
ocular assessment until the symptoms resolve 
to grade 1 or baseline (Section 5.10.3) or are 
deemed to be irreversible by the investigator. 
 
Permanently discontinue 
IMGN853 dosing. 
1Appendix D includes CTCAE version 4.03 Grade definitions for select ocular disorders. 
 
5.9.3.      Monitoring of Non-Infectious Pneumonitis Following the Administration of Study 
Treatment 
Non-infectious pneumonitis has been observed following the administration of IMGN853 and 
may result in fatigue, shortness of breath, cough or respiratory distress. Drug-induced 
pneumonitis may be immediately life-threatening. If a patient presents with signs or symptoms 
consistent with pneumonitis and/or a clinically meaningful change in pulse oximetry value, the 
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. 
Table 6:     Management of Non-Infectious Pneumonitis 
Severity Grade 
(CTCAE v4.03 
Grade) 
Medical Management of Pneumonitis 
Guidelines for Dose 
Modifications 
Grade 1 
 
Radiologic assessment (CT scan and/or chest 
x-ray) should be performed as clinically 
indicated. 
 
Monitor for pulmonary symptoms 
 
Continue dosing after discussion 
with Grantor. 

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Grade 2 
 
Radiologic assessment (CT scan and/or chest 
x-ray) should be performed as clinically 
indicated. 
 
Patient must be evaluated by a pulmonary 
specialist. 
 
Treatment with corticosteroids may be 
indicated as recommended by a pulmonary 
specialist and/or institutional guidelines. 
 
Hold dosing until symptoms 
improve. 
 
IMGN853 may be resumed at 
same dose level after discussion 
with the Grantor. 
Grade 3 
 
Radiologic assessments (CT scan and/or chest 
x-ray) should be performed as clinically 
indicated. 
 
Patient must be evaluated by a pulmonary 
specialist. 
 
Treatment with corticosteroids until resolution 
of symptoms may be indicated as 
recommended by a pulmonary specialist 
and/or institutional guidelines. 
 
Bronchoscopy with lavage and/or biopsy 
when clinically feasible should be performed. 
 
The pneumonitis event must be followed until 
resolution 
 
Hold IMGN853 dosing until 
symptoms resolve. 
 
IMGN853 may be resumed at a 
lower dose level after discussion 
with the Grantor. 
Grade 4 
 
Radiologic assessments (CT scan and/or chest 
x-ray) should be performed as clinically 
indicated. 
 
Patient must be evaluated by a pulmonary 
specialist. 
 
Treatment with corticosteroids until resolution 
of symptoms may be indicated as 
recommended by a pulmonary specialist 
and/or institutional guidelines. 
 
Bronchoscopy with lavage and/or biopsy 
when clinically feasible should be performed. 
 
The pneumonitis event must be followed until 
resolution. 
 
Permanently discontinue 
IMGN853 dosing. 
 
5.9.4. Monitoring and Management of Diarrhea Following the Administration of Study 
Treatment 
 
Mild to moderate diarrhea has been frequently 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 2 
hours until symptoms resolve (Wadler, 1998). 
 
5.9.5. Monitoring and Management of Nausea and Vomiting Following the Administration 
of Study Treatment 

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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 American Society of Clinical Oncology (ASCO) 
Clinical Practice Guidelines for the use of antiemetics (Basch, 2011) outlined in Table 7. 
 
Table 7:       Management of Nausea and Vomiting 
Severity Grade 
(CTCAE v4.03 Grade) 
Management 
Grade 1 
 
No additional therapy required 
Grade 2 
 
Administer a 5-HT3 receptor antagonist on day 1 (e.g. palonosetron, 
granisetron, or ondansetron) in combination with dexamethasone on days 1-3 
or treat as per institutional guidelines. Aprepitant may be added to the 
combination. 
Grades 3 and 4 
 
Administer a neurokinin 1 receptor antagonist (e.g. aprepitant on days 1-3 or 
fosaprepitant on day1), in combination with 5-HT3 receptor antagonist on day 
1 only, and dexamethasone on days 1-3 or 1-4 or treat per institutional 
guidelines. 
 
5.9.5.1.            Management of Electrolytes Imbalance 
Prompt attention should be given to the correction of potential electrolytes imbalance, especially 
hypokalemia and hypomagnesemia. 
 
5.10. Treatment Guidelines 
5.10.1. Re-treatment Criteria 
5.10.1.1. To Begin a New Cycle of Treatment or continue treatment within a cycle 
In the absence of a toxicity requiring dose reduction or dose delay, for a patient to begin a new 
cycle or continue a cycle of therapy, the following criteria must be met. 
• ANC must be ≥ 1.5x109/L (1,500/µL) (Cycle 1 Day 1 only) 
• ANC must be ≥ 1.0x109/L (1,000/µL) 
• Platelet count must be ≥ 75 x 109/L (75,000/µL) 

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      All non-hematologic toxicities for which a causal association to study treatment   
cannot be ruled out, must be ≤ Grade 2 (except alopecia) or returned to baseline; the 
exceptions to this rule are: 
 Treatment-emergent ocular disorders, which must have recovered to < Grade 1 or 
baseline 
 Treatment-emergent pneumonitis which must have recovered to ≤ Grade 1 
If the patient does not meet these criteria, dosing will be delayed and the patient should be re-
evaluated within 48-72 hours. Dosing with study drug may resume if these criteria have been 
met. If the adverse event can be attributed to study drug, drug will be held or discontinued as per 
the Dose Modification Guidelines described in (Section 5.10.4.). However, if the next cycle is 
delayed by greater than 14 days because of insufficient recovery from a treatment-related 
toxicity, this will be viewed as a toxicity requiring dose reduction or dose delay (Section 4.1.2.). 
If the next cycle is delayed due to treatment-related toxicity longer than 3 weeks then the patient 
should be removed from study treatment. In such cases, continuation of study treatment may be 
considered for those patients who have experienced clinical benefit if agreed upon between the 
Grantor and the Investigator.  
The use of granulocyte growth factors in accordance with ASCO guidelines may be implemented 
at the discretion of the treating physician after Cycle 1. 
5.10.2.         Follow-up for AEs Leading to Discontinuation 
Patients who experience a non-laboratory AE requiring dose reduction or dose delay must be 
evaluated weekly, at a minimum, until resolution to ≤ Grade 1 or baseline and then at least 
monthly until return to baseline or stabilization of the event, whichever comes first. For 
abnormal laboratory values that qualify as a toxicity requiring dose reduction or dose delay, 
patients will be followed twice weekly until values return to < Grade 1 or baseline, whichever 
comes first.  
Patients who discontinue study treatment for an AE or an abnormal laboratory value must be 
followed at least once a week for 4 weeks, and subsequently at 4-week intervals until resolution 
or stabilization of the adverse event or laboratory abnormality, whichever occurs first.  
5.10.3.       Criteria for Re-Initiation of Study Treatment Following Occurrence of a 
Toxicity Requiring Dose Modification  
Study treatment will be stopped if a patient experiences a toxicity requiring dose modification at 
any time during the study. It may resume, with applicable dose adjustments (Section 5.10.4.1) if 
the following criteria are met: 
• ANC must be ≥ 1.0 x109/L (1,000 /µL) 
• Platelet count must be ≥ 75 x 109/L (75,000/µL) 
• All clinically-significant non-hematologic toxicities for which a causal association to study 
treatment cannot be ruled out must be ≤ Grade 1 (except alopecia) or returned to baseline 
 

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If the patient does not meet these criteria, dosing will be delayed and the patient should be re-
evaluated within 48-72 hours. Dosing may resume if these criteria have been met. If the next 
cycle is delayed due to treatment-related toxicity longer than 3 weeks then the patient should be 
removed from study treatment. In such cases, continuation of study treatment may be considered 
for those patients who have experienced clinical benefit if agreed upon between the Grantor and 
the Investigator. 
5.10.4.         Dose Modification Guidelines 
5.10.4.1.     IMGN853 Dose Reduction Following a Toxicity Requiring Dose Modification  
Patients with toxicity requiring dose modifications of IMGN853 should be dose reduced 
according to Table 8.  Patients who develop toxicity requiring dose modifications or adverse 
events requiring an interruption of IMGN853 for >1 week may resume treatment at a reduced 
dose level as shown in Table 8 provided the criteria outlined in Section 5.10.3.are met. Patients 
experiencing an initial event requiring dose reduction should receive subsequent therapy using 
dose level -1. If a second event requiring dose reduction occurs, subsequent therapy should be 
administered using dose level -2. If a third event occurs, the patient will discontinue protocol 
therapy. 
 
Table 8:         IMGN853 Dose Modification Guidelines 
Dose Level  
IMGN8531 
(mg/kg, IVq3W) 
Cohort A 
1 
6 
-1 
5 
-2 
4 
No further treatment; patient will discontinue protocol therapy. 
Cohort B 
1 
6 
-1 
5 
-2 
4 
No further treatment. Patient will be recommended to go to surgery. 
1IMGN853 dose calculated using adjusted ideal body weight (AIBW). Maximum 
allowable dose is 6 mg/kg AIBW. All patients begin at Dose Level 1 for Day 1, Cycle 1. 
 
 

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5.10.5. Discontinuation of Study Treatment Due to Adverse Events 
If IMGN853 is discontinued, the patient will enter follow up for survival endpoints. 
Study treatment should not be resumed in the case of the following treatment-related events. 
• ≥ Grade 3 cardiac event 
• Other non-hematologic events of Grade 4 severity that do not respond to appropriate 
medical management within 48 hours. 
• Failure to meet re-treatment criteria within 3 weeks 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 Grantor and the Investigator. 
 
5.11.   Removal of the Patient from the Study or from Study Drug 
Administration 
The patient or legal guardian acting on behalf of the patient is free to withdraw consent and 
discontinue participation in the study at any time without prejudice to further treatment. For this 
protocol, patients withdrawn for reasons other than toxicity or disease progression during Cycle 
1 may be replaced. 
Patients will be removed from the study treatment when their disease worsens, and there is no 
clinical benefit. Additionally, a patient’s participation in the study may be discontinued at any 
time at the discretion of the Investigator. The following may be justifiable reasons for the 
Investigator to remove a patient from the study: 
• The patient suffers an intolerable adverse event 
• Non-compliance, including failure to appear at one or more study visits 
• The patient was erroneously included in the study 
• The study is terminated by the Grantor 
If a patient or the patient’s legal guardian(s), acting on behalf of the patient, discontinues 
participation in the study, or the patient is discontinued by the Investigator, the reason for 
discontinuation must be captured in the eCRF. Any AEs experienced up to the point of 
discontinuation must be documented on the AE eCRF. All serious adverse events (SAEs), and 
those AEs assessed by the Investigator as at least possibly related to study drug should continue 
to be followed until they resolve or stabilize, whichever comes first. 
5.11.1.       Replacement of Patients who are Withdrawn Prior to the End of Cycle 1 
Only patients who sign the informed consent form and receive at least one dose of IMGN853 
will be considered enrolled. If an enrolled patient is discontinued from study treatment for 
reasons other than safety (e.g., withdrawal of consent, non-compliance, death due to disease 

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progression) prior to the end of Cycle 1, he or she will be replaced (i.e., an additional patient will 
be added to the cohort). Patients who do not complete Cycle 1 due to an AE will not be replaced. 
Patients who are replaced will be followed for safety and other assessments according to the 
protocol. 
5.12.       Period of Observation 
For purposes of this study, the period of safety observation extends from the time of informed 
consent until the final evaluation during the study, including the 30-day follow-up safety visit. 
Short-term follow-up for patients who discontinue study therapy without documented 
progressive disease will continue every 3 months until the patient’s disease worsens, until the 
patient begins subsequent anti-cancer treatment, or until the patient dies, whichever comes first. 
5.13.      Concomitant Medications and Procedures 
All concomitant medications and supportive therapy taken within 4 weeks of 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, and route of administration, frequency, duration of 
administration, and indication for use will be recorded in the appropriate sections of the eCRF. 
 
5.13.1.       Lubricating Artificial Tears 
Patients will be required to regularly use preservative-free, lubricating artificial tears on a daily 
basis (as directed by the product label or treating physician). 
 
5.13.2.       Antiemetic and antidiarrheal medications 
Antiemetic (e.g. 5-HT3 serotonin receptor antagonists such as palonosetron, granisetron or 
ondansetron) and antidiarrheal (e.g. loperamide) medications may be used at the discretion of the 
treating physician. 
5.13.3.       Folate-Containing Vitamins 
Folate-containing vitamins are not to be taken during the course of the study. 
5.13.4.        Antineoplastic Therapy 
Other chemotherapy, investigational agents, immunotherapy, or biologic therapy will not be 
permitted during the study. 
Palliative radiotherapy during study treatment should be discussed with the Grantor prior to 
implementation. If the Investigator and Grantor 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 if treatment was performed on a target or 
non-target lesion. 
5.13.5.         Hematopoietic Growth Factors 

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Patients receiving recombinant erythropoietin or darbepoietin-α prior to study start may continue 
to receive pre-treatment doses.  
The use of erythropoietic and granulocyte growth factors in accordance with ASCO guidelines 
may be implemented at the discretion of the treating physician after Cycle 1. 
5.13.6.        Other Concomitant Medications 
Medications for the treatment of adverse events or cancer symptoms (e.g. packed red blood cells 
and pain medications), are allowed. Prophylactic use of steroids and/or antihistamines will be 
considered if needed to alleviate mild-moderate infusion-related reactions. Additionally 
medications (not addressed above) used to treat underlying medical conditions at study entry 
including anti-emetics and anti-diarrheal will be allowed to continue. 
 
5.13.7.           Medication Metabolized Through Cytochrome P450 (CYP3A) 
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 1 
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 E) should be carefully monitored. 
 
5.14.          Overdose and Medication Error 
Overdose – There is no known treatment/antidote available for IMGN853. Supportive measures 
should be instituted if an instance arises in which a patient suffers an overdose of any study drug. 
Medication Error – The Grantor must be immediately notified in the event of error in 
prescribing, dispensing, administering and/or use of IMGN853 or 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 Report Form must be submitted within 24 hours of the event (see Section 7.14.1). 
 
 

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6. 
TRANSLATIONAL RESEARCH STUDIES (COHORT B ONLY) 
Several biomarkers, including FRα, will be evaluated as potential biomarkers of clinical response 
to IMGN853. These will help guide further clinical development of IMGN853. It is anticipated 
that expression of the gene that encodes FR (FOLR1) as measured by RNAseq may predict 
response to therapy and response will be correlated in tumors categorized as FOLR1+ using level 
of expression. Similarly, it is anticipated that FR+ staining will also be correlated with 
response. 
Additionally, preclinical data have shown that antibody drug conjugates that include 
microtubule-targeted agents such as the maytansinoid DM4 that is incorporated in mirvetuximab 
soravtansine, enhance the maturation and activation of dendritic cells.  This in turn leads to 
stimulation of an anti-tumor T cell response that can be augmented with antibodies targeting the 
T cell inhibitory molecules PD-1 (and its ligand PD-L1) and CTLA-4.  Based on these data, a 
study combining mirvetuximab soravtansine with the anti-PD-1 antibody pembrolizumab has 
been initiated for patients with FRα-positive ovarian cancer. 
There is also significant interest in using agents targeting T cell inhibitory molecules in TNBC.  
The Keynote 012 trial (Nanda et al SABCS, 2014) enrolled patients with locally advanced or 
metastatic TNBC with some degree of PD-L1 expression.  Patients received the anti-PD-1 
antibody pembrolizumab dosed at 10mg/kg every two weeks.  The overall response rate was 
18.5%.  For those who responded, those responses appears to be durable.  At a median follow-up 
of 9.9 months, the median duration of response had not been reached.  At the 2015 annual 
meeting of the AACR, Emens et al. reported that the anti-PD-L1 antibody atezolizumab was safe 
with evidence of clinical activity.  The 24-week progression-free survival rate was 27% with an 
objective response rate of 19%.  At the 2015 SABCS, Dirix and colleagues presented data from 
the Javelin trial that investigated the anti-PD-L1 antibody avelumab.  In patients with TNBC, the 
objective response rate was approximately 10%.  Correlative studies in this trial showed that 
patients with tumors with an immune cell infiltrate expressing PD-L1 were more likely to 
respond to treatment. In order to provide the necessary preclinical data to support a trial 
combining mirvetuximab soravtansine with immune checkpoint blockade agents, to include 
those targeting PD-1 or PD-L1, we will characterize the immunophenotype of the tumor and 
microenvironment in specimens obtained pre- and post-treatment from patients treated with 
mirvetuximab soravtansine.  
Enrollment onto ARTEMIS mandates that patients undergo biopsies at the following time points: 
pretreatment, after 4 cycles of anthracycline-based chemotherapy, and at the time of surgical 
resection (upon completion of all neoadjuvant therapy). Tissue from these biopsies will be used 
to generate molecular profiles by RNAseq, comprehensive gene sequencing and 
immunohistochemistry as part of the MD Anderson TNBC Cancer Moon Shot. Slides will be 
made available to perform the IHC studies proposed and to evaluate FOLR1 by RNAseq. 
 

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6.1. 
Correlation between FRα Expression and IMGN853 anti-tumor 
activity 
FRα expression varies with tumor histology, as reported in the literature and demonstrated in our 
pre-clinical studies (Sections 1.1 and Investigators’ Brochure). Based on the hypothesis that 
tumors expressing higher levels of FRα are more likely to be susceptible to anti-tumor activity of 
IMGN853, a threshold for FRα expression was determined for enrollment in this study. This was 
done based on molecular epidemiology data generated in a number of patient samples 
representative of different tumor types, as well as clinical anti-tumor activity data from the FIH 
study 0401. 
6.1.1. 
Evaluation of FRα Expression in Tumor Tissue  
FRα expression in tumors will be analyzed via IHC. All patients must submit archived tumor 
tissue, or formalin-fixed, paraffin embedded slides for analysis of FRα expression by IHC prior 
to enrollment.  
Only patients with the required FRα expression levels by IHC (>25% of tumor at >1+ intensity) 
will be eligible to enroll in the study. 
The tumor samples will be analyzed for FRα expression in the Companion Diagnostics Pharma 
Services CAP-accredited or CLIA-certified laboratory and Pathology Services at Ventana 
Medical Systems, Inc. or local lab using Ventana Class I IVD. 
To determine FRα expression in patient tumor specimens and support patient selection, 
ImmunoGen engaged the services of Ventana Medical Systems, Inc. (VMSI) to develop an IHC-
based clinical trial assay. The assay utilizes FOLR1-2.1, a murine monoclonal antibody 
recognizing the receptor in FFPE samples and discovered at ImmunoGen, and the Ventana 
OptiView DAB Detection Kit on a Ventana BenchMark XT fully automated slide stainer. The 
assay has been optimized and analytically validated with respect to specificity, sensitivity, and 
precision using normal and tumor tissue controls, and is suitable for the semi-quantitative 
determination of FRα protein expression in formalin-fixed paraffin embedded tissue samples.  
Assay Interpretation 
Board certified pathologists evaluate FRα expression in tumor cells. Membrane and cytoplasmic 
staining (the latter for information only) are scored separately for the percentage of cells stained 
at 1+ (weak), 2+ (moderate), and 3+ (strong) staining intensity. Zero (0) indicates the absence of 
FRα expression. H score is calculated as 1*(% cells stained at intensity 1+) + 2*(% cells stained 
at intensity 2+) + 3*(% cells stained at intensity 3+) and has a range of 0-300. 
 
VENTANA has developed the VENTANA FOLR1 (FOLR1-2.1) CDx Assay to aid in the 
selection of patients who may benefit from mirvetuximab soravtansine treatment. VENTANA 
FOLR1 (FOLR1-2.1) CDx Assay encompasses a combination of the anti- FRα (FOLR1-2.1) 
mouse monoclonal primary antibody for use with the BenchMark ULTRA automated staining 
platform and the OptiView DAB IHC Detection kit. This assay has been optimized and 

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analytically validated with respect to specificity, sensitivity, and reproducibility per FDA 
guidance for Investigational Use Only (IUO) assays, and is suitable for determining eligibility.  
Patient sample screening using this assay will be done in the Ventana Translational Diagnostics 
(TDx) CAP/CLIA Laboratory. 
 
IHC data will be used to further define associations between FRα expression and clinical 
response. 
 
6.2. 
Exploratory Biomarker Studies (Cohort B Only) 
In order to provide the necessary preclinical data to support a trial combining mirvetuximab 
soravtansine with immune checkpoint blockade agents, to include those targeting PD-1 or PD-
L1, we propose to characterize the immunophenotype of the tumor and microenvironment in 
specimens obtained pre- and post-treatment from patients enrolled on this proposed neoadjuvant 
trial. Multiplex immunofluorescence will be performed on pre- and post-treatment specimens 
using the Opal™ multiplex staining kit and imaged using the Vectra™ microscope.  We will use 
2 panels that have been optimized in collaboration with the Immunotherapy Platform at MD 
Anderson.  Panel 1 includes the following antibodies:  AE1/AE3 (pan-cytokeratins), CD3 (pan T 
cell marker), CD4 (helper T cell marker), CD8 (cytotoxic T cell marker), PD-L1 and CD68 
(macrophage marker).  Panel 2 include:  AE1/AE3, PD1, and FOXP3 (regulatory T cells), CD45 
Ro (memory T cell response), CD57 (NK cell marker) and granzyme B. 
 

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7. 
STUDY PROCEDURES 
7.1. 
Informed Consent (Pre-screening and Study) 
Each patient or legally authorized representative must provide written informed consent before 
any study-required procedures are conducted, unless those procedures are performed as part of 
the patient’s standard care.  
7.1.1   Pre-screening informed consent – identifies triple-negative breast cancer patients that 
appear to be eligible candidates. The pre-screening ICD allows for either archived tissue 
(cohort A) or fresh tumor biopsy (cohort B) to be tested for FRα. Only patients found to be 
FRα positive, per protocol criteria, will be enrolled into the clinical trial. 
7.1.2   Study informed consent – once patients have been determined FRα positive, per 
protocol criteria, they may sign the study informed consent. The patients will then begin 
screening tests required for the clinical trial. Patients not found to be FRα positive will not 
sign the study informed consent. 
7.2. 
Inclusion and Exclusion Criteria 
The inclusion and exclusion criteria will be assessed during screening (within 28 days prior to 
the first dose of any study drug on Cycle 1, day 1). A patient is considered enrolled when 
administered the first dose of drug. 
7.3. 
Confirmation of Disease Diagnosis 
At screening, disease diagnosis and current disease status will be confirmed from information in 
the source record. 
7.4. 
Demographic/Medical History 
The age, race, and gender of the patient are to be recorded during screening. 
During the Screening period, a complete medical history will be compiled for each patient. The 
history will include the background and progress of the patient’s primary malignancy and 
include a description of all prior therapies for the primary malignancy. 
7.5. 
Physical Examination, Weight and Height 
Physical examination, height (screening only) and weight must be performed as indicated in the 
Schedule of Clinical Assessments (Appendix A.). A complete physical examination will be 
completed at screening and end of treatment. Directed physical examinations will be completed 
at additional time points as specified in the Schedule of Events. 
Weight will be measured at screening and at other times specified in the Schedule of Clinical 
Assessments (Appendix A). 
 

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7.6. 
Vital Signs 
Vital signs will be measured as outlined below and in Appendix A. 
 
 
 
 
 
Table 9:         Vital Sign Measurements 
 
Screening 
Day 1 of All 
Cycles a 
(Predose) 
Every 30 
Minutes 
During 
IMGN853 
Infusion b 
Immediately 
Following 
Completion 
of IMGN853 
Infusion c 
4-Hous Post 
End of 
IMGN853 
Infusion d 
End of 
Treatment 
and Follow 
Up Visits 
Blood 
Pressure 
 
 
 
 
 
 
Pulse 
 
 
 
 
 
 
Respiratory 
Rate 
 
 
 
 
 
 
Temperature 
 
 
 
 
 
 
 a Within 10 minutes prior to start of infusion of IMGN853 
 b ± 10 minutes 
 c Within 10 minutes following completion of infusion of IMGN853 
 d Cycle 1 only. If the patient's infusion was well-tolerated, the 4-hour post IMGN853 infusion assessment will not 
be required in Cycles ≥2. 
 
7.7. 
Laboratory Assessments 
Patients should be in a seated or supine position during blood collection. Screening labs 
(hematology, clinical chemistry, and urinalysis) may be performed within 28 days of first dose 
prior to the start of Cycle 1, Day 1. Laboratory assessments may be performed up to 48 hours 
prior to day 1 of subsequent cycles but must be evaluated by the treating practitioner prior to 
administration of therapy. Repeat testing will be performed as outlined in the Schedule of 
Clinical Assessments (Appendix A) and as clinically indicated.  
Note that prior to each administration of IMGN853, laboratory results must be reviewed to 
evaluate for potential toxicity.  

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7.7.1. 
Clinical Laboratory Panels 
A list of clinical laboratory tests are found in Table 10. 
 
 
 
 

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Table 10: 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Coagulation Tests 
 
Hematocrit 
 
Hemoglobin 
 
WBC (with 5-part 
differential) 
 
RBC 
 
Platelet count 
 
Albumin 
 
Alkaline phosphatase 
 
ALT 
 
AST 
 
BUN 
 
Calcium 
 
Carbon dioxide 
 
Chloride 
 
Creatinine 
 
Glucose 
 
LDH 
 
Magnesium 
 
Phosphorus 
 
Potassium 
 
Sodium 
 
Total Bilirubin 
 
PT 
 
aPTT (APTT) 
 
INR 
WBC, white blood cell count; RBC, red blood cell count; ALT, alanine aminotransferase; AST, aspartate 
aminotransferase; BUN, blood urea nitrogen; LDH, lactic acid dehydrogenase; GFR, glomerular filtration rate; INR, 
International Normalized Ratio; PT, Prothrombin time; aPTT, Activated partial thromboplastin time 
 
7.8. 
Pregnancy Screen and Prevention 
Women of child bearing potential (WCBP), defined as a sexually mature woman who has not 
undergone surgical sterilization or who has not been naturally postmenopausal for at least 12 
consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months) 
must agree to use effective contraceptive methods. Acceptable single methods include: 
intrauterine device, vasectomy of a female patient’s male partner, and contraceptive rod 
implanted into the skin. 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 (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception.  Acceptable combination methods 
(requiring use of two of the following) are acceptable:  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), or hormonal contraceptive such as oral contraceptive pill, 
estrogen/progestin pill or progestin-only pill), contraceptive skin patch, vaginal contraceptive 
ring, or subcutaneous contraceptive injection.  Acceptable methods of contraception must be 
used while on study treatment and for at least twelve weeks after the last dose of IMGN853. 

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All female patients of child-bearing potential will complete a serum beta-human chorionic 
gonadotropin (β-HCG) or urine pregnancy test (not more than 3 days before the first dose of 
IMGN853); this test must be negative for the patient to be enrolled and to receive the study drug. 
If a female patient becomes pregnant or suspects pregnancy while participating in this study, the 
Investigator and Grantor must be informed immediately and the patient will be withdrawn from 
study treatment. 
7.9. 
Eastern Cooperative Oncology Group Performance Status 
ECOG performance status (Appendix B) will be assessed during screening and at other times 
specified in the Schedule of Clinical Assessments (Appendix A). An assessment is not necessary 
on day 1 of Cycle 1 if the screening assessment was obtained within 3 days prior to day 1. 
7.10. 
Radiologic 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 and at every 6 weeks thereafter (±1 
week) (Appendix A ). The same radiographic assessment used at screening must be used at all 
subsequent radiographic evaluations.  
7.11. 
Tumor Response Assessment 
7.11.1. 
RECIST  
Tumor response for patients with measurable lesions should be assessed using RECIST 1.1 
(Eisenhauer 2009, 0). Patients with measurable lesions should be assessed using CT or MRI scan 
approximately every second cycle, from the date of first dose until the 30-day Follow-up visit. 
Although progression may be determined by the investigator based upon clinical deterioration, 
every effort should be made to document progression using radiographic methods. The basis for 
determination of progression per clinical deterioration should be documented.  
The site is expected to maintain a copy of digital data for the retention period applicable to the 
protocol, Good Clinical Practice (GCP), and federal, international, and/or state legal and medical 
requirements.  
Note: It is very important that the same method of radiologic assessment be used 
throughout the study and that the same lesions are followed.  
7.12. 
Eligibility Based on FRα Expression  
Instructions regarding processing and shipment of biopsy samples and archival tissues are 
detailed in the Laboratory Manual. The assay used to assess FRα is an investigational IHC assay 
developed by Ventana. 
All patients must have documented expression of FRα by IHC (>25% of tumor staining at >1+ 
intensity) prior to enrollment. IHC may be performed on archival tissue to determine eligibility. 
If archival tissue is not available, then a fresh tumor biopsy must be obtained. Assessment of 
Safety 

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7.13. 
Recording Adverse Events and Serious Adverse Events 
AEs (including SAEs) will be documented in an AE eCRF, Research Electronic Data Capture 
(REDCap), and monitored continuously throughout the study from the time of informed consent 
until 30 days after the patient’s last study treatment or until the event has resolved or stabilized 
or becomes chronic, whichever comes first.  AEs attributed to study procedures should also be 
documented in REDCap.   
For patients who discontinue study treatment due to a study-related AE, the reporting time-
period may be extended.  These patients must be followed at least once a week for 4 weeks, and 
subsequently at 4-week intervals until resolution, stabilization or chronic state of the adverse 
event or laboratory abnormality, whichever comes first (see Section 5.10.2.). 
If the Investigator considers it necessary to report an AE considered study drug related in a study 
patient occurring after the end of study, he or she should contact the Grantor to determine how 
the AE should be documented and reported. 
7.13.1. 
Definition of Adverse Events 
7.13.1.1. 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 must be reported in REDCap, 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, resolve or are 
considered chronic. 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. 

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Table 11: Adverse Event Recording Guidelines 
Recommended Adverse Event Recording Guidelines 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II   
 
Phase I 
Phase II   
Phase III 
Phase I  
Phase II   
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I  
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Possible 
Phase I 
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Probable 
Phase I 
Phase II  
 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Definitive 
Phase I 
Phase II  
  
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II  
Phase III  
Phase I 
Phase II   
Phase III 
 
 
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 (e.g., the reason for study discontinuation or 
constitutes in and of itself a Serious Adverse Event, or require therapy, e.g., any hematologic 
abnormality that requires transfusion or growth factor treatment); and should be recorded in 
REDCap under the signs, symptoms or diagnosis associated with them. In the event of an out-of-
range value, the laboratory test should be repeated until it returns to normal or can be explained 
and the patient’s safety is not at risk.  
7.13.1.2. Serious Adverse Event (SAE) Reporting 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the patient, in 
the view of the initial reporter, at immediate risk of death from the adverse experience as it 
occurred. It does not include an adverse experience that, had it occurred in a more severe form, 
might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 

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• A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject 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, or the development of drug dependency or drug abuse (21 CFR 312.32). 
 
• Important medical events as defined above, may also be considered serious adverse events. 
Any important medical event can and should be reported as an SAE if deemed appropriate by the 
Principal Investigator or the IND Sponsor, IND Office. 
• All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in “The 
University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and Devices”.  
Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported to 
the IND Office, regardless of attribution (within 5 working days of knowledge of the event). 
• All life-threatening or fatal events, that are unexpected, and related to the study drug, must 
have a written report submitted within 24 hours (next working day) of knowledge of the event to 
the Safety Project Manager in the IND Office.   
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB.  
• Serious adverse events will be captured from the time of informed consent, until 30 days after 
the last dose of drug, unless the participant withdraws consent. Serious adverse events must be 
followed until clinical recovery is complete and laboratory tests have returned to baseline, 
progression of the event has stabilized, or there has been acceptable resolution of the event. 
• Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
 
Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 

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It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
7.13.1.3. 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 Grantor’s product for which ongoing monitoring and rapid 
communication by the investigator to the Grantor could be appropriate.   These are reportable to 
the Grantor using an SAE form and in the same timeframe as SAEs 
7.13.1.3.1. IMGN853 
IMGN853 has one AESI:  pneumonitis 
7.13.2. 
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 12. 
 
Table 12:     Adverse Event Severity 
Severity 
Definition 
Grade 1 (Mild) 
No limitations 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 listed in Table 13. Relationship should be attributed not only to the 
combination regimen, but also to each drug within the combination regimen. 
Table 13:         Adverse Event Causal Relatedness 
Relationship to the Product(s) 
Definition 
Not Related 
No relationship between the event, including laboratory test 
abnormality, and the administration of study drug. There is no 

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temporal relationship and there is ambiguous evidence supporting 
another case. 
Relationship to the Product(s) 
Definition 
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 the 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. 
 
7.14. 
Adverse Events 
7.14.1. 
Reporting Serious Adverse Events 
Any SAE, regardless of relationship to study medications, which occurs in a patient from the 
time of informed consent until 30 days after the last study treatment of IMGN853 should be 
recorded by the clinical site on an SAE report form. The SAE must also be recorded in the 
patient’s eCRF, including the causality assessment of the Investigator as to the relationship of the 
SAE to the study treatment [IMGN853]. The Investigator will promptly supply all information 
identified and requested by the Grantor (or contract research organization [CRO]) regarding the 
SAE.  
The Investigator must report the SAE to ImmunoGen Pharmacovigilance (or designee) on an 
SAE Report Form. This form must be completed and submitted within 24 hours of the 
Investigator’s learning of the event, to the contact persons listed in the Safety Management Plan 

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provided to each site and maintained in the Investigator study files. Any follow-up information 
must also be completed on a follow-up an SAE Report Form, and submitted to the same contacts. 
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). 
 Progression of disease should not be reported as an SAE unless it is considered to be 
drug-related by the investigator; any serious medical event/condition that results from 
progression of underlying disease should be reported as the SAE. 
 Death should not be reported as an SAE, but rather as an outcome of a specific SAE, 
unless the event preceding the death is unknown. In these exceptional cases, death 
may be used as an event term. If an autopsy was performed, the autopsy report should 
be provided. 
It is the responsibility of the Grantor to ensure that each Investigator receives a copy of any 
CIOMS/MedWatch report that has been submitted to the appropriate national regulatory 
agencies as notification of a suspected unexpected serious adverse reaction (SUSAR). The 
Investigator (or Grantor or Grantor’s representative if so designated) must promptly report all 
SUSARs to the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for review 
in accordance with national regulations. IRB/IEC notification of the SUSAR may take the form 
of a submission of a copy of the CIOMS/MedWatch report or other format accepted by the 
IRB/IEC. A copy of the CIOMS/MedWatch report and notification to IRB/IEC should be 
retained in the site’s study files.  
In addition to CIOMS/MedWatch reports, the Grantor will also notify the Investigators and 
IRBs/IECs of all deaths that occur during the study, irrespective of relationship to study 
medication through annual updates to the IB. 
Disease progression and/or progression of the disease under study are anticipated occurrences in 
oncology drug development, and as such, are considered expected as per the current 
investigator’s brochure for the compound. If a patient expires from progression of disease and/or 
from the disease under study during the period of obligation to report serious adverse events, 
disease progression and/or progression of the disease under study with a fatal outcome do not 
need to be reported as serious adverse events. The applicable protocol CRF page(s) pertaining to 
death should be appropriately completed however, as disease progression. 
Additionally, any serious adverse event, considered by an investigator who is a qualified physician 
to be related to the Grantor's product that is brought to the attention of the investigator at any time 
following consent through the end of the specified safety follow-up period specified in the 
paragraph above, or at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Grantor. 
All patients with serious adverse events must be followed up until the event returns to baseline, 
stabilizes or becomes chronic. 

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SAE Reporting to ImmunoGen and NCCN 
SAEs, including those that are expedited (MedWatch/CIOMS preferred.  Listing acceptable) 
should be sent to ImmunoGen at: IMGNPVGSAFETY@immunogen.com; AND to NCCN at 
ORPreports@nccn.org OR 215-358-7699 
 
IND SAFETY REPORTS (final MedWatch only) must be sent, upon submission to FDA, to:   8 
IND SAFETY REPORTS (final 53IST_SUSAR@immunogen.com 
 
7.14.2. 
Reporting Adverse Events of Special Interest 
Any AESI, regardless of relationship to study medications, which occurs in a patient from the 
time of informed consent until 30 days after the last study treatment, should be recorded by the 
clinical site on an SAE report form.  The reporting procedures outlined in Section 7.14.1.will be 
followed for reporting any AESI, including AESIs are reportable to the Grantor in the same 
timeframe as SAEs. 
7.14.3. 
Reporting a Pregnancy 
Pregnancy and lactation are exclusion criteria.  The Grantor 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 IMGN853 and through 30 days following cessation of study treatment if the 
subject initiates new anticancer therapy, whichever is earlier.  Pregnancy is not to be reported as 
an AE; the pregnancy report form should be used to report a pregnancy.  All reported 
pregnancies must be followed to the completion/termination of the pregnancy. Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, 
fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events).  The reporting procedures in Section 7.14.1, will be followed, 
including pregnancies and pregnancy outcomes listed above are reportable to the Grantor in the 
same timeframe as SAEs.  If the pregnancy continues to term, the outcome (health of infant) 
must also be reported. 
 

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8. 
STUDY ACTIVITIES 
All study visits and assessments that must be performed during the study and follow-up are 
included in Appendix A. 
8.1. 
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. The 
following screening procedures must be performed within 28 days prior to day 1, unless 
otherwise specified.  
8.1.1. 
Standard of Care Assessments 
In some cases, clinical assessments performed prior to obtaining informed consent may be used 
to qualify the patient for the study. These include radiological tumor assessment, physical 
examinations, hematology, serum chemistry results, coagulation studies, urinalysis, or other 
assessments which may be considered part of normal standard of care. In these cases, repeat 
assessments may not be necessary prior to enrollment, unless individual parameters require 
further study or confirmation and are clinically appropriate. 
8.2. 
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 5.11.  
Patients who withdraw or are removed from the study treatment will have an end of treatment 
visit within 7 days of the decision to discontinue study treatment. Additionally, these patients 
will undergo a 30-day follow-up safety visit. The eCRF will capture reasons for withdrawal.  
8.3. 
Follow-up Assessments 
8.3.1. 
Safety Follow-up  
A safety follow-up visit will occur 30 days (+ 14 days) after the last treatment.  
All serious adverse events, and those adverse events assessed by the Investigator as at least 
possibly related to study drug should continue to be followed until they resolve or stabilize, 
whichever comes first.  Reporting of SAEs are detailed in Section 7.14.1. 
8.3.2. 
Response Follow-up 
Patients who have discontinued study treatment for reasons other than PD will be followed per 
Revised Response Criteria (RECIST 1.1, see 0) every 12 weeks (+/- 3 weeks) until 
documentation of PD, or until the patient starts subsequent anti-cancer therapy, whichever comes 
first.  

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9. 
STATISTICAL METHODS 
Advanced/Metastatic Disease (Cohort A): A 20% response rate in metastatic TNBC is 
considered clinically meaningful and would be the threshold to activate the proposed 
neoadjuvant cohort. Using a standard inference-based Simon-type design, p0 is specified as the 
response rate threshold below which a treatment would be clearly unacceptable and p1 is 
specified as the response rate above which the treatment would be clearly acceptable. For this 
cohort, p0 will be defined as 2.5% and p1 will be 20%. Response (defined as confirmed CR or 
PR by RECIST) will be assessed after 10 patients with measurable metastatic disease have 
undergone response assessment. If at least 1 patient develops response to therapy, the cohort will 
continue to accrue until a total of 20 patients with measurable disease have undergone response 
assessment. If at any point, 2 patients develop response to therapy, the 20% activity threshold 
will have been met and accrual can begin to the neoadjuvant cohort while accrual to the 
metastatic cohort continues to a total of 20 patients. If no patient develops confirmed response in 
the initial 10 patients, accrual to the single agent regimen will be stopped. This two-phase design 
has the following properties where p=true response rate, PET=probability of early termination 
(after the first stage, n=10) and PDS=probability of declaring success (i.e. that the treatment is 
worthy of further study) after the second stage: 
Table 14:        Probability of Protocol Success 
P 
PET 
PDS 
0.010 
0.90 
0.02 
0.025 
0.78 
0.07 
0.050 
0.60 
0.21 
0.100 
0.35 
0.51 
0.150 
0.20 
0.73 
0.200 
0.11 
0.86 
0.250 
0.06 
0.93 
0.300 
0.03 
0.97 
PDS at p0 is equal to alpha (probability of false positive conclusion) and PDS at p1 is equal to 
the power (1- beta = probability of true positive conclusion). So, for the proposed design, alpha = 
7% and we have 86% power. The probability of early termination at p0 = 78%. 
Following this design, for subsequent patient safety, enrollment will be halted while waiting for 
one of the first 10 patients to respond to therapy. If there are no responses within the first six 
months of starting treatment in the first 10 patients or <2 responses in the 20 patients treated 
using single agent therapy, then accrual will be held and a discussion for amending the trial will 
be held with NCCN and ImmunoGen to either: 1) include a doublet of mirvetuximab 
soravtansine in combination with carboplatin, or 2) to expand accrual as a single agent in the 
metastatic setting and forgo the neoadjuvant cohort of patients. 

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Neoadjuvant (Cohort B): This will be a non-randomized open label phase II study. Counting 
pCR (RCB-0) or RCB-I as response, a two-stage Gehan-type design will be employed with 14 
patients in the first stage. If at least one patient responds, 23 more patients will be added for a 
total of 37 patients. This design has a 49% chance of terminating after the first stage if the true 
response rate is 0.05, 23% chance if the true rate is 0.10, 10% if the true rate is 0.15 and 4% if 
the true rate is 0.20. If accrual continues to the second stage and a total of 37 patients are 
enrolled, the 95% confidence interval for a 0.20 response rate will extend from 0.10 to 0.35. For 
patients who complete 4 cycles of mirvetuximab soravtansine, the proportion of patients with 
pCR (RCB-0) or RCB-I as the response rate along with a Wilson (score) 95% confidence 
interval (CI) will be estimated. 
Secondary Objectives: 
Radiographic response rate (partial response + complete clinical response) will be estimated, and 
reported with a 95% CI. 
Toxicity will be measured according to CTCAE v4.0.  Adverse events and serious adverse events 
will be summarized in order of prevalence, with the highest grade experienced by each patient 
reported for each adverse event.   
DFS, PFS, and OS will be estimated using the Kaplan-Meier method from the date of enrollment 
onto this study until the date of progression or death without evidence of progression (for DFS), 
date of disease progression (for PFS) or death (for OS). Patients alive and disease-free at the 
latest clinical evaluation will be censored for DFS and OS at the date of that evaluation. DFS, 
PFS and OS will be reported with a 95% CI. Duration of response will be measured from the 
date of confirmed response to the date of disease progression (as measured by RECIST) or 
discontinuation of study drug due to toxicity. 
In the neoadjuvant setting (Cohort B), disease response (as measured by pCR/RCB-I) in patients 
with chemotherapy resistant disease treated with mirvetuximab soravtansine will be compared to 
those with similar molecular features who receive standard taxane-based chemotherapy while 
enrolled in the ARTEMIS trial. Though this comparison will not be a randomized comparison, it 
will provide evidence as to whether patients treated with mirvetuximab soravtansine derive 
additional clinical benefit and the comparison can be used to provide preliminary data for 
confirmatory phase III clinical trial design. A one-sided Fisher’s exact test will be used to 
compare the pCR rate (RCB=0 or I) between the standard therapy patients and the mirvetuximab 
soravtansine treated patients.  Assuming 13 standard therapy patients with a true pCR rate of 5% 
and 37 mirvetuximab soravtansine patients with a pCR rate of 40%; we will have 76.9% power 
to detect a significant increase in the pCR rate at the 0.05 significance level.  As an exploratory 
analysis, the distribution of RCB scores measured on a continuous scale will be compared 
between these two groups using a Wilcoxon rank-sum test.  Assuming that there is a 0.72 
probability that the RCB is less for the mirvetuximab soravtansine treated group, the Wilcoxon 
rank-sum test will have approximately 81% power to detect a difference in the distribution of 
RCB scores. 
Exploratory Objectives: 
Potential biomarkers of response will be correlated with pathologic response to mirvetuximab 
soravtansine versus paclitaxel (patients who receive standard of care on ARTEMIS) using 

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appropriate statistical analyses for the biomarker of interest. It is anticipated that expression of 
the gene that encodes FR (FOLR1) as measured by RNAseq may predict response to therapy 
and response will be correlated in tumors categorized as FOLR1+ using level of expression. 
Similarly, it is anticipated that FR+ staining will also be correlated with response. Protein 
expression will be graded 0, 1+, 2+ or 3+ by IHC by a single collaborating pathologist. Degree 
of expression will then be correlated with presence of FOLR1 as measured by RNAseq as well as 
response to therapy. Presence of mutations will also be correlated with response. Further, 
multivariate logistic regression models will be fitted to the data that include three explanatory 
variables; namely dichotomous variables for treatment (targeted therapy vs paclitaxel), FOLR1 
expression, and the interaction.  The interaction will be examined to investigate if the 
relationship between FOLR1 expression status and pathologic response (RCB-0 or I) is different 
for the two treatments.  
The Investigator is responsible for completing the cohort summary report and submitting it to the 
IND office Medical Monitor for review and approval.  
Cohort A (Metastatic TNBC Cohort): 
A Response/Toxicity Summary will be submitted after the first ten evaluable patients complete 
the fourth cycle of study, prior to continue enrollment, and after all 20 evaluable patients 
complete the fourth cycle of study therapy  
Cohort B (Neoadjuvant Cohort): 
A Response/Toxicity Summary will be submitted to IND Office Medical Monitor after the first 
fourteen evaluable patients, and after all 37 patients complete the fourth cycle of study therapy. 
9.1. 
Quality control and assurance 
Data will be captured using validated systems. Adverse events will be coded using Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.03; National Cancer Institute; 
June 14, 2010; NIH Publication No 09-5410. 
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. 
Data should be entered in the system must be verifiable against source documents.  

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10. 
ADMINISTRATIVE CONSIDERATIONS, STUDY 
MONITORING AND DATA MANAGEMENT 
10.1. 
Investigators and Study Administrative Structure 
Before initiation of the study, the Investigators must complete a Form FDA 1572. Study 
medications may be administered only under the supervision of the Investigators listed on this 
form. Curriculum vitae must be kept on file 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. 
10.2. 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval 
Before initiation of the study, the Investigator must provide the Grantor with a copy of the 
written IRB/IEC approval of the protocol and the study ICF. 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. 
Grantor Status reports must be submitted to the IRB/IEC at least once per year or as per 
institutional guidelines. The IRB/IEC must be notified of completion of the study and a final 
report must be provided to the IRB/IEC. A copy of these reports will be sent to the study clinical 
monitor or designee. The Investigators must maintain an accurate and complete record of all 
submissions made to the IRB/IEC, including a list of all reports and documents submitted. AEs 
which are subject to expedited reporting to the US Food and Drug Administration (FDA) or 
other regulatory agencies (SUSARs) must be submitted promptly to the IRB/IEC. 
10.3. 
Ethical Conduct of the Study 
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Grantor and Investigators abide by 
Good Clinical Practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonisation (ICH) GCP Guidelines. Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in the 
Declaration of Helsinki. 
10.4. 
Patient Information and Consent 
Before enrolling in the clinical study, the patient or the patient’s legally authorized 
representative(s) must consent to participate after the nature, scope, and possible consequences 
of the clinical study have been explained in a form understandable to him or her. An ICF that 
includes information about the study will be prepared and given to the patient, or the patient’s 
legally authorized representative(s). This document will contain all FDA and ICH-required 
elements. The ICF must be in a language understandable to the patient or the patient’s legally 

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authorized representative(s) and must specify who informed the patient or the patient’s legally 
authorized representative. 
After reading the informed consent document, the patient or the patient’s legally authorized 
representative(s) must give consent in writing. If the patient or the patient’s legally authorized 
representative(s) is unable to read, oral presentation and explanation of the written ICF and 
information to be supplied must take place in the presence of an impartial witness. Consent must 
be confirmed at the time of consent orally and by the personally dated signature of the patient or 
by the patient’s legally authorized representative(s). The witness and the person conducting the 
informed consent discussions must also sign and personally date the informed consent document. 
It should also be recorded and dated in the source document that consent was given. 
A copy of the signed and dated consent document(s) must be given to the patient or the patient’s 
legally authorized representative(s). The original signed and dated consent document will be 
retained by the Investigator. Patient confidentiality will be maintained as outlined in Section 10.5. 
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained. 
10.5. 
Patient Confidentiality 
Patient names will not be supplied to the Grantor. If the patient name appears on any documents, 
it must be redacted before a copy of the document is supplied to the Grantor. Study findings 
stored on a computer will be stored in accordance with local data protection laws. Patient blood 
and tissue samples sent to outside laboratories and/or CROs (e.g. IHC laboratory) are identified 
by study patient number only to ensure maintenance of confidentiality. The patient consent form 
will state publications resulting from this study will not refer to patient name or include any other 
information that might disclose the identity of the subject. The patients will be told that 
representatives of the Grantor, 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. 
10.6. 
Study Monitoring 
Monitoring procedures that comply with current GCP guidelines will be followed. On-site 
review of the case report forms (CRFs) for completeness and clarity, cross-checking with source 
documents, and clarification of administrative matters should be performed. 
10.7. 
Grantor Case Report Forms and Study Reports 
Case report forms (paper or electronic) are provided for each patient. All forms must be filled out 
by authorized study personnel. All corrections to the original CRF entry must indicate the reason 
for change. The Investigator is required to sign/e-sign the CRF after all data have been captured 
for each patient. If corrections are made after review and signature by the Investigator, he or she 
must be made aware of the changes, and his or her awareness documented by re-signing the CRF. 

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10.8. 
Critical Documents 
Before the trial initiates (i.e., obtains informed consent from the first patient), it is the 
responsibility of the Investigator to ensure that the following documents are available: 
 Curricula vitae of Investigator and sub-investigator(s) (current, dated and signed or 
supported by an official regulatory document) 
 Signed and dated agreement of the final protocol 
 Signed and dated agreement of any amendment(s), if applicable 
 Approval/favorable opinion from the IRB/IEC clearly identifying the document and 
document revision reviewed, including but not limited to: the protocol, any protocol 
amendments, Investigator’s Brochure, Patient Information/Informed Consent Form, 
and any other written information to be provided regarding patients recruitment 
procedures 
 Copy of IRB/IEC approved Patient Information/Informed Consent Form/any other 
written information/advertisement 
 List of IRB/IEC Committee members/constitution or equivalent compliance statement 
 Study and Financial agreement(s) 
 Completed Form FDA 1572 
 Completed Financial Disclosure Form 
10.9. 
Protocol Violations/Deviations 
The Investigator will conduct the study in compliance with the protocol. The protocol will not be 
initiated until the IRB/IEC and the appropriate regulatory authorities have given 
approval/favorable opinion. Modifications to the protocol will be made in consultation with 
NCCN and Grantor. Changes to the protocol will require written IRB/IEC approval/favorable 
opinion prior to implementation, except when the modification is needed to eliminate an 
immediate hazard(s) to patients. The IRB/IEC may provide, if applicable regulatory authorities 
permit, expedited review and approval/favorable opinion for minor change(s) in ongoing studies 
that have the approval/favorable opinion of the IRB/IEC. The Grantor-investigator will submit 
all protocol modifications to the regulatory authorities in accordance with the governing 
regulations. 
A record of patients screened, but not entered into the study, is also to be maintained.  
When immediate deviation from the protocol is required to eliminate an immediate hazard to 
patients, the Investigator will contact the Grantor or its designee if circumstances permit, to 
discuss the planned course of action. Any departures from the protocol must be fully documented 
as a protocol deviation. Protocol deviations will need to be reviewed by the Medical Monitor and 
may be required to be submitted to the IRB/IEC as per institutional guidelines. 
 
 

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Protocol modifications will only be initiated by the Grantor-investigator and must be approved 
by the IRB/IEC and submitted to the FDA or other applicable international regulatory authority 
before initiation. 
10.10. 
End of Study 
End of study is defined as the date when the last patient on study has withdrawn or been 
discontinued from the study and all necessary follow up visits have been completed in order to 
complete safety and anti-tumor activity assessments. 
10.11. 
Study termination 
10.11.1. 
Study Termination 
If the Grantor, an Investigator, or Study Clinical Monitor discovers conditions arising during the 
study that indicate that the clinical investigation should be halted due to an unacceptable patient 
risk, the study must be terminated after appropriate consultation between ImmunoGen and the 
Investigator. 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. 
10.11.2. 
Site Termination 
A study may be terminated for, but not limited to, the following conditions: 
 The discovery of an unexpected, significant, or unacceptable risk to the patients 
enrolled at the site 
 Failure of the Investigator to enter patients at an acceptable rate 
 Insufficient adherence by the Investigator to protocol requirements 
 Insufficient, incomplete, and/or unevaluable data 
10.12. 
Access to Source Documentation 
Regulatory authorities, the IEC/IRB, or the Grantor may request access to all source documents, 
CRFs, and other study documentation for on-site audit or inspection. Direct access to these 
documents must be guaranteed by the Investigator, who must provide support at all times for 
these activities. Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed. On-site review of the CRFs for completeness and clarity, cross-checking with 
source documents, and clarification of administrative matters will be performed. 
10.13. 
Data Generation and Analysis 
The clinical database will be developed and maintained by the investigator or designee and will 
be responsible for performing study data management activities and analyses. 

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10.14. 
Retention of Data 
Essential documents should be retained until the following requirements are met: 
 A minimum of 2 years has elapsed following the last approval of a marketing application 
and, 
 there are no pending or contemplated marketing applications, or 
 at least 2 years have elapsed since the formal discontinuation of clinical development of 
the investigational product, or  
 the record retention policies and guidelines for countries in which the study is being 
conducted are followed (whichever is longer) 
It is the responsibility of the Grantor to inform the Investigator or institution as to when these 
documents no longer need to be retained. 
10.15. 
Financial Disclosure 
The Investigator should disclose any financial interests in the Grantor as described in 21 CFR 
Part 54 prior to beginning this study and 12 months after the study has completed. The 
appropriate form will Grantor be signed and dated by the Investigator, prior to the start of the 
study.  
10.16. 
Publication and Disclosure Policy 
The information obtained during the conduct of this clinical study is confidential, and disclosure 
to third parties other than those noted below is prohibited. All information concerning the 
product as well as any matter concerning the operation of the Grantor, 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 Grantor and are unpublished, are confidential and must remain 
the sole property of the Grantor. 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 Grantor is obtained. 
Information obtained during the conduct of this study may be used by ImmunoGen in connection 
with the development of the study drug. This information may be disclosed to other physicians 
who are conducting similar studies and to the FDA as deemed necessary by the Grantor. 

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SUPPORTER MAY PUBLISH THE RESULTS OF OR SUBMIT ABSTRACTS OF THE 
STUDIES AFTER REVIEW BY NCCN AND GRANTOR. SHOULD THE RESULTS OF A 
STUDY OR STUDIES BE DERIVED FROM A MULTICENTER STUDY, NEITHER NCCN, 
NOR ANY MEMBER INSTITUTION(S) SHALL PUBLISH ITS OWN INDIVIDUAL RESULTS, 
BUT RATHER, ALL SHALL PARTICIPATE IN A JOINT, MULTICENTER PUBLICATION 
OF THE STUDY RESULTS. NCCN SHALL CONTRACTUALLY REQUIRE EACH MEMBER 
INSTITUTION TO AGREE TO (A) PROVIDE GRANTOR A COPY OF ANY MANUSCRIPT 
OR ABSTRACT RELATING TO A STUDY, (B) NOT PUBLISH ANY MANUSCRIPT OR 
ABSTRACT RELATING TO A STUDY UNTIL GRANTOR HAS HAD AN OPPORTUNITY TO 
REVIEW IT, (C), UPON THE WRITTEN REQUEST OF GRANTOR, DELAY THE 
PUBLICATION AND DISCLOSURE OF SUCH MANUSCRIPT OR ABSTRACT TO ANY 
THIRD PARTY FOR UP TO AN ADDITIONAL SIXTY (60) DAYS SO THAT GRANTOR MAY 
SEEK PATENT PROTECTION OF INTELLECTUAL PROPERTY RIGHTS, (D) DELETE 
FROM ANY MANUSCRIPT OR ABSTRACT ANY INFORMATION THAT GRANTOR 
REQUESTS AND BELIEVES IS ITS CONFIDENTIAL INFORMATION, (E) ACKNOWLEDGE 
GRANTOR AS THE SUPPLIER OF THE STUDY DRUG AND (F) NOT ISSUE A PRESS 
RELEASE THAT REFERENCES THE STUDIES OR RESULTS WITH GRANTOR’S NAME 
OR TRADEMARKS WITHOUT THE PRIOR WRITTEN CONSENT OF GRANTOR.  NCCN 
SHALL CONTRACTUALLY REQUIRE EACH MEMBER INSTITUTION TO PROVIDE A 
FINAL REPORT OR MANUSCRIPT FOR PUBLICATION FOR REVIEW WITHIN NINE (9) 
MONTHS OF THE CONCLUSION OF THE APPLICABLE STUDY  
 

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11. 
LIST OF  REFERENCES: 
Ab O, Whiteman KR, Bartle LM, et al. IMGN853, a folate receptor-α (FRα)-targeting antibody-
drug conjugate, exhibits potent targeted antitumor activity against FRα-expressing tumors. 
Molecular Cancer Therapeutics 14(7): 1605-1613, 2015. 
Aghajanian C, Sill MW, Darcy KM, et al.  Phase II trial of bevacizumab in recurrent or 
persistent endometrial cancer: A Gynecologic Oncology Group Study. Journal of Clinical 
Oncology 29:2259-2265, 2011. 
Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-
controlled phase II trial of chemotherapy with or without bevacizumab in patients with platinum-
sensitive recurrent eithlial ovarian, primary peritoneal or Fallopian tube cancer. Journal of 
Clinical Oncology 30 (17): 2039-2045, 2012.   
Akram T, Masseelall P, Fanning J, Carboplatin and paclitaxel for the treatment of advanced or 
recurrent endometrial cancer. American Journal of Obstetrics and Gynecology 192: 1365-7, 
2004. 
Allard JE, Risinger JI, Morrison C, et al. Overexpression of folate binding protein is associated 
with shortened progression-free survival in uterine adenocarcinomas. Gynecologic Oncology 
107: 52-57, 2007. 
Basal E, Eghbali-Fatourechi GZ, Kalli KR, et al. Functional folate receptor alpha is elevated in 
the blood of ovarian cancer patients. PLOS ONE 4: e6292, 2009. 
Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology 
Clinical Practice Guideline Update. Journal of Clinical Oncology 29: 4189-4196, 2011. 
Burger R, Brady M, Bookman M, et al. Incorporation of bevacizumab in the primary treatment 
of ovarian cancer. New England Jornal of Medicine 365: 2473–2483, 2011. 
Cannistra SA. Cancer of the Ovary. New England Journal of Medicine 351:2519-2529, 2004. 
Chen YL, Chang MC, Huang CY et al. Serous ovarian carcinoma patients with high alpha-folate 
receptor had reducing survival and cytotoxic chemo-response Molecular Oncology 6: 360-369, 
2012.  
Crane LMA, Arts JG, van Oosten M, et al. The effect of chemotherapy on expression of folate 
receptor-alpha in ovarian cancer. Cellular Oncology 35(1): 9-18, 2012. 
Dainty LA, Risinger JI, Morrison C, et al. Overexpression of folate binding protein and 
mesothelin are associated with uterine serous carcinoma. Gynecologic Oncology 105: 563-570, 
2007. 
Eisenhauer E, Therasse P, Bogaerts J, et al. New response criteria in solid tumors: Revised 
RECIST Guideline (version 1.1). European Journal of Cancer 45: 228-247, 2009. 

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Elnakat H, Ratnam M. Distribution, functionality and gene regulation of folate receptor 
isoforms: implications for targeted therapy. Advanced Drug Delivery Reviews 56: 1067-1084, 
2004. 
Erickson HK, Park PU, Widdison WC, et al. Antibody-Maytansinoid conjugates Are Activated 
in Target Cancer Cells by Lysosomal Degradation and Linker-Dependent Intracellular 
Processing. Cancer Research 66:4426-4433, 2006. 
Fisher RE, Siegel BA, Edell SL, et al., Exploratory study of 99mTc-EC20 imaging for 
identifying patients with folate-receptor positive solid tumors. Journal of Nuclear Medicine 
49:899-906, 2008.  
Garcia A, Singh H. Bevacizumab and ovarian cancer. Therapeutic Advances in Medical 
Oncology 5 (2): 133-141, 2013. 
Garin-Chesa P, Campbell I, Saigo PE, et al. Trophoblast and ovarian cancer antigen LK26, 
sensitivity and specificity in immunopathology and molecular identification as a folate binding 
protein. American Journal of Pathology 142: 557-567, 1993. 
Gordon AN, Granai CO, Rose PG et al. Phase II study of liposomal doxorubicin in platinum- and 
paclitaxel-refractory epithelial ovarian cancer, Journal of Clinical Oncology 18: 3093–3100, 
2000. 
Hoskins PJ, Swenerton KD, Pike JA, et al. Paclitaxel and carboplatin, alone or with irradiation, 
in advanced or recurrent endometrial cancer: a phase II study. Journal of Clinical 
Oncology 19:4048–4052, 2001, 
Hough CD, Cho KR, Zonderman AB, et al. Coordinately up-regulated genes in ovarian cancer. 
Cancer Research. 61: 3869-3876, 2001. 
Humber CE, Tierney JF, Symonds RP, et al. Chemotherapy for advanced, recurrent or metastatic 
endometrial cancer: a systematic review of Cochrane collaboration. Annals of Oncology 18: 409-
20, 2007. 
Jones MB, Neuper C, Clayton A, et al., Rationale for folate receptor alpha targeted therapy in 
“high risk” endometrial carcinomas. International Journal of Cancer 123: 1699-1703, 2008. 
Kalli KR, Oberg AL, Keeney GL, et al. Folate receptor alpha as a tumor target in epithelial 
ovarian cancer. Gynecologic Oncology 108: 619-629, 2008. 
Kelemen LE. The role of folate receptor α in cancer development, progression and treatment: 
cause, consequence or innocent bystander? International Journal of Cancer 119: 243-250, 2006. 
Markman M, Kennedy A, Webster K, et al, Phase 2 trial of liposomal doxorubicin (40mg/m2) in 
platinum/paclitaxel-refractory ovarian and fallopian tube cancers and primary carcinoma of the 
peritoneum, Gynecologic Oncology 78: 369–372, 2000. 

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Mantovani LT, Miotti S, Menard S, et al. Folate binding protein distribution in normal tissues 
and biological fluids from ovarian carcinoma patients as detected by the monoclonal antibodies 
MOv18 and MOv19. International Journal of Cancer 30A: 363-369, 1994. 
Muggia FM, Hainsworth JD, Jeffers S, et al. Phase II study of liposomal doxorubicin in 
refractory ovarian cancer: antitumor activity and toxicity modification by liposomal 
encapsulation. Journal of Clinical Oncology 15: 987-993, 1997. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. American Journal of Clinical Oncology 5(6):649-655, 1982. 
Rustin GJS, Quinn M, Thigpen T, et al. New guidelines to evaluate the Response to Treatment in 
Solid Tumors (Ovarian Cancer). Journal of Clinical Oncology 96(6): 487-88, 2004. 
Scorer P, Lawson N and Quinn A. A full immunohistochemical evaluation of a novel 
monoclonal antibody to folate receptor-alpha (FR-α). Novacastra Journal of Histopathology 3: 
8-12, 2010.  
Surveillance, Epidemiology, and End Results (SEER) Cancer Stat Fact Sheets. 
htpp://seer.cancer.gov/statfacts/html/corp/html Accessed August 10, 2015 
van Dam GM, Themelis G, Crane LM, et al. Intraoperative tumor-specific fluorescence imaging 
in ovarian cancer by folate receptor-α targeting: first in-human results. Nature Medicine 17: 
1315-1319, 2011. 
Wadler S, Benson A, Engelking C, et al. Recommended Guidelines for the Treatment of 
Chemotherapy-Induced Diarrhea. Journal of Clinical Oncology 16: 3169-3178, 1998. 
Weitman SD, Lark RH, Coney LR et al. Distribution of the folate receptor GP38 in normal and 
malignant cell lines and tissues. Cancer Research 52: 3396-3401, 1992. 
Younes A, Kim S, Romaguera J, et al. Phase I multidose-escalation study of the anti-CD19 
maytansinoid immunoconjugate SAR3419 administered by intravenous infusion every 3 weeks 
to patients with relapsed/refractory B-cell lymphoma. Journal of Clinical Oncology 30:2776-
2782, 2012.

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APPENDIX A. SCHEDULE OF CLINICAL ASSESSMENTS COHORT A –  
Activity 
Screening 
Cycle 1 
Cycle2 
Cycle 3 
Cycle 
>4 
End of 
Treatment 
30-Day 
Follow-up 
(+14 Days) 
Day 
1 
Day 
2 
Day 
8& 
15 
Day 
1 
Day 
8& 
15 
Day 15 
to 21 
Da
y 1 
Day 
2 
Day 
8 & 
15 
Day 1 
Informed Consent 
a 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
a 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
a 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm Disease 
Diagnosis/Current Stage 
and Prognostic Index 
Evaluation 
a 
 
 
 
 
 
 
 
 
 
 
 
 
Record Baseline Signs 
and Symptoms 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review and document 
IC/EC 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm patient continues 
to satisfy I/E Criteria 
including expression of 
FRα 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm patient meets 
retreatment criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
a 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationb 
c 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
c 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsd 
c 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse Oximetry 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS 
c 
m 
 
 
 
 
 
 
 
 
 
 
 
Hematology and 
Chemistry f 
c 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation (PT/INR/ 
aPTT) f 
c 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (urine or 
serum) e 
c, g 
g 
 
 
g 
 
 
g 
 
 
g 
 
g 
Ophthalmic 
examinations h 
 
Every other cycle (from point at which toxicity first reported)k 
 
 
Schirmer’s Test h 
 
For patients who experience treatment-emergent eye disorders, the 
Schirmer’s Test will be repeated at the first on-study ophthalmic 
examination and at subsequently if clinically indicated 
 
 

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79 
 
Activity 
Screening 
Cycle 1 
Cycle2 
Cycle 3 
Cycle 
>4 
End of 
Treatment 
30-Day 
Follow-up 
(+14 Days) 
Day 
1 
Day 
2 
Day 
8& 
15 
Day 
1 
Day 
8& 
15 
Day 15 
to 21 
Da
y 1 
Day 
2 
Day 
8 & 
15 
Day 1 
Ocular Symptom 
Assessment h 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biopsy n 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiologic tumor 
assessment i 
a 
 
 
 
 
 
Every 2 
cyclesi 
 
 
 
 
j 
j 
IMGN853 
Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE and SAE 
assessments 
l 
 
 
 
 
 
 
 
 
 
 
 
 
Record concomitant 
medication 
a 
 
 
 
 
 
 
 
 
 
 
 
 
a. 
Within 28 days prior to the start of Cycle 1, Day 1 
b. Directed physical examination is acceptable while on study treatment. Full examination is required at screening 
and the EOT visit. 
c. 
Within 14 days prior to the start of Cycle 1, Day 1 
d. Vital Signs (blood pressure, pulse, respiration rate, and temperature) will be measured as outlined in the full 
protocol (Section 8.6) 
e. 
Only for WCBP 
f. 
Day 1 laboratory assessments may be performed up to 4 days prior to study agent administration. Laboratory 
results must be reviewed prior to each scheduled administration of IMGN853. In the event of severe toxicity, 
laboratory tests must be repeated as necessary until toxicity resolves or stabilizes. 
g. 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 in symptomatic patients by a board-certified ophthalmologist and 
will include the following: visual acuity, indirect fundoscopy, slit lamp examination under dilatation, intraocular 
pressure measurement, and optional corneal photography. A Schirmer’s test will be performed at baseline for all 
patients, and for patients who experience ocular symptoms, it will be repeated at the first on-study ophthalmic 
examination and at subsequently if clinically indicated. May be performed within 14 days of Cycle 1, Day 1. 
Ocular symptom assessment will be performed prior to the start of each cycle by the treating physician or other 
qualified individual. If the subject reports ocular symptoms then IMGN853 will be stopped and the subject will 
then be referred to an ophthalmologist for a complete examination (detailed in full protocol). Patients who 
experience ocular toxicity will have a complete ophthalmologic exam performed every other cycle, including 
patients with blurred vision but normal eye exams. All patients will have complete ophthalmologic exam 
performed at the End of Treatment visit or 30-Day Follow-up. 
i. 
Radiographic tumor assessment by CT or MRI scan is to be performed every 2 cycles (± 1 week)   
j. 
If a patient discontinues prior to documentation of PD, a tumor assessment is to be performed at the End of 
Study visit or 30-Day Follow up visit, if not performed within the previous 6 weeks. Tumor assessments will be 
performed every 12 weeks until progression is documented or the patient begins a new treatment regimen. 
Patients who have discontinued study treatment for reasons other than PD will be followed per RECIST 1.1 
every 12 weeks (±3 weeks) until documentation of PD, starting a subsequent anti-cancer therapy or for up to 
one year from Cycle 1, Day 1, whichever comes first. 
k. As clinically indicated. 
l. 
All AEs and SAEs from the time of informed consent are recorded. 

Protocol# 2016-0683 
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80 
 
m. ECOG assessment is not necessary on Cycle 1 Day 1 if screening assessment was performed within 3 days prior 
to Day 1.  
n. For Cohort A collection of archival tissue/biopsy for FRα screening only. 
 
 

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81 
 
SCHEDULE OF CLINICAL ASSESSMENTS COHORT B    
Activity 
Screening 
Cycle 1 
Cycle2 
Cycle 3 
Cycle 
>4 
End of 
Treatment 
30-Day 
Follow-up 
(+14 Days) 
Day 
1 
Day 
2 
Day 
8& 
15 
Day 
1 
Day 
8& 
15 
Day 15 
to 21 
Da
y 1 
Day 
2 
Day 
8 & 
15 
Day 1 
Informed Consent 
a 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
a 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
a 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm Disease 
Diagnosis/Current Stage 
and Prognostic Index 
Evaluation 
a 
 
 
 
 
 
 
 
 
 
 
 
 
Record Baseline Signs 
and Symptoms 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review and document 
IC/EC 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm patient continues 
to satisfy I/E Criteria 
including expression of 
FRα 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm patient meets 
retreatment criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
a 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationb 
c 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
c 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsd 
c 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse Oximetry 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS 
c 
m 
 
 
 
 
 
 
 
 
 
 
 
Hematology and 
Chemistry f 
c 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation (PT/INR/ 
aPTT) f 
c 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (urine or 
serum) e 
c, g 
g 
 
 
g 
 
 
g 
 
 
g 
 
g 
Ophthalmic 
examinations h 
 
Every other cycle (from point at which toxicity first reported)k 
 
 
Schirmer’s Test h 
 
For patients who experience treatment-emergent eye disorders, the 
Schirmer’s Test will be repeated at the first on-study ophthalmic 
examination and at subsequently if clinically indicated 
 
 

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Activity 
Screening 
Cycle 1 
Cycle2 
Cycle 3 
Cycle 
>4 
End of 
Treatment 
30-Day 
Follow-up 
(+14 Days) 
Day 
1 
Day 
2 
Day 
8& 
15 
Day 
1 
Day 
8& 
15 
Day 15 
to 21 
Da
y 1 
Day 
2 
Day 
8 & 
15 
Day 1 
Ocular Symptom 
Assessment h 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biopsy n 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiologic tumor 
assessment i, j 
a 
 
 
 
 
 
Every 6 
weeks 
(+1 
week)i, j 
 
 
 
 
j 
 
IMGN853 
Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE and SAE 
assessments 
l 
 
 
 
 
 
 
 
 
 
 
 
 
Record concomitant 
medication 
a 
 
 
 
 
 
 
 
 
 
 
 
 
a.   Within 28 days prior to the start of Cycle 1, Day 1 
b.   Directed physical examination is acceptable while on study treatment. Full examination is required at 
screening and the EOT visit. 
c.   Within 14 days prior to the start of Cycle 1, Day 1 
d.  Vital Signs (blood pressure, pulse, respiration rate, and temperature) will be measured as outlined in the full 
protocol (Section 8.6) 
e.   Only for WCBP 
f.   Day 1 laboratory assessments may be performed up to 4 days prior to study agent administration. 
Laboratory results must be reviewed prior to each scheduled administration of IMGN853. In the event of severe 
toxicity, laboratory tests must be repeated as necessary until toxicity resolves or stabilizes. 
g.  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 in symptomatic patients by a board-certified ophthalmologist 
and will include the following: visual acuity, indirect fundoscopy, slit lamp examination under dilatation, 
intraocular pressure measurement, and optional corneal photography. A Schirmer’s test will be performed at 
baseline for all patients, and for patients who experience ocular symptoms, it will be repeated at the first on-
study ophthalmic examination and at subsequently if clinically indicated. May be performed within 14 days of 
Cycle 1, Day 1. Ocular symptom assessment will be performed prior to the start of each cycle by the treating 
physician or other qualified individual. If the subject reports ocular symptoms then IMGN853 will be stopped 
and the subject will then be referred to an ophthalmologist for a complete examination (detailed in full protocol). 
Patients who experience ocular toxicity will have a complete ophthalmologic exam performed every other cycle, 
including patients with blurred vision but normal eye exams. All patients will have complete ophthalmologic 
exam performed at the End of Treatment visit or 30-Day Follow-up. 
i.   Radiographic tumor assessment of breast and/or involved lymph nodes by ultrasound or MRI is to be 
performed every 6 weeks (± 1 week)   
j.   If a patient has evidence of progression on exam or by symptoms report, a tumor imaging is to be 
performed. 
k. As clinically indicated. 
l.   All AEs and SAEs from the time of informed consent are recorded. 
m.  ECOG assessment is not necessary on Cycle 1 Day 1 if screening assessment was performed within 3 days 
prior to Day 1.  
n.  At EOT if primary tumor size > 1cm. 

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

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

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Non-target lesions: All other lesions (or sites of disease) including all non-measurable lesions 
(including pathological lymph nodes with ≥ 10 to < 15 mm short axis) and all measurable lesions 
over and above the 5 target lesions are to be identified as non-target lesions and recorded at 
baseline.  
 Measurements of these lesions are not required, but the presence, absence, 
unequivocal progression of each is to be recorded throughout follow-up.  
 Lymph nodes that have a short axis < 10 mm are considered non-pathological and are 
not to be recorded or followed. 
Special Considerations 
Clinical Examination of Lesions: Superficial or visible lesions that cannot be assessed by CT 
scan or MRI will only be considered for response assessment if these lesions are biopsy-proven 
metastatic lesions and ≥ 10 mm in diameter. These lesions will be considered non-measurable 
and thus non-target for response assessment. 
Cystic lesions: Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesion.  
Bone lesions: Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions. However, these techniques can be used to confirm the 
presence or disappearance of bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
 Blastic bone lesions are non-measurable. 
Lesions with prior local treatment: Lesions situated in a previously irradiated area, or in an 
area subjected to other loco-regional 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 (e.g., 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 6 
weeks thereafter (±1 week). 
At baseline, tumors and lymph nodes are classified and documented as target or non-target per 
the definitions provided above. It is possible to record multiple non-target lesions involving the 
same organ as a single item (e.g., ‘multiple liver metastases’).  
At all post-baseline evaluations, the baseline classification (target, non-target) is to be maintained 
and lesions are to be documented and described in a consistent fashion over time (e.g., recorded 
in the same order on source documents and CRFs). 
For target lesions, measurements should be taken and recorded in metric notation. All tumor 
measurements must be recorded in millimeters. 
At each assessment, a sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported. The baseline sum of the 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. 

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

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New Lesion TPR 
Yes 
Lesion present at follow-up visit either for the very first time or re-appearing 
(i.e., lesion was present at baseline, disappeared at a follow-up visit and re-
appeared later). 
No 
No new lesions present at follow up 
Unable to Evaluate (UE) 
Patient non assessed or incompletely assessed for new lesion 
Determining Overall TPR 
Target Lesion TPR 
Non-Target TPR 
New Lesions TPR 
Overall TPR 
CR 
CR or NA 
No 
CR* 
CR 
Non-CR/non-PD 
No 
PR* 
CR 
UE 
No 
PR* 
PR 
Non-PD or NA or UE 
No 
PR* 
SD 
Non-PD or NA or UE 
No 
SD 
UE 
Non-PD 
No 
UE 
PD 
Any 
No or Yes or UE 
PD 
Any 
PD 
No or Yes or UE 
PD 
Any 
Any 
Yes 
PD 
NA 
CR 
No 
CR* 
NA 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Non-PD 
Non-PD 
UE 
UE 
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; UE, unable to evaluate; 
NA, not applicable (no such lesions at screening); Any, CR, PR, SD, PD, NA or UE. 
The overall response at a given time point does not depend upon the overall response assigned at any prior time 
point. 
*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 
Confirmation - The main goal of confirmation of objective response is to avoid overestimating 
the observed response rate. For patients with an overall response of PR or CR a given time point, 
changes in tumor measurements must be confirmed by repeat assessments that should be 
performed no less than 4 weeks after the criteria for response are first met. However, the 
presence or absence of confirmation is not considered when assigning a time point response. 
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 D.   CTCAE Version 4.03 Grading for selected Adverse Events 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03; National Cancer 
Institute; June 14, 2010; NIH Publication No 09-5410 
 
Adverse Event 
Grade 
1 
2 
3 
4 
5 
Pneumonitis 
Asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not 
indicated 
Symptomatic; 
medical intervention 
indicated; limiting 
instrumental ADL 
Severe symptoms; 
limiting self-care 
ADL; oxygen 
indicated 
Life-threatening 
respiratory 
compromise 
Death 
Blurred vision 
Intervention not 
indicated 
Symptomatic; 
limiting instrumental 
ADL 
Limiting self-care 
ADL 
 
- 
Dry Eye 
Asymptomatic; 
clinical or diagnostic 
observations only; 
mild symptoms 
relieved by lubricants 
Symptomatic; 
multiple agents 
indicated; limiting 
instrumental ADL 
Decrease in visual 
acuity (<20/40); 
limiting self-care 
ADL 
 
- 
Keratitis 
 
Symptomatic; 
medical intervention 
indicated (e.g., 
topical agents); 
limiting instrumental 
ADL 
Decline in vision 
(worse than 20/40 
but better than 
20/200); limiting 
self-care ADL 
Perforation or 
blindness (20/200) 
or worse) in the 
affected eye 
- 
Eye disorders – 
Other, specify 
Asymptomatic or 
mild symptoms; 
clinical or diagnostic 
observations only; 
intervention not 
indicated 
Moderate; minimal, 
local or noninvasive 
intervention 
indicated; limiting 
age-appropriate 
instrumental ADL 
Severe or medically 
significant but not 
immediately sight-
threatening; 
hospitalization or 
prolongation of 
existing 
hospitalization 
indicated; disabling; 
limiting self-care 
ADL 
Sight-threatening 
consequences; 
urgent intervention 
indicated; blindness 
(20/200 or worse) in 
the affected eye 
- 
Abbreviations:  Activities of Daily Living (ADL) 

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APPENDIX E.   EXAMPLES OF SENSITIVE IN VIVO CYP SUBSTRATES                      
AND   CYP SUBSTRATES WITH NARROW THERAPEUTIC RANGE    
(7/28/2011) 
CYP Enzyme 
Sensitive Substrates 
Substrates with Narrow Therapeutic 
Range 
CYP3A 
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 (Accessed on June 9, 2016) 
(http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionlabeling/ucm093664.
htm#classSub)