A Phase 2, Two-stage, Study of Mirvetuximab Soravtansine (IMGN853) in Combination With Pembrolizumab in Patients With Microsatellite Stable (MSS) Recurrent or Persistent Endometrial Cancer (EC)
Phase: PHASE2
Conditions: Endometrial Cancer
Sponsor: Dana-Farber Cancer Institute

NCI Protocol #: N/A
DF/HCC Protocol #: 18-602
Protocol Version Date:  December 11, 2023
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NCI Protocol #:
N/A
DF/HCC Protocol #: 18-602
TITLE:  A Phase 2, two-stage, study of mirvetuximab soravtansine (IMGN853) in combination 
with pembrolizumab in patients with microsatellite stable (MSS) recurrent or persistent 
endometrial cancer (EC)
Coordinating Center:
Dana-Farber/Harvard Cancer Center (DF/HCC)
Principal Investigator (PI):
Rebecca Porter, MD, PhD
Dana-Farber Cancer Institute
450 Brookline Ave
Boston, MA 02215
Telephone: 617-632-2334
Fax: 617-582-7921
Rebecca_Porter@dfci.harvard.edu
Statistician:
Co-PI: 
Nabihah Tayob, PhD
Panagiotis Konstantinopoulos, MD, PhD
Dana-Farber Cancer Institute
Dana-Farber Cancer Institute
450 Brookline Ave
450 Brookline Ave
Boston, MA 02215
Boston, MA 02215
Telephone: 857-215-0006
Telephone: 617-632-5269
ntayob@ds.dfci.harvard.edu
Fax: 617-582-7921
                                                                             Panagiotis_Konstantinopoulos@dfci.harvard.edu 
Responsible Research Nurse:
Project Manager:
 
Sarah Hindenach, RN
Martin Hayes
Dana-Farber Cancer Institute
Dana-Farber Cancer Institute
450 Brookline Ave.
450 Brookline Ave.
Boston, MA 02215
Boston, MA 02215
Telephone: 617-632-3472
Telephone: 857-215-2911
Fax: 617-582-7921
Fax: 617-582-7921
Sarah_Hindenach@dfci.harvard.edu
Martin_Hayes@dfci.harvard.edu
NCI-Supplied Agent(s):  N/A
Other Agent(s):  Mirvetuximab soravtansine (IMGN853, ImmunoGen, Inc.); Pembrolizumab 
(Keytruda, Merck)
IND #:  140407
IND Sponsor: Panagiotis Konstantinopoulos, MD, PhD
Protocol Type / Version # / Version Date: Amendment 14 / Version 15 / 11 December 2023

2
SCHEMA
1 cycle = 21 days
MSS and FRα positive 
Advanced/recurrent 
serous endometrial 
cancer (EC)
IMGN853 + 
Pembrolizumab
Enroll 16 
Patients
Assessment of 
Treatment 
Response
≥ 2 Patients with 
Objective 
Responses or 
Progression-Free 
at 6 Months
< 2 Patients with 
Objective 
Responses or 
Progression-Free 
at 6 Months
Expand Cohort to 
Enroll 19 
Additional 
Patients
Cohort 
Enrollment 
Stops
Screening
Registration

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TABLE OF CONTENTS
SCHEMA
2
OBJECTIVES6
1.1
Study Design............................................................................................................6
1.2
Primary Objectives...................................................................................................6
1.3
Secondary Objectives...............................................................................................6
1.4
Exploratory Objectives ............................................................................................6
BACKGROUND .............................................................................................................................7
2.1
Endometrial Cancer .................................................................................................7
2.2
Investigational agents – Mirvetuximab Soravtansine (IMGN853)..........................8
2.3
Rationale ................................................................................................................12
2.4
Correlative Studies Background ............................................................................14
PARTICIPANT SELECTION.......................................................................................................15
3.1
Eligibility Criteria..................................................................................................15
3.2
Exclusion Criteria ..................................................................................................17
3.3
Inclusion of Women and Minorities ......................................................................19
REGISTRATION PROCEDURES ...............................................................................................19
4.1
General Guidelines for DF/HCC Institutions ........................................................19
4.2
Registration Process for DF/HCC Institutions.......................................................19
4.3
General Guidelines for Other Investigative Sites ..................................................19
4.4
Registration Process for Other Investigative Sites.................................................20
TREATMENT PLAN....................................................................................................................20
5.1
Treatment Regimen................................................................................................20
5.2
Pre-Treatment Criteria ...........................................................................................21
5.3
Agent Administration.............................................................................................21
5.4
General Concomitant Medication and Supportive Care Guidelines......................26
5.5
Criteria for Taking a Participant Off Protocol Therapy.........................................29
5.6
Duration of Follow Up...........................................................................................30
5.7
Criteria for Taking a Participant Off Study ...........................................................30
DOSING DELAYS/DOSE MODIFICATIONS ...........................................................................31
6.1
Mirvetuximab Soravtansine (IMGN853)...............................................................31
6.2
Pembrolizumab ......................................................................................................35
6.3
Re-treatment Criteria .............................................................................................39
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ........................................40
7.1
Expected Toxicities................................................................................................40
7.2
Adverse Event Characteristics...............................................................................41
7.3
Serious Adverse Events .........................................................................................41
7.4
Adverse Event Reporting to Overall PI .................................................................42
7.5
Reporting Period....................................................................................................43

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7.6
Adverse Event Reporting to ImmunoGen..............................................................43
7.7
Adverse Event Reporting to Merck .......................................................................44
7.8
Reporting to the Food and Drug Administration (FDA) .......................................46
7.9
Reporting to Hospital Risk Management...............................................................47
7.10
Routine Adverse Event Reporting .........................................................................47
PHARMACEUTICAL INFORMATION......................................................................................47
8.1
Mirvetuximab Soravtansine (IMGN 853)..............................................................47
8.2
Pembrolizumab ......................................................................................................53
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ....................................................57
9.1
Biomarker Studies..................................................................................................57
9.2
Laboratory Correlative Studies..............................................................................58
STUDY CALENDAR ...................................................................................................................59
MEASUREMENT OF EFFECT ...................................................................................................61
11.1
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Guidelines ..............................................................................................................61
11.2
Immune-related Response Criteria Derived from RECIST 1.1 (irRECIST).........64
11.3
Methods for Evaluation of Disease........................................................................66
DATA REPORTING / REGULATORY REQUIREMENTS.......................................................68
12.1
Data Reporting.......................................................................................................68
12.2
Data Safety Monitoring..........................................................................................68
12.2
Multi-Center Guidelines ........................................................................................68
STATISTICAL CONSIDERATIONS...........................................................................................69
13.1
Study Design/Endpoints ........................................................................................69
13.2
Sample Size, Accrual Rate and Study Duration ....................................................70
13.3
Stratification Factors..............................................................................................71
13.4
Interim Monitoring Plan ........................................................................................71
13.5
Analysis of Primary Endpoints..............................................................................71
13.6
Analysis of Secondary Endpoints..........................................................................71
13.7
Reporting and Exclusions ......................................................................................72
PUBLICATION PLAN .................................................................................................................72
REFERENCES ..............................................................................................................................74
APPENDIX AECOG Performance Status ....................................................................................77
APPENDIX B: Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring 
Plan
78
1. INTRODUCTION .....................................................................................................................80
1.1.
Purpose...................................................................................................................80

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2. GENERAL ROLES AND RESPONSIBILITIES .....................................................................80
2.1.
Coordinating Center...............................................................................................80
2.2.
External Site...........................................................................................................81
3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS .....................................81
3.1.
Protocol Revisions and Closures ...........................................................................81
3.2.
Informed Consent Requirements ...........................................................................82
3.3.
IRB Re-Approval...................................................................................................82
3.4.
DF/HCC Multi-Center Protocol Confidentiality ...................................................82
3.5.
Participant Registration..........................................................................................83
3.6.
Initiation of Therapy ..............................................................................................83
3.7.
Eligibility Exceptions.............................................................................................83
3.8.
Data Management..................................................................................................83
3.9.
Protocol Reporting Requirements..........................................................................84
4.
MONITORING: QUALITY CONTROL..........................................................................84
4.1.
Ongoing Monitoring of Protocol Compliance.......................................................84
4.2.
Monitoring Reports................................................................................................85
4.3.
Accrual Monitoring................................................................................................85
5.
AUDITING: QUALITY ASSURANCE ...........................................................................85
5.1.
DF/HCC Internal Audits........................................................................................85
5.2.
Audit Notifications.................................................................................................85
5.3.
Audit Reports.........................................................................................................85
5.4.
External Site Performance .....................................................................................86
APPENDIX CCTCAE Version 5.0 Grading for selected Adverse Events...................................87
APPENDIX DSchema for administration of study-required eye drops........................................89

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OBJECTIVES
1.1
Study Design
An open label, two-stage, non-randomized phase 2 trial examining mirvetuximab soravtansine 
(IMGN853) and pembrolizumab in participants with advanced or recurrent serous endometrial 
cancer (EC). The combination will be tested in patients with microsatellite stable (MSS) and FRα 
positive tumors. 
Enrollment will follow a standard Simon two-stage optimal design [1] for a single cohort to 
inform whether the combination has significant clinical activity worthy of further evaluation. 
Statistical considerations are developed for co-primary objectives to evaluate the objective 
response rate (ORR) and rate of progression-free survival at 6 months (PFS6), with a two-stage 
design that allows for early stopping for futility. 
Target enrollment is a maximum of 35 patients. 
1.2
Primary Objectives
To assess the activity of mirvetuximab soravtansine and pembrolizumab in advanced or recurrent 
EC as determined by the frequency of patients who are alive and progression-free for a minimum 
of 6 months (PFS6) after initiating therapy, or who have objective tumor responses by RECIST 
1.1 criteria.
1.3
Secondary Objectives
1. To determine the duration of progression-free survival (PFS), overall survival (OS) and 
duration of response (DoR)
2. To determine the nature and degree of toxicity of protocol therapy as classified using the 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
3. To determine Immune-related objective response rate (irORR)
4. To determine Immune-related progression-free survival (irPFS) rate defined as time from 
treatment initiation to death or to immune-related progression of disease (irPD) as 
defined in Sections 11.2 and 13.6
1.4
Exploratory Objectives
Correlative studies will be performed in the Immune Oncology and DNA Repair Centers at 
DFCI and Ventana Medical Systems. The aims are to:
1. To assess CD3+ tumor infiltrating lymphocytes (TILs) and circulating 
lymphocytes,CD8+ TILs, CD8+/CD4+FOXP3+ TIL ratio, CD137+CD8+ TILs, 
CD137+CD8+/CD4+FOXP3+ TIL ratio and correlate with response.
2. To assess myeloid, stromal and other immunoactive cell types from blood, tissue and 
fluid samples and correlate with response.
3. To assess the expression pre-, during, and at time of progression of immune checkpoints 
including TIM-3, LAG-3, CTLA-4, PD-L2, PD-L1, PD-1, IDO within tumor and/or 

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blood samples and correlate with response.
4. To perform whole exome sequencing (WES) to assess for specific DNA gene repair 
mutations and neoantigens as well as for single nucleotide polymorphisms (SNPs) in 
immunologically relevant genes and correlate with response
Additional exploratory analyses will include a comparison of the activity of mirvetuximab 
soravtansine and pembrolizumab in patients with and without prior exposure to IO therapy as 
determined by the frequency of patients who are alive and progression-free for a minimum of 6 
months (PFS6) after initiating therapy, or who have objective tumor responses by RECIST 1.1 
criteria in each category.  The secondary objectives as defined in Section 1.3 will also be 
evaluated in each category.
BACKGROUND
2.1
Endometrial Cancer
Endometrial cancer (EC) is the most common gynecologic malignancy in the United States with 
approximately 60,000 new cases and 10,000 deaths anticipated in 2017 [2]. Approximately two 
thirds of women with endometrial cancer present with early-stage, uterus-confined disease. This 
is typically treated surgically with or without radiotherapy with excellent outcomes. However, 
women with recurrent disease or metastatic disease are incurable with a five-year survival rate 
of 17% and limited treatment options [3]. 
There have been several randomized studies performed to ascertain the optimal therapy in 
patients with recurrent or metastatic disease. These studies have focused on three active 
chemotherapy agents identified to have significant activity as monotherapy in phase 2 trials: 
doxorubicin, platinum agents, and paclitaxel. In GOG-0107, 281 women were randomized to 
doxorubicin alone versus doxorubicin plus cisplatin (AP). There was a statistically significant 
advantage to combination therapy with regard to response rate (RR) (25% versus 42%; p=0.004) 
and PFS (3.8 vs 5.7 months; HR 0.74, 95% CI 0.58, 0.94; p=0.14), although no difference in OS 
was observed [4]. Phase 2 data published by the GOG in 1996 demonstrated that paclitaxel had 
significant single agent activity with a response rate of 36% in advanced or recurrent endometrial 
cancer [5]. Thus 317 patients were randomized to paclitaxel and doxorubicin or the standard arm 
of AP in GOG-0163 [6]. This trial failed to demonstrate a significant difference in RR, PFS, or 
OS between the two arms, and AP remained the standard of care. 
However, since both platinum and paclitaxel had demonstrated high single agent activity, there 
was a strong interest in including paclitaxel and cisplatin in a front-line regimen for advanced 
and recurrent endometrial cancer. Subsequently, GOG-0177 randomized 263 patients to AP 
versus doxorubicin, paclitaxel, and cisplatin (TAP): doxorubicin and cisplatin on day 1, followed 
by paclitaxel on day 2. TAP was superior to AP in terms of ORR (57% vs 34%; p<0.01), median 
PFS (8.3 vs 5.3 months; p<0.01), and OS with a median of 15.3 (TAP) versus 12.3 months (AP) 
(p=0.037) [7]. This improved efficacy came at the cost of increased toxicity. In GOG-0209 TAP 
was compared in a randomized fashion to paclitaxel and carboplatin (CT) in an attempt to 
address the issue of toxicity; CT was not inferior to TAP in terms of PFS and OS. At the reported 
interim analysis, the median PFS was 14 months in both arms (HR, 1.03), while median OS was 

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32 months vs. 38 months in patients treated with CT vs. TAP (not significant, HR, 1.01). 
Additionally, CT was better tolerated than TAP. 
Patients with a relapse not amenable to local therapy currently receive treatment with a CT 
combination as a first-line alternative to the more toxic triplets [8]. In the second line setting, 
there is currently no single standard of care – various cytotoxic agents have been used including 
paclitaxel, docetaxel, liposomal doxorubicin, topotecan, oxaliplatin, ixabepilone, pemetrexed, 
gemcitabine with response rates of 4-27%, with only paclitaxel having a response rate >20% [9, 
10]. Other agents with modest activity in the second line setting include hormonal (progestins, 
antiestrogens, estrogen modulators), and targeted therapies including human epidermal growth 
factor receptor 2 (Her-2), vascular endothelial growth factor (VEGF) inhibitors, and 
PI3K/mTOR inhibitors, among others. The treatment of women with advanced, recurrent, or 
metastatic EC represents an important unmet need.
2.2
Investigational agents – Mirvetuximab Soravtansine (IMGN853)
Investigational Agent Rationale
Mirvetuximab soravtansine (IMGN853) is a specific, targeted antibody drug conjugate (ADC) 
that binds with high affinity to folate receptor alpha (FRα), a glycophosphatidylinositol-linked 
protein which is highly expressed on the surface of solid tumors, particularly epithelial ovarian 
cancer (EOC), endometrial cancer, and non-small cell lung carcinoma (NSCLC). Mirvetuximab 
soravtansine consists of a humanized anti-FRα monoclonal antibody attached via a disulfide 
containing linker to the cytotoxic maytansinoid, DM4. Once released within the target cell, DM4 
acts as an anti-mitotic agent that inhibits tubulin polymerization and microtubule assembly, 
resulting in cell cycle arrest and apoptosis. 
Rationale for Dose Selection
Dose selection for this study is based on the recommended Phase 2 dose (RP2D) of the 
combination of IMNG853 and pembrolizumab, as determined from the Phase Ib Study 0402.
Clinical Safety Data Related to Dose
 As of 22 October 2020, 737 patients had received at least 1 dose of MIRV in 1 of 7 studies. Two 
hundred and six patients were dosed in Study IMGN853-0401, a first-in-human, Phase 1, single-
agent, dose escalation and dose expansion study; 264 patients have been dosed in the ongoing 
Study IMGN853-0402, Phase 1b/2, dose escalation, dose expansion combination study with 
BEV, Carbo, Pembro, PLD, or BEV + Carbo (data cut-off 16 October 2020); 243 patients were 
dosed in the pivotal stage of Study IMGN853-0403, a Phase 3, single-agent, pivotal study; 10 
patients have been dosed with MIRV monotherapy in the ongoing Study IMGN853-0416, Phase 
3, safety and efficacy study of MIRV versus IC Chemo (Pac, PLD, or topotecan) (data cut-off 16 
October 2020); 14 patients have been dosed in the ongoing Study IMGN853-0417, Phase 3 
safety and efficacy monotherapy study (data cut-off 22 October 2020); and 1 patient received 
MIRV in Study IMGN853-EAP-01, a single-agent, single-patient, expanded access study to 

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provide continued access to MIRV for a patient with advanced platinum-resistant primary 
peritoneal cancer.
TEAEs experienced by > 10% of patients in monotherapy Study IMGN853-0401 (expansion 
phase) or Study IMGN853-0403 (Phase 3 portion) clustered around the following SOCs: 
Gastrointestinal disorders, Eye disorders, General and administration site disorders, Nervous 
system disorders, Investigations, and Metabolism and nutrition disorders. The most common PTs 
within these SOCs were diarrhea, vision blurred, aspartate aminotransferase increased, nausea, 
vomiting, headache, asthenia, dry eye, keratopathy, decreased appetite, ALT increased, 
abdominal pain, fatigue, constipation, vomiting, visual acuity reduced, and peripheral 
neuropathy. The majority of TEAEs were ≤ Grade 2. The nature, frequency, and severity of 
TEAE were consistent with the safety profile of MIRV, and there were no clinically significant 
differences between the EOC and Endometrial cohorts.
The most common SAEs in Study IMGN853-0401 and Study IMGN853-0403 included 
abdominal pain, constipation, diarrhea, large intestinal obstruction, nausea, small intestinal 
obstruction, vomiting, metastatic neoplasm, gastroenteritis, pneumonia, urinary tract infection, 
decreased appetite, dehydration, organizing pneumonia, and pneumonitis. The nature and 
frequency of SAEs experienced were consistent with the drug’s known safety profile and/or 
underlying disease.
Review of preliminary safety data from Study 0402 (combination therapy), did not indicate any 
trend with regard to the nature, severity, or frequency of treatment-emergent adverse events seen 
in the combination regimens as compared to the known safety profiles of either mirvetuximab 
soravtansine or the marketed drug.
TEAEs experienced by > 10% of patients treated with MIRV in combination with BEV or 
Pembro or BEV + Carbo in the expansion phase of Study IMGN853-0402 and ≥ 10% patients 
treated with MIRV in combination with Carbo or PLD in the escalation phase of Study 
IMGN853-0402 clustered around the following SOCs: Gastrointestinal disorders, Eye disorders, 
General disorders and administration site conditions, Nervous system disorders, Respiratory, 
thoracic, and mediastinal disorders, and Metabolism and nutritional disorders. The majority of 
TEAEs were ≤ Grade 2 and consistent with underlying disease and/or the known safety profiles 
of each drug.
SAEs occurring in 3 or more BEV or Pembro or BEV + Carbo patients included intestinal 
obstruction, nausea, vomiting, pneumonitis, general physical health deterioration, and small 
intestinal obstruction. SAEs across expansion cohorts were consistent with the known safety 
profiles of the drugs administered.
There were no clinically significant trends identified in hematology, chemistry, coagulation, or 
ECG data.
Please refer to the Investigator Brochure for detailed safety information. 
Mirvetuximab soravtansine received accelerated approval for the treatment of adult patients with 
FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, 

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from the FDA on November 14, 2022.
Clinical Efficacy Data Related to PK
Study 0401 is a first-in-human (FIH) Phase 1 trial designed to establish the MTD and determine 
the recommended Phase 2 dose (RP2D) of mirvetuximab soravtansine 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 includes two stages: dose escalation 
and dose expansion and two dosing schedules, Schedule A (mirvetuximab soravtansine on Day 
1, every 21 days; Q3W) and Schedule B (mirvetuximab soravtansine on Days 1, 8, and 15, every 
28 days; modified weekly schedule).  The primary aim of the dose-escalation phase was to 
evaluate the safety and tolerability of mirvetuximab soravtansine, to identify the MTD, and to 
characterize the pharmacokinetics (PK) profile of mirvetuximab soravtansine for each of the two 
schedules. The dose escalation stage is complete and the RP2D for Schedule A was determined 
to be 6.0 mg/kg adjusted ideal body weight (AIBW). Schedule A (Q3W) was evaluated in the 
dose expansion cohorts, which are defined as follows: 
a. Dose Expansion Cohort 1:  Patients with Platinum-Resistant Epithelial Ovarian Cancer 
(EOC) – 40 patients planned/46 enrolled (enrollment complete) 
b. Dose Expansion Cohort 2:  Advanced or recurrent uterine cancer – 20 patients/24 
enrolled (enrollment complete)
c. Dose Expansion Cohort 3:  Patients with relapsed EOC, which is amenable to biopsy – 20 
patients planned/27 enrolled (enrollment complete) 
d. Dose Expansion Cohort 4:  Relapsed/refractory NSCLC adenocarcinoma or 
bronchoalveolar carcinoma (BAC) – not yet opened 
e. Dose Expansion Cohort 5: Patients with EOC which has relapsed following platinum-
based therapy: this cohort of patients will self-administer prophylactic corticosteroid eye 
drops – 40 patients planned/40 enrolled (enrollment complete )
At the time of data cut off (January 31, 2018), preliminary PK data were available for up to a 
total of 172 patients dosed with mirvetuximab soravtansine on Schedule A (Q3W; N=154). 
Following the administration of the first dose of mirvetuximab soravtansine, mean exposure 
(Cmax and AUC0-inf) increased with dose in a generally proportional manner from 1.0 to 7.0 
mg/kg. For Cycle 1 cohorts ≥ 1.0 mg/kg, mean t1/2 of mirvetuximab soravtansine ranged from 
~79 to 121 hours across doses with no meaningful dose-dependence noted in CL or Vss. In the 
two lowest dose cohorts (0.15 & 0.5 mg/kg), there appeared to be a trend towards higher CL, 
however, due to low patient numbers in these groups definitive conclusions are not possible. 
Exposure metrics (Cmax and AUC0-inf) at Cycle 3 indicated that there was no meaningful 
accumulation following multiple doses of mirvetuximab soravtansine. 
Study 0402 (FORWARD-II) is an open-label, Phase 1b, non-randomized study of mirvetuximab 
soravtansine in combination with Bevacizumab (BEV), Carboplatin (Carbo), Pegylated 
Liposomal Doxorubicin (PLD) or Pembrolizumab in adult patients with FRα positive advanced 
EOC, primary peritoneal, fallopian tube, or endometrial cancer.  There is no apparent effect of 
combination therapy in Study 0402 on preliminary mirvetuximab soravtansine PK parameters, 
where values are generally consistent among Regimens A, B, C and D, and with data reported 
for Study 0401.

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Single agent mirvetuximab soravtansine has a 26% confirmed overall response rate (95% CI 
14%-41%), including 1 complete and 11 partial responses in FRα positive platinum-resistant 
EOC in the patient expansion cohort in study 0401 [11]. Median PFS (mPFS) was 4.8 months 
(95% CI 3.9-5.7 months). The overall response rate was 39% (95% CI 20%-62%) and the 
median PFS (mPFS) is 6.7 months (95% CI 3.9-11 months) in the subset of 16 patients with one 
to three prior regimens [11]. Evaluation of the efficacy of mirvetuximab soravtansine in 
combination with pembrolizumab at the R2PD is ongoing in Study 0402 in ovarian cancer 
patients.  
Based on these data, mirvetuximab soravtansine 6 mg/kg AIBW in combination with 
pembrolizumab 200 mg on day 1 of every 21-day cycle has been recommended as the phase 2 
dose and appears to have a tolerable risk benefit profile and thus represents an appropriate dose 
for further evaluation in this patient population. 
Nonclinical Pharmacology
The suitability of FRα as a target in the treatment of solid tumors was demonstrated by 
immunohistochemistry (IHC). FRα was shown to have limited normal tissue expression and 
marked expression in solid tumors, particularly cancers of the ovary, endometrium, lung, and 
kidney. In vitro studies demonstrated that mirvetuximab soravtansine binds cell surface FRα with 
high apparent affinity (≤ 0.1 nM) and shows potent (IC50 ≤ 1 nM) and selective cytotoxicity 
against cells expressing FRα.
Nonclinical Pharmacokinetics
Upon binding to the FRα receptor, mirvetuximab soravtansine undergoes receptor-mediated 
internalization and subsequent lysosomal degradation, resulting in intracellular release of DM4-
containing cytotoxic catabolites. Binding of DM4 and a second metabolite, S-methyl-DM4, to 
tubulin inhibits 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. Mirvetuximab soravtansine demonstrated significant activity against FRα-
positive xenografts. Partial and/or complete regressions in xenograft models of epithelial ovarian 
cancer and NSCLC were seen at doses well below its maximum tolerated dose (MTD).
Toxicology
Nonclinical toxicology studies were performed to assess the potential clinical risks of 
mirvetuximab soravtansine, to define the maximum recommended starting dose (MRSD) and to 
support initiation of the pivotal Phase 3 study (Study 0403). These included the following: 
1. IHC tissue cross reactivity and binding studies to define the most representative 
toxicology species. 
2. A Ki-67 IHC study to define the mitotic activity of FRα-positive normal human tissues. 
3. A single dose GLP toxicology study in cynomolgus monkeys to define the MRSD. 

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4. A repeat dose (Q3W for 4 doses) GLP 3-month chronic toxicology study in cynomolgus 
monkeys to support initiation of the pivotal Phase 3 study (Study 0403). 
5. Single dose acute toxicity studies with DM4 in mice and cynomolgus monkeys to assess 
toxicity of the mirvetuximab soravtansine cytotoxic payload. 
6. Single dose acute toxicity studies in mice to compare the tolerability and toxicity of 
mirvetuximab soravtansine (M9346A-sulfo-SPDB-DM4), which contains the novel 
sulfo-SPDB linker to an SPDB-DM4 conjugate (M9346A-SPDB-DM4), for which 
extensive preclinical toxicity data exists. 
Toxicology Summary
Single dose (1, 3, 5, or 10 mg/kg) and 3-month repeat-dose (2, 4, or 8 mg/kg Q3 weekly) GLP 
toxicology studies were conducted in cynomolgus monkeys (a cross reactive species). The 
principal findings of the single-dose were changes in hematology parameters, depletion of bone 
marrow and lymphoid tissue, changes in serum chemistry, and injection site reactions. All 
mirvetuximab soravtansine-related events were considered non-adverse and had returned to 
normal or showed significant restoration towards normal by Day 29. The principal findings of 
the repeat dose study were similar and included hematologic abnormalities, electrolyte 
alterations, dermal reactions at the injection site and other skin areas and ophthalmic findings. 
The no-observed-adverse-effect level (NOAEL) established from repeat doses was 4 mg/kg.
Interactions
The risk of a clinically significant in vivo drug-drug interaction caused by DM4 inhibition of 
CYP3A is unknown; therefore, treatment of patients with concomitant medications that are 
sensitive substrates of CYP3A or are CYP3A substrates with a narrow therapeutic index should 
be carefully monitored (Section 5.4). Drinking greater than one serving (250 ml) of grapefruit 
juice per day should be avoided. 
2.3
Rationale
Endometrial cancers have been historically classified as either type I or type II cancers. Type I 
cancers, which are typically of endometrioid histology, comprise approximately 85% of 
endometrial cancers and are linked to increased estrogens, obesity, hormone receptor positivity 
and generally favorable prognosis. Type II cancers include non-endometrioid cases, most 
commonly of papillary serous histology, and are more common in older, non-obese women and 
have a worse outcome. Recent identification of distinct genomic subtypes of endometrial cancer 
from The Cancer Genome Atlas (TCGA) has opened the opportunity to stratify response to 
therapy by subtype. This study examined 373 primary endometrioid and serous endometrial 
cancers and identified four major molecular subgroups associated with outcome: POLE-mutated, 
microsatellite unstable (MSI-H), copy number low, and copy number high groups [12].  POLE-
mutated and MSI-H endometrial cancers are associated with high number of tumor-infiltrating 
lymphocytes and high neoantigen load [13], and are predicted to respond well to immunotherapy. 
Although outcomes are favorable in these two subgroups, the majority of endometrioid (72%) 
and serous (98%) of cases were classified in the copy number low or copy number high groups, 

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which lacked evidence of microsatellite instability and were associated with inferior outcome.
There are limited data on the use of immune checkpoint inhibitors in endometrial cancer in the 
clinic.  Le et al. evaluated pembrolizumab in a phase II study of patients with or without 
mismatch repair deficiency. This study enrolled nine patients with non-colorectral mismatch 
repair-deficient tumors, and in this cohort, which included two endometrial cancer patients, there 
was an objective response rate of 71% (five out of seven) patients [14]. In the ongoing, 
multicenter phase 2 study of pembrolizumab in patients with non-colorectal MSI-H tumors 
(KEYNOTE-158), enrolled 4 endometrial cancer patients. The overall response rate at the time 
of reporting at ASCO 2016 was 42.9% with a disease control rate of 66.7% with 8 confirmed 
responses, and 1 complete response among the 21 MSI-H non-colorectal cancer cases. The 
responses appeared durable, and were continuing at the time of report [15]. The endometrial 
cancer cohort of the KEYNOTE-28 pembrolizumab study selected patients for PD-L1 expression 
(but did not evaluate mutation burden or MSI status) and enrolled 24 heavily pretreated patients. 
The objective response rate was 26% with 3 patients achieving partial response and three patients 
achieving stable disease, and all responses appeared durable, with two patients remaining on 
treatment at the time of reporting [16].
Pembrolizumab is now FDA approved in MSI tumors, including endometrial cancers, which 
have failed standard treatment options. Responses to checkpoint inhibitors alone in MSS patients 
are likely to be modest, though have not yet been reported.  Strategies are needed to improve 
response rates to immunotherapy in MSS patients.
Folate receptor-alpha (FRα) is a receptor expressed on the surface of many solid tumors, 
including endometrial cancer.  It is present in limited amounts in normal endometrium, however 
is highly expressed in endometrial hyperplasia and endometrial cancers [17]. Moderate to strong 
staining intensity is associated with increased grade, stage and poor prognosis in endometrial 
cancers [18]. Mirvetuximab soravtansine is an antibody drug conjugate (ADC) comprised of a 
FRα-binding antibody conjugated to the maytansinoid DM4 by a cleavable linker.  DM4 is a 
potent tubulin-targeting agent.  Early clinical evaluation of this drug has had good tolerability 
and encouraging single-agent activity in several cancer types, including endometrial cancer.  In a 
Phase 1 expansion trial mirvetuximab soravtansine in previously treated patients with FRα 
positive advanced or recurrent endometrial cancer, there were 2 confirmed partial responses and 
11 with stable disease out of 24 patients for an overall clinical benefit rate greater than 50% [19]. 
In the study, 16/24 (67%) tumors were of serous histology, and 5/24 (21%) were endometrioid 
histology.  Antitumor activity was particularly pronounced in serous histology.
In addition to its direct toxicity on tumor cells bearing the folate receptor target, there are also 
emerging preclinical data that an additional mechanism of action of ADCs are on the local tumor 
immune microenvironment [20-22].  Most antibody drug conjugates in development use 
maytansinoid (DM1 or DM4, eg. T-DM1 Kadcycla), or auristatins (MMAE, eg. Brentuximab 
Vendotin) which are microtubule destabilizers.  These agents have been identified as potent 
activators of dendritic cells.  Mueller et al. showed that the MMAE and the MMAE analog, 
dolastatin were able to promote tumor directed immunity by inducing the maturation of dendritic 
cells, increased migration of dendritic cells to tumor-draining lymph nodes, and promoted 
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setting [21]. While the mechanism of how anti-tubulin agents activate dendritic cells in the tumor 
microenvironment is not yet understood, preclinical data suggest that tumor cytotoxicity is not 
sufficient, as other cytotoxic agents including cisplatin and etoposide were not sufficient to 
activate dendritic cells, and potent dendritic cell activation by dolastatin occurred in the absence 
of tumor cell death. The mirvetuximab soravtansine ADC also activates monocytes and promotes 
phagocytosis of mirvetuximab-treated FRα-positive tumor cells through a mechanism of Fc-
FcγR interaction [22].
In addition to effects of ADCs in monotherapy, there is strong preclinical rationale for the 
combination of ADCs with immune checkpoint inhibitors.  Treatment of mice bearing a Her2-
expressing orthotopic tumor model with the anti-Her2 ADC T-DM1 promoted increased tumor-
associated macrophage PD-L1 expression [20]. Combined treatment of orthotopic models with 
T-DM1 and anti CTLA-4/PD-1 caused complete tumor regression in a model with primary 
resistance to immunotherapy, and was accompanied by massive T-cell activation, proliferation, 
and increased tumor T-cell infiltration [20]. Similarly, in a preclinical study of the MMAE 
analog dolastain 10, treatment of immune-competent mice bearing MC38 mouse 
adenocarcinoma xenografts with systemic dolastatin 10 synergized with anti CTLA4/PD-1 to 
cause complete tumor regression in 7/12 animals [21].
In a phase 1 dose finding and dose expansion clinical trial, monotherapy with the ADC 
mirvetuximab soravtasine had a tolerable safety profile and demonstrated promising results in 
patients with recurrent platinum-resistant ovarian cancer and recurrent endometrial cancer.  
Based on these results, a multi-arm phase Ib/II clinical trial (FORWARD II, NCT02606305) of 
mirvetuximab soravtansine in combination with carboplatin, liposomal doxorubicin, 
bevacizumab, or pembrolizumab was developed and preliminary safety results demonstrate the 
combination is tolerable [23]. A dose expansion phase is ongoing. The response of microsatellite 
stable endometrial cancer to immune checkpoint inhibitor monotherapy is expected to be low, 
and combination therapy with immune-stimulatory drug-antibody conjugates is particularly 
relevant in this population.  Thus, we propose in this study to measure the response of FRα 
positive, microsatellite stable advanced and recurrent endometrial cancers to the ADC 
mirvetuximab soravtansine in combination with the PD-1 checkpoint inhibitor, pembrolizumab. 
2.4
Correlative Studies Background
Correlative studies may be performed in the Immune Oncology and DNA Repair Centers here at 
DFCI and Ventana Medical Systems. Depending on funding availability these may include: i) 
determination of CD3+, CD8+ TILs, CD8+/CD4+FOXP3+ TIL ratio, CD137+CD8+ TILs, 
CD137+CD8+/CD4+FOXP3+ TIL ratio, peritumoral lymphocytes and correlation with response; 
ii) expression of immune checkpoints including TIM-3, LAG-3, CTLA-4, PD-L2, PD-L1, PD-1, 
IDO and correlation with response; iii) targeted next generation sequencing (Oncopanel) to 
determine specific genetic alterations and correlate with response
The identification of predictive correlates to response to treatment with checkpoint blockade has 
proven a critical, but elusive goal, with numerous proposed approaches across different tumor 
types, but none that has thus far gained widespread clinical acceptance [24, 25]. Several efforts 
have focused on the identification of PD-L1 expression via immunohistochemistry (IHC) on the 

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surface of tumor, or infiltrating immune cells. Some studies have suggested a significant 
correlation between tumoral PD-L1 expression and response in nonsmall cell lung cancer [26], 
although others utilizing a similar approach have failed to identify a significant correlation [27, 
28]. Notable challenges in this strategy include the lack of standardization among IHC assays, 
the use of differential thresholds for assay positivity and a lack of consensus regarding the 
importance of explicitly accounting for PD-L1 expression on infiltrating immune cells. 
Complicating the development of these approaches are concerns that inadequate negative 
predictive value and full understanding of the underlying immune dynamics between the host 
and tumor may result in the exclusion of patients who may benefit from treatment.
For this trial we may characterize PD-L1 and PD-L2 expression on tumor cells and infiltrating 
immune cells in baseline formalin fixed paraffin embedded (FFPE) blocks of cancer tissue 
(which are required for eligibility) in conjunction with the Dana Farber Cancer Institute Center 
for Immunooncology. We may also characterize CD3+ T-cells, CD8+ T-cells and CD4+ T-cells 
as well as other immune cell markers and checkpoints in baseline FFPE blocks of cancer tissue..
Although less advanced in clinical development and practice, characterization of ex vivo surface 
markers on tumor cells, T-cells and other immune cells via multiparametric analysis (e.g. via 
flow cytometry or mass cytometry) has significant potential to reveal predictive biomarkers 
given the ability to measure multifarious combinations and to identify combinatorial patterns of 
expression among diverse cell populations. Using multiparametric assays developed in 
conjunction with the Dana Farber Cancer Institute Center for Immunooncology, we may 
determine the relative frequencies of T-cell subsets and evaluate the expression of immune 
checkpoints PD-1, PD-L1, PD-L2 and other immunologically active markers including TIM-3, 
LAG-3, CTLA-4, and IDO.
Genomic predictive correlates for response to checkpoint blockade have taken several forms. 
First, and serving as a critical line of evidence supporting this trial, numerous studies have 
suggested a correlation between mutational and neoepitope burden and response to checkpoint 
blockade [14, 29, 30]. Furthermore, as noted above, identification of microsatellite instability 
resulting from defects in the mismatch repair pathway and specifically within MLH1, MSH2, 
MSH6 and PMS2 have been suggested to portend a significantly improved response to 
checkpoint blockade [14]. This trial is limited to MSS tumors, therefore additional genomic 
alterations that correlate with response to the combination may be sought by characterizing 
genomic changes in FFPE tissue specimen. These include specific DNA gene repair mutations, 
neoantigens, and single nucleotide polymorphisims (SNPs) in immunologically relevant genes.
PARTICIPANT SELECTION
Remote consenting procedures may be implemented in the FRα pre-screening process for this 
trial as allowed per institutional policy.
3.1
Eligibility Criteria 

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3.1.1
Participants must have advanced or recurrent serous endometrial cancer.  Patients with 
mixed histologies/tumors are eligible if the serous component is the dominant 
histological subtype.  In addition, the tumors must be: 
1) microsatellite stable (MSS) as documented by either intact immunohistochemical 
(IHC) nuclear expression of the mismatch repair genes MSH2, MSH6, MLH1 and PMS2; 
or microsatelitte stable by polymerase chain reaction (PCR), next generation sequencing, 
or other CLIA-approved method; 
AND
2) FRα positive by central immunohistochemistry (IHC, Section 9.1). If archival tissue 
does not meet FRα criteria, a fresh biopsy tumor sample may be submitted and used to 
meet this criterium. If a fresh tumor biopsy cannot be done safely the patient will not be 
allowed to enroll on this study.  
3.1.2
Participants must have measurable disease as defined by RECIST 1.1. Lesions situated in 
a previously irradiated area are considered measurable if progression has been 
demonstrated in such lesions.
3.1.3
Prior therapy: Patients must have had one, but no more than four lines of chemotherapy 
for endometrial carcinoma.

Prior hormonal therapy is allowed (no washout period is required after hormonal therapy) 
and does not count as a prior line of therapy. Hormonal therapy in combination with 
CDK4/6 inhibitors or mTOR or other PI3K-pathway inhibitors is allowed and does not 
count as a line of prior therapy. 

Prior IO therapy targeted to the PD-1/PD-L1 pathway is allowed in up to 19 patients of 
the total cohort.

Patients must NOT have received prior therapy with any folate receptor ortholog agents.
3.1.4
Age 18 or greater years.  Because insufficient dosing or adverse event data are currently 
available on the use of mirvetuximab soravtansine and pembrolizumab in participants 
<18 years of age, children are excluded.  Endometrial cancer is rare in the pediatric 
population.  
3.1.5
ECOG performance status 0 or 1
3.1.6
Availability of archival tissue for research purposes in the form of a formalin-fixed 
paraffin embedded (FFPE) block or 5 unstained slides (Section 9).  Participants without 
available archival tissue may be eligible for enrollment after discussion with the Principal 
Investigator.
3.1.7
Participants must have normal organ and marrow function as defined below:

leukocytes
≥3,000/mcL

absolute neutrophil count
≥1,500/mcL

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
platelets
≥100,000/mcL

hemoglobin
≥ 9.0 g/dL

total bilirubin
≤ 1.5 x institutional upper limit of normal

AST(SGOT)/ALT(SGPT)
≤2.5 × institutional upper limit of normal

creatinine
≤ institutional upper limit of normal
OR

creatinine clearance
≥40 mL/min/1.73 m2 for participants with creatinine 
levels above institutional normal.
3.1.8
Time from prior therapy:
a.
Systemic anti-neoplastic therapy: 5 half-lives or 4 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 4 weeks, or focal radiation completed at least 2 weeks, prior to 
starting study treatment
3.1.9
The effects of agents used in this study on the developing human fetus are unknown.  For 
this reason, women of child-bearing potential must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry, during 
study treatment, and for at least twelve weeks after the last dose of study treatment.  
Should a woman become pregnant or suspect she is pregnant while she is participating in 
this study, she should inform her treating physician immediately.
3.1.10 Women of child-bearing potential must have a negative serum pregnancy test within 3 
days prior to the first dose of study treatment.
3.1.11 Ability to understand and the willingness to sign a written informed consent document.
3.2
Exclusion Criteria
3.2.1
Participants who have had chemotherapy within 5 half-lives or 4 weeks (whichever is 
shorter) or radiotherapy within 2 weeks prior to entering the study. Patients completing 
wide-field radiotherapy (e.g. >30% of marrow-bearing bones) must not have had 
treatment within 4 weeks prior to entering study. Participants must have recovered from 
all AEs due to previous therapy to Grade 1 ≤ or baseline, except alopecia. Participants 
with endocrine-related AEs who are adequately treated with hormone replacement are 
eligible.
3.2.2
Participants who are receiving any other investigational agents.
3.2.3
Participants with prior exposure to IO agents targeting the PD-1/PD-L1 pathway who 
discontinued therapy due to treatment-related toxicity deemed to be specifically related to 
IO therapy.
3.2.4
Required use of folate-containing supplements (e.g. folate deficiency).

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3.2.5
Known active CNS metastases and/or carcinomatous meningitis.  Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note 
that the repeat imaging should be performed during study screening),  clinically stable 
and without requirement of steroid treatment for at least 14 days prior to first dose of 
study treatment.
3.2.6
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to monoclonal antibodies (including antibody drug-conjugates or checkpoint 
inhibitors).
3.2.7
Uncontrolled intercurrent illness including, but not limited to, any of the following within 
6 months of first study treatment: symptomatic congestive heart failure, unstable angina 
pectoris, uncontrolled hypertension (≥ Grade 3), hypertensive crisis or hypertensive 
encephalopathy, uncontrolled cardiac arrhythmias, thrombotic or ischemic stroke, 
clinically-significant vascular disease (e.g. aortic aneurysm, or dissecting aneurysm), 
severe aortic stenosis, clinically significant peripheral vascular disease, or ≥ Grade 3 
cardiac toxicity following prior chemotherapy, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements.
3.2.8
Active or chronic corneal disorder, including but not limited to the following: Sjogren’s 
syndrome, Fuchs corneal dystrophy (requiring treatment), history of corneal 
transplantation, active herpetic keratitis, and also active ocular conditions requiring on-
going treatment/monitoring such as wet age-related macular degeneration requiring 
intravitreal injections, active diabetic retinopathy with macular edema, presence of 
papilledema, and acquired monocular vision.  
3.2.9
Serious clinically-relevant active infection, including known HIV infection, varicella-
zoster virus, cytomegalovirus infection, has a known history of Hepatitis B (defined as 
Hepatitis B surface antigen [HbsAg] reactive) or known active Hepatitis C virus (defined 
as HCV RNA is detected) or any other known concurrent infectious disease requiring IV 
antibiotics with within 2 weeks of study enrollment are ineligible because of the potential 
for immune side effects.
3.2.10 Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first 
dose of study drug.  Administration of killed vaccines is allowed. 
3.2.11 Current or prior use of immunosuppressive medication within 7 days prior to enrollment 
with the following exceptions to this exclusion criterion:
a.
Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection);
b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or equivalent;
c.
Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication).

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3.2.12 Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agent. Patients with diabetes type I, vitiligo, psoriasis, hypo-or hyperthyroid disease not 
requiring immunosuppressive treatment are eligible.
3.2.13 Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
3.2.14 Pregnant or nursing women are excluded from this study because effects of agents used 
in this study on infants or the developing human fetus are unknown 
3.2.15 Presence of other malignancies unless they are considered cured by patient’s oncologist.
3.3
Inclusion of Women and Minorities
Women of all races and ethnic groups are eligible for this trial. This disease does not affect men.
REGISTRATION PROCEDURES
4.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following registration, participants may begin protocol-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator (PI). If the subject does not receive protocol therapy following registration, the 
subject must be taken off-study in the CTMS (OnCore) with an appropriate date and reason 
entered.  
4.2
Registration Process for DF/HCC Institutions
Applicable DF/HCC policy (REGIST-101) must be followed.  
4.3
General Guidelines for Other Investigative Sites
Eligible participants will be entered on study centrally at the Dana-Farber Gynecologic Oncology 
Coordinating Center by the Project Manager.  All sites should contact the Project Manager 
(Martin Hayes; Martin_Hayes@dfci.harvard.edu) when a potential participant is identified to 
confirm enrollment availability.  

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Following registration, participants should begin protocol therapy within 5 days.  Issues that 
would cause treatment delays should be discussed with the Overall PI.  If the subject does not 
receive protocol therapy following registration, the subject must be taken off study in the CTMS 
(OnCore) with an appropriate date and reason entered.  
4.4
Registration Process for Other Investigative Sites
To register a participant, the following documents should be completed by the participating non-
DF/HCC site and e-mailed (Martin_Hayes@dfci.harvard.edu) to the Project Manager:

Copy of required laboratory tests: complete blood count with differential and serum 
chemistries (including liver function tests)

Screening clinic note (including documentation of oncologic history, past medical 
history, concomitant medications, performance status, and vitals)

Pathology report (with documentation of MSS status)

CT scan (with documentation of measurable disease per RECIST 1.1)

Documentation of FRα positivity 

Clinic note from pulmonary function test

Clinic note from eye exam

Documentation of consent process

Signed informed consent form 

HIPAA authorization form (if separate from the informed consent document)

Eligibility Checklist
The participating site will then e-mail (Martin_Hayes@dfci.harvard.edu) the Project Manager to 
verify eligibility.  The Project Manager will follow DF/HCC policy (REGIST-101) and register 
the participant on the protocol.  The Project Manager will e-mail the participant study number, 
and if applicable the dose treatment level, to the participating site.  
TREATMENT PLAN
5.1
Treatment Regimen
Treatment will be administered on an outpatient basis.  
Following premedications, mirvetuximab soravtansine will be administered at 6 mg/kg by 
Adjusted Ideal Body Weight (AIBW) intravenously on Day 1 of a 21-day cycle. Then, 
pembrolizumab will be administered intravenously over 30 minutes at 200 mg flat dose on Day 1 
of 21-day cycle (one cycle =21 days), after all procedures and assessments have been completed. 
Study medications may be administered up to 3 days before or after the scheduled day of 
administration of each cycle due to administrative reasons.
The duration of treatment with the combination will be until progression or adverse event up to 
35 cycles. Beyond 35 cycles, mirvetuximab soravtansine will be continued until progression or 
adverse event.

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Agent
Dose
Route
Schedule
Cycle Length
Mirvetuximab soravtansine 
(IMGN853)*
6 mg/kg 
(AIBW)
IV before 
Pembrolizumab 
+/- 10 min**
Day 1 each 
cycle
Pembrolizumab
200 mg
IV over 30 
minutes -5/+10 
min
Day 1 each 
cycle
21 days 
(3 weeks)
*Note: Mirvetuximab soravtansine is incompatible with 0.9% sodium chloride (saline)
** Infusion rate will vary based on patient tolerability as described in Section 5.3.1
Reported adverse events and potential risks are described in Section 7.  Appropriate dose 
modifications are described in Section 6.  No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the participant's 
malignancy.
5.2
Pre-Treatment Criteria
5.2.1
Cycle 1, Day 1 (or within 7 days prior to Cycle 1, Day 1)

Absolute neutrophil count ≥1,500/mcL

Platelets ≥100,000/mcL

Hemoglobin ≥ 9g/dL

Total bilirubin ≤ 1.5 x institutional upper limit of normal

AST (SGOT) / ALT (SGPT) ≤2.5 x institutional upper limit of normal

Creatinine ≤ institutional upper limit of normal or creatinine clearance ≥ 40 mL/min/1.73 
m2 for subjects with creatinine levels above institutional normal

All toxicities of previous therapy (aside from alopecia) must have resolved to ≤ grade 1

ECOG performance of 0 or 1

No evidence of life-threatening medical problems
5.2.2
Subsequent Cycles 

Absolute neutrophil count ≥1,000/mcL

Platelets ≥75,000/mcL

AST (SGOT) / ALT (SGPT) ≤ 2.5 x institutional upper limit of normal

Creatinine ≤ institutional upper limit of normal or creatinine clearance >= 40 
mL/min/1.73 m2 for subjects with creatinine levels above institutional normal

All toxicities pf previous cycles must have resolved to ≤ grade 2

ECOG performance of 0 to 2

No evidence of life-threatening medical problems
5.3
Agent Administration
5.3.1
Mirvetuximab Soravtansine (IMGN853)
Dosing

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Mirvetuximab soravtansine 6 mg/kg by Adjusted Ideal Body Weight (AIBW) IV on Day 1 of 
each 21-day cycle.   Dosing by AIBW as follows:
Adjusted Ideal Body Weight (AIBW)
IBW1 + 0.4 ( Actual weight – IBW1)
Where:
Ideal Body Weight (IBW)
IBW1 (male) = 0.9H1-88
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). 
Preparation and Administration
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic and investigational agents. Mirvetuximab soravtansine will be administered at 
the investigational site. Investigational product should be prepared and dispensed by an 
appropriately qualified and experienced member of the study staff (eg, physician, nurse, 
physician’s assistant, practitioner, or pharmacist) as allowed by local, state, and institutional 
guidance
The desired amount should be withdrawn from the vial(s) and diluted using 5% dextrose or 5% 
D-glucose to a final concentration as outlined in Section 8.1.7. Note: Mirvetuximab 
soravtansine is incompatible with saline (0.9% sodium chloride). Therefore, dilutions must 
be made using 5% dextrose or 5% D-glucose. Infusion bags must be labeled with the protocol 
number, patient number, storage temperature, dose, and volume of mirvetuximab soravtansine 
filtered into the bag, or according to institutional protocol. Light protection is not required for 
prepared IMGN853. The infusion must be completed within 8 hours of preparation.
If necessary, study drug from different drug lots may be mixed in a single-dose administration.
Mirvetuximab soravtansine 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 mirvetuximab soravtansine infusion rate may be increased to 5mg/min. Subsequent 
infusions may be delivered at the tolerated rate. For patients who have been administered 
mirvetuximab soravtansine as a prior anti-cancer therapy, mirvetuximab soravtansine should be 
administered at the tolerated rate of prior mirvetuximab soravtansine infusions. Therefore, the 
overall length of infusion will vary depending on dose and patient tolerability. Following 

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infusion, the IV line should be flushed with 5% dextrose or 5% D-glucose as needed to ensure 
delivery of the full dose. 
In combination, mirvetuximab soravtansine should be administered first, followed by 
pembrolizumab. Mirvetuximab soravtansine will be administered as an IV infusion following 
preparation as outlined in Section 8.1.7.
Drug, Tubing and Filtration
An IV tubing administration set with a 0.2 micron or 0.22 micron in-line filter must be used for 
infusion. Refer to section 8.1.4 for more information.
Observation Period
Patients will be carefully observed during each infusion and vital signs taken as outlined in the 
Study Calendar. They will remain in the clinic under observation for 2 hours after the completion 
of the first infusion of mirvetuximab soravtansine, and for at least 1 hour after each subsequent 
infusion, during which pembrolizumab infusion can be administered. The observation period will 
start after completion of the mirvetuximab soravtansine infusion for all infusions.
Infusion Reactions
Some patients treated with IV infusions of therapeutic drugs have experienced concurrent 
infusion-related reactions (see CTCAE Version 5.0). 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 1. 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 1: Management Guidelines for Potential Mirvetuximab Soravtansine Infusion-
related Reactions

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CTCAE v5.0 Severity Grade
Management
Grade 1
 Mild reaction; infusion 
interruption not indicated; 
intervention not indicated

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
Grade 2
Therapy or infusion interruption 
indicated but responds promptly 
to symptomatic treatment (e.g., 
antihistamines, NSAIDs, 
narcotics, IV fluids); prophylactic 
medications indicated for ≤24 hrs

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. 
Grades 3 or 4
Grade 3: Prolonged (i.e. 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)

Permanently discontinue study medication treatment
Order of Administration
Mirvetuximab soravtansine should be administered first, followed by pembrolizumab.
Caregiver Precautious
Mirvetuximab soravtansine 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 and clean-up of any spills or 
bodily fluids from a patient treated with mirvetuximab soravtansine.  Refer to Section 8.1 and 
package inserts for more information.
5.3.2
Pembrolizumab (MK-3475)
Dosing

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Pembrolizumab 200 mg as a 30 minute infusion on Day 1 of each 21-day cycles
Sites should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
Drug, Tubing and Filtration
The liquid drug product (DP) can be diluted with normal saline or 5% dextrose in the 
concentration range of 1 to 10 mg/mL in IV containers made of  material listed in Section 8.2.7.  
Section 8.2.7 contains specific instructions for the preparation of the pembrolizumab infusion 
fluid and administration of infusion solution.
Infusion Reactions
Infusion-related reactions have been reported with pembrolizumab, and are non-immune-
mediated events.
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab associated infusion reaction 
are provided in Table 2. 
Table 2: Management Guidelines for Potential Pembrolizumab Infusion-related Reactions
CTCAE v5.0 Severity Grade
Treatment
Premedication at Subsequent 
Dosing
Grade 1
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator.
None
Grade 2
Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDs, narcotics, 
IV fluids); prophylactic 
medications indicated for ≤24 hrs
Stop Infusion.
Additional appropriate medical 
therapy may include but is not 
limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator.
If symptoms resolve within 1 hour 
Participant may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg po 
(or equivalent dose of analgesic).

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of stopping drug infusion, the 
infusion may be restarted at 50% of 
the original infusion rate (e.g. from 
100 mL/hr to 50 mL/hr).  Otherwise 
dosing will be held until symptoms 
resolve and the participant should 
be premedicated for the next 
scheduled dose.
Participants who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further study drug treatment
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical sequelae 
Grade 4:
Life-threatening consequences, 
urgent intervention indicated
Stop Infusion.
Additional appropriate medical 
therapy may include but is not 
limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, 
epinephrine should be used 
immediately.
Participant is permanently 
discontinued from further study 
drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of 
drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Order of Administration
Mirvetuximab soravtansine should be administered first, followed by pembrolizumab.
5.4
General Concomitant Medication and Supportive Care Guidelines
All concomitant medications, over-the-counter, herbal supplements and supportive therapy taken 
within 28 days 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, 

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frequency, duration of administration, and indication for use will be recorded in the appropriate 
sections of the eCRF.
5.4.1
Required Supportive Care Medications
5.4.1.1
Premedications
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 30-90 minutes prior to each infusion of mirvetuximab 
soravtansine. If individual patients require more intensive treatment to prevent infusion-related 
reactions, investigators may modify the regimen accordingly. 
5.4.1.2
Eye drops
Lubricating artificial tears and corticosteroid eye drops are mandatory for all patients receiving 
mirvetuximab soravtansine as follows (Appendix D):
•
Patients are required to use corticosteroid eye drops as prescribed by the treating 
physician unless the risk outweighs the benefit as per the ophthalmologist/physician. All 
patients enrolled will be instructed to self-administer 1% prednisolone (Pred Forte® or 
generic equivalent) six times daily on Days 1-4 and four times daily on Days 5-8 of each 
cycle during the study. For individual patients who cannot tolerate the preservative 
contained in 1% prednisolone, other corticosteroid eye drops may be substituted (e.g. 
difluprednate 0.05%; Durezol®) and administered on Days 1-8 of each cycle at a 
frequency prescribed by the ophthalmologist. 
•
Patients will be required to use preservative-free, lubricating artificial tears on a daily 
basis (as directed by the product label or the treating physician). Patients should be 
advised to wait at least 15 minutes following steroid administration before instilling 
lubricating eye drops.
•
The patient should continue use of the corticosteroid eye drops per the ophthalmologist 
recommendation after discontinuation of mirvetuximab soravtansine. The patient should 
continue the lubricating eye drops for 4 weeks following discontinuation of 
mirvetuximab soravtansine. 
5.4.2
Other supportive care

Antiemetic (e.g. 5-HT3 serotonin receptor antagonists such as palonosetron, granisetron or 
ondansetron), antidiarrheal (e.g. loperamide) medications, and other supportive care may be 
used at the discretion of the treating physician, unless prohibited below in Section 5.4.3.

Patients are strongly advised to avoid using contact lenses while on mirvetuximab 
soravtansine. 

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
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 in full daylight during the course of the 
study. 

The use of temporary lower punctal plugs to increase lubrication of the eyes is optional if 
lubricating artificial tears and corticosteroid eye drops are not sufficient.
The management and dose modification for ocular symptoms is outlined in Section 6.
5.4.3
Prohibited Medications
Potent CYP3A4 inhibitors such as ketoconazole and erythromycin should be avoided during 
study treatment. 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.
In addition, participants are prohibited from receiving the following therapies during Screening 
and Treatment phase of the trial 
•
Antineoplastic systemic chemotherapy or biological therapy
•
Immunotherapy not specified in this protocol
•
Investigational agents other than the study drugs
•
Folate-containing vitamins
•
Growth factors (G-CSF, GM-CSF) cannot be used during cycle 1, but are allowed on 
subsequent cycles of treatment as per published ASCO or institutional guidelines.
•
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 should be carefully monitored.
•
Grapefruit juice and or the oral consumption of grapefruit should be avoided.
•
Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 

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vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed. 
•
Systemic glucocorticoids for any purpose other than to modulate symptoms from an event 
of clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Overall PI.
•
Contact lens use should be avoided during study treatment period
5.5
Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment with both agents 
may continue for up to 35 doses (approximately 2 years), or with mirvetuximab soravtansine 
alone after 35 cycles, or until one of the following criteria applies:

Disease progression (as defined in sections 5.5.1 and 5.5.2)

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant’s condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
When a participant is removed from protocol therapy and/or is off of the study, the relevant Off-
Treatment/Off-Study information will be updated in OnCore.
5.5.1
Tumor Response Assessments
Antitumor activity will be assessed through radiological tumor assessments conducted at 
baseline (screening) of starting therapy and every 2 cycles (6 weeks) thereafter. In addition, 
radiological tumor assessments will also be conducted whenever disease progression is suspected 
(eg, symptomatic deterioration) and at the time of withdrawal from the treatment (if not done in 
the previous 4 weeks). Complete, partial responses and progressive disease must be confirmed 
on repeated imaging ≥ 4 weeks after initial documentation, but not more than 6 weeks after 
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Assessment of response will be made using RECIST version 1.1 and as per immune-related
RECIST criteria (irRECIST).
5.5.2
Treatment after Initial Evidence of Radiologic Disease Progression
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses. The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with 
chemotherapeutic agents, and may manifest as a clinical response after an initial increase in 
tumor burden or even the appearance of new lesions.
If radiologic imaging shows progression, tumor assessment should be repeated > 4 weeks later in 
order to confirm progression, and study treatment may be continued at the Investigator’s 
discretion while awaiting radiologic confirmation of disease progression. For the subjects who 
continue on study therapy beyond progression, further progression is defined as an additional 
10% increase in tumor burden from time of initial PD. This includes an increase in the sum of 
diameters of all target lesions and/ or the diameters of new measurable lesions compared to the 
time of initial PD. Study treatment should be discontinued permanently upon documentation of 
further progression. If repeat imaging shows a reduction in the tumor burden demonstrating CR, 
PR or SD compared to the initial scan, treatment with study treatment may be continued or 
resumed.
5.6
Duration of Follow Up
Participants will be followed for 3 years by phone after removal from study or until death, 
whichever occurs first. Survival status should be checked every 6 months during that time. 
Participants removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event. Date and cause of death should be provided for 
participants who become deceased within the 3-year interval following removal from the study. 
Should a participant become pregnant while on trial, the patient will be withdrawn from the 
study. However, the outcome of the pregnancy and the newborn’s health, if the pregnancy is 
carried to term, will be monitored.
5.7
Criteria for Taking a Participant Off Study
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, patient is lost to follow up, or patient is not compliant with study 
procedures.
Patients who withdraw or are removed from the study treatment will have an off-treatment visit 
within 7 days of the decision to discontinue study treatment.  The final visit will occur at the time 
the participant discontinues study medication. Following the Final Visit, participants will be 
followed for disease progression (if reason for treatment discontinuation is other than 

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progression) and survival, and reassessment for toxicity will be performed up to 30 days after the 
last treatment dose. Participants will be followed for up to 3 years by phone after removal from 
study or until death, whichever occurs first. Survival status should be checked every 6 months 
during that time
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). In addition, the study team will ensure Off 
Treatment/Off Study information is updated in OnCore in accordance with DF/HCC policy 
REGIST-101.
DOSING DELAYS/DOSE MODIFICATIONS
Every effort should be made to administer study treatment on the planned dose and schedule. 
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Patients experiencing AEs that can be clearly attributed to mirvetuximab soravtansine or 
pembrolizumab will have the corresponding agent modified or withheld. In case of an AE 
recurrence, the other drug in the combination regimen will then be modified or withheld. If a 
relationship of an AE to a particular drug cannot be clearly determined, the order in which the 
drugs are to be reduced will require approval from the Overall PI.
6.1
Mirvetuximab Soravtansine (IMGN853)
6.1.1
Monitoring and Management of Potential Ocular Disorders
In early dose escalation, there was a relationship between mirvetuximab soravtansine plasma 
exposure with increased likelihood of an ocular event as well as with response. Exposure-
response modeling suggested that a dose of 6.0 mg/kg AIBW provided adequate exposure for 
response while also maintaining overall exposure within a range that decreased the potential for 
ocular adverse events. Due to the observation of ocular disorders consistent with reversible 
keratopathy/corneal epitheliopathy in patients treated with mirvetuximab soravtansine, ocular 
function will be carefully monitored. Ocular symptom assessments will be performed at baseline 
and at Day 1 of every cycle thereafter (Study Calendar and Appendix C). Complete 
ophthalmologic exams will be performed in all patients at baseline and every other cycle 
thereafter if there is a TEAE reported (Study Calendar and Appendix C). 
Patients are strongly advised to avoid using contact lenses while on mirvetuximab soravtansine. 
Baby shampoo and a soft cloth should be used to clean the eyes, and a warm compress at 
bedtime may be used to decrease any possible inflammation on the eyelid’s surface. Please refer 

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to Section 5.4 for details on the prophylactic use of steroid eye drops and lubricating artificial 
tears. The use of UVA/UVB sunglasses is recommended in full daylight during the course of the 
study. The use of temporary lower punctal plugs to increase lubrication of the eyes is optional if 
lubricating artificial tears and corticosteroid eye drops are not sufficient. If patients report signs 
or symptoms of ocular disorders, including, but not limited to, blurred vision or eye irritation, the 
management and dose modification is outlined below.
If a patient develops ocular symptoms of any grade, the patient is required to have a complete 
examination by an ophthalmologist. If a patient develops ≥ CTCAE Grade 2 ocular symptoms, 
treatment with mirvetuximab soravtansine will be interrupted. Therapy may resume if ocular 
symptoms improve to Grade 1 or baseline within 28 days of the next scheduled mirvetuximab 
soravtansine dose (refer to Table 3 for details). Subsequent eye examinations will be scheduled 
to occur in every other cycle going forward, from the time that the AE was initially reported, and 
at either the End of Treatment visit or 30-day follow-up visit following treatment 
discontinuation, even if the results of the patient’s ocular exam shows no obvious clinical 
findings. Management of treatment-emergent ocular AEs with inflammatory characteristics 
should include corticosteroid eye drops and/or other measures as indicated by an 
ophthalmologist.
Table 3: Management of Ocular Disorders
CTCAE v5.0 Severity 
Grade*
Management
Guidelines for Mirvetuximab 
Soravtansine Dose 
Modifications
Grade 1

Complete eye exam as outlined in 
Study Calendar and Appendix C.

Monitor for worsening symptoms

Repeat complete exam as clinically 
indicated, at least every other cycle 
(from point at which toxicity first 
reported) at a minimum

Continue mirvetuximab 
soravtansine dosing
Grade 2

Complete eye exam as outlined in 
schedule of clinical assessments 
(Study Calendar and Appendix C). 

Repeat complete exam as clinically 
indicated 

Patients should have weekly 
symptomatic ocular assessments until 
the symptoms resolve to Grade 1 or 
baseline or are deemed to irreversible 
by investigator

Repeat complete exam as clinically 
indicated, at least every other cycle 
(from point at which toxicity first 
reported) at a minimum

Hold mirvetuximab 
soravtansine dosing until AE 
has resolved to Grade 1 or 
better. 

Patients with ocular 
symptoms lasting < 14 days 
may be allowed to resume 
mirvetuximab soravtansine at 
the same dose level 

Patients with ocular 
symptoms lasting ≥ 14 days 
but no more than 28 days 
may resume mirvetuximab 
soravtansine reduced by one 
dose level

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Grade 3

Complete eye exam as outlined in 
schedule of assessments (Study 
Calendar and Appendix C). Repeat 
complete exam as clinically indicated. 

Patients should have weekly 
symptomatic ocular assessments until 
the symptoms resolve to Grade 1 or 
baseline or are deemed to be 
irreversible by the investigator. 

Repeat complete exam as clinically 
indicated, at least every other cycle 
(from point at which toxicity first 
reported) at a minimum

Hold mirvetuximab 
soravtansine dosing. 

Patients may be allowed to 
resume mirvetuximab 
soravtansine reduced by one 
dose level after AE has 
resolved to Grade 1 or better 
within 28 days. 
Grade 4

Complete eye exam as outlined in 
Study Calendar and Appendix C 
Repeat complete exam as clinically 
indicated.

Patients should have weekly 
symptomatic ocular assessments until 
the symptoms resolve to Grade 1 or 
baseline (Study Calendar and 
Appendix C) or are deemed to be 
irreversible by the investigator.

Repeat complete exam as clinically 
indicated, at least every other cycle 
(from point at which toxicity first 
reported) at a minimum

Permanently discontinue 
mirvetuximab soravtansine 
dosing.
* Appendix C includes CTCAE version 5.0 Grade definitions for select ocular disorders
6.1.2
Monitoring of Non-Infectious Pneumonitis Following the Administration of Study 
Treatment
Non-infectious pneumonitis has been observed following the administration of mirvetuximab 
soravtansine and pembrolizumab 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 4 should be followed.
Table 4: Management of Pneumonitis
CTCAE v5.0 Severity 
Dose Modifications
irAE management 
Monitor and follow-

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Grade
with corticosteroid 
and/or other therapies
up
Grade 1
Continue dosing after 
discussion with the 
Overall PI
Grade 2
Withhold mirvetuximab 
soravtansine and 
pembrolizumab (both 
agents)
Mirvetuximab 
soravtansine can be 
resumed at a dose 
reduced by one dosing 
level (see Table 6), and 
pembrolizumab can be 
resumed at same dosing 
level after discussion 
with the Overall PI 
when symptoms 
resolve to ≤ Grade 1
Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper*

Monitor 
participants for 
signs and 
symptoms of 
pneumonitis

Evaluate 
participants with 
suspected 
pneumonitis with 
radiographic 
imaging and initiate 
corticosteroid 
treatment

Add prophylactic 
antibiotics for 
opportunistic 
infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue 
mirvetuximab 
soravtansine and 
pembrolizumab (both 
agents)
Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper*

Monitor 
participants for 
signs and 
symptoms of 
pneumonitis

Evaluate 
participants with 
suspected 
pneumonitis with 
radiographic 
imaging and initiate 
corticosteroid 
treatment

Add prophylactic 
antibiotics for 
opportunistic 
infections
* Notes on steroids for irAE:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over 
at least 4 weeks.
2.
Pembrolizumab and mirvetuximab soravtansine can be resumed after AE has been reduced to Grade 1 or 
0 and corticosteroid has been tapered. Both agents should be permanently discontinued if AE does not 
resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or 
equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids.

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6.1.3
Other symptoms 
Mirvetuximab soravtansine dose may be reduced at the discretion of the Investigator after 
discussion with the Overall PI. Patients who develop adverse events requiring an interruption of 
mirvetuximab soravtansine may resume treatment at a reduced dose level as shown in Tables 5 
and 6 provided the criteria outlined in Section 5.2 are met.
Table 5: Mirvetuximab Soravtansine Dose Modification Guidelines
Adverse Event
Management/Next Dose for Mirvetuximab Soravtansine
≤ Grade 1
No change in dose
Grade 2
Hold until ≤ Grade 1.  Resume at same dose level.
Grade 3
Holduntil < Grade 2.  Resume at one dose level lower..
Grade 4
Off protocol therapy
Table 6: Mirvetuximab Soravtansine Dose Levels
Dose Level
Mirvetuximab Soravtansine Dose
-2
4 mg/kg AIBW, Q21 day
-1
5 mg/kg AIBW, Q21 day
0
6 mg/kg AIBW, Q21 day
A second dose reduction will be permitted for second event of Grade 3 or higher. Dose 
reductions below 4 mg/kg (Dose Level -2) will not be permitted. 
Mirvetuximab soravtansine may be interrupted for situations other than treatment-related Aes 
such as medical / surgical events or logistical reasons not related to study therapy. Participants 
should be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Overall PI. The reason for interruption should be documented in the 
patient’s study record.
6.2
Pembrolizumab 
AEs associated with pembrolizumab exposure, including coadministration with additional 
compounds, may represent an immunologic etiology. These immune-related AEs (irAEs) may 
occur shortly after the first dose or several months after the last dose of 
pembrolizumab/combination treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical study data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab/combination treatment, administration of 
corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate evaluation to 
confirm etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, skin biopsy may be included as part of the evaluation. Based on the severity of 

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irAEs, withhold or permanently discontinue pembrolizumab and administer corticosteroids. Dose 
modification and toxicity management guidelines for irAEs associated with 
pembrolizumab/combination treatment are provided in Table 7.
Attribution of Toxicity:
When study interventions are administered in combination, attribution of an adverse event to a 
single component is likely to be difficult.  Therefore, while the investigator may attribute a 
toxicity event to the combination, to mirvetuximab soravtansine alone or to pembrolizumab 
alone, for adverse events listed in Table 7, both interventions must be held according to the 
criteria in Table 7 Dose Modification Guidelines for Pembrolizumab.
Holding Study Interventions:
When study interventions are administered in combination, if the AE is considered immune-
related, both interventions should be held according to recommended dose modifications.
Restarting Study Interventions:
Participants may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab in this study, as described in Table 7.

If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study interventions.

If the toxicities do not resolve and conditions are aligned with what is defined in Table 7, the 
combination of mirvetuximab soravtansine and pembrolizumab bay be restarted at the 
discretion of the investigator.  In these cases where the toxicity if attributed to the 
combination or to mirvetuximab soravtansine alone, re-initiation of pembrolizumab as a 
monotherapy may be considered at the PI’s discretion.
Table 7: Dose Modification Guidelines for Pembrolizumab
Instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over 
at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot 
be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv5.0)
Action taken to 
pembrolizumab
irAE management 
with corticosteroid 
and/or other 
therapies
Monitor and 
follow-up
Pneumonitis 
See Table 4
See Table 4
See Table 4
See Table 4

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Grade 2 or 3
Withhold
Diarrhea / Colitis 
Grade 4
Permanently 
discontinue

Administer 
corticosteroids 
(initial dose of 1-
2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper

Monitor 
participants for 
signs and 
symptoms of 
enterocolitis (ie, 
diarrhea, 
abdominal pain, 
blood or mucus 
in stool with or 
without fever) 
and of bowel 
perforation 
(ie, peritoneal 
signs and ileus).

Participants 
with ≥ Grade 2 
diarrhea 
suspecting 
colitis should 
consider GI 
consultation 
and performing 
endoscopy to 
rule out colitis. 

Participants 
with 
diarrhea/colitis 
should be 
advised to drink 
liberal 
quantities of 
clear fluids.  If 
sufficient oral 
fluid intake is 
not feasible, 
fluid and 
electrolytes 
should be 
substituted via 
IV infusion.
Grade 2
Withhold

Administer 
corticosteroids 
(initial dose of 
0.5- 1 mg/kg 
prednisone or 
equivalent) 
followed by 
taper
AST / ALT 
elevation or 
Increased bilirubin
Grade 3 or 4 
Permanently 
discontinue

Administer 
corticosteroids 
(initial dose of 1-
2 mg/kg 
prednisone or 
equivalent) 

Monitor with 
liver function 
tests (consider 
weekly or more 
frequently until 
liver enzyme 
value returned 
to baseline or is 
stable

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followed by 
taper
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia
Newly onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin 
replacement 
therapy for 
participants with 
T1DM 

Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 

Monitor 
participants for 
hyperglycemia 
or other signs 
and symptoms 
of diabetes.
Grade 2
Withhold
Hypophysitis
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 

Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated.  

Monitor for 
signs and 
symptoms of 
hypophysitis 
(including 
hypopituitarism 
and adrenal 
insufficiency) 
Grade 2
Continue 
Hyperthyroidism 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1

Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate 

Monitor for 
signs and 
symptoms of 
thyroid 
disorders. 
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyroinine) 
per standard of 
care

Monitor for 
signs and 
symptoms of 
thyroid 
disorders. 
Grade 2
Withhold 
Nephritis and Renal 
dysfunction
Grade 3 or 4 
Permanently 
discontinue

Administer 
corticosteroids 
(prednisone 1-2 
mg/kg or 
equivalent) 
followed by 
taper.

Monitor 
changes of 
renal function
Neurological 
Toxicities
Grade 3 or 4
Permanently 
discontinue

Based on 
severity of AE 
administer 
corticosteroids

Ensure 
adequate 
evaluation to 
confirm 
etiology and/or 
exclude other 
causes
Grade 1
Withhold
Myocarditis
Grade 2, 3 or 4
Permanently 
discontinue

Based on 
severity of AE 
administer 
corticosteroids

Ensure 
adequate 
evaluation to 
confirm 
etiology and/or 
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causes
Suspected SJS, 
TEN, or DRESS
Withhold
Exfoliative 
Dermatologic 
Conditions
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue

Based on 
severity of AE 
administer 
corticosteroids

Ensure 
adequate 
evaluation to 
confirm 
etiology or 
exclude other 
causes
Intolerable/ 
persistent Grade 2
Withhold
Grade 3
Withhold or 
discontinue based 
on the type of event.  
Events that require 
discontinuation 
include and not 
limited to:  Gullain-
Barre Syndrome, 
encephalitis
All other immune-
related AEs
Grade 4 or recurrent 
Grade 3 
Permanently 
discontinue

Based on type 
and severity of 
AE administer 
corticosteroids 

Ensure 
adequate 
evaluation to 
confirm 
etiology and/or 
exclude other 
causes
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician.  
NOTE: 

For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is 
required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal 
replacement therapy or achieved metabolic control (in case of T1DM).  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as medical / 
surgical events or logistical reasons not related to study therapy. Participants should be placed back on 
study therapy within 3 weeks of the scheduled interruption, unless otherwise discussed with the Overall 
PI. The reason for interruption should be documented in the patient's study record.
6.3
Re-treatment Criteria
For a patient to begin a new cycle or continue a cycle of therapy after a dose modification, the following 
criteria must be met.

Pre-treatment criteria as described in Section 5.2.2 with the following exceptions
o
Treatment-emergent ocular disorders, which must have recovered to < Grade 1 or baseline
o
Treatment-emergent pneumonitis which must have recovered to ≤ Grade 1
If the patient does not meet these criteria, dosing with the two agents in the combination regimen will be 
delayed and the patient should be re-evaluated within 48-72 hours. Dosing with both agents may resume 
if these criteria have been met. If the adverse event can be attributed to one of the agents in the 
combination regimen, that agent will be held or discontinued as per the Dose Modification Guidelines 

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described in Sections 6.1 and 6.2 respectively; however, treatment with the second agent may resume 
provided all the other criteria are met. However, if the next cycle is delayed due to treatment-related 
toxicity longer than 12 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 Overall PI and the Investigator. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following list of 
reported and/or potential AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting in addition to routine reporting. 
7.1
Expected Toxicities
7.1.1
Adverse Events List(s)
7.1.1.1
Adverse Event List(s) for Mirvetuximab Soravtansine (IMGN853)
For the purposes of regulatory reporting the events listed in Table 8 are considered expected for 
mirvetuximab soravtansine. 
Table 8: Mirvetuximab Soravtansine Adverse Drug Reactions (ADR)
Number of Patients Exposed N = 404
All SARs
Occurrence 
of Fatal 
SARs
Occurrence 
of Life-
threatening 
SARs
MedDRA SOC 
SARs 
n (%)
n (%)
n (%)
Diarrhea ≤ Grade 3
137 (34)
0
0
Nausea ≤ Grade 3 
167 (41)
0
0
Gastrointestinal disorders 
Vomiting ≤ Grade 3 
64 (16)
0
0
Fatigue ≤ Grade 3
129 (32)
0
0
General disorders and site 
conditions 
Asthenia ≤ Grade 3
45 (11)
0
0
Metabolism and nutrition 
disorders 
Dehydration ≤ Grade 3 
11 (3)
0
0
Respiratory, thoracic and 
mediastinal disorders 
Pneumonitis ≤ Grade 2 
34 (8)
0
0
Abbreviations: IB = Investigator Brochure; MedDRA = Medical Dictionary for Regulatory Activities; MIRV = 
mirvetuximab soravtansine; SAR = serious adverse reaction; SOC = system organ class.
Additional detailed information can be found in the Investigators Brochure.
7.1.1.2
Adverse Event List(s) for Pembrolizumab
Detailed information on adverse events associated with pembrolizumab can be found in the 
Investigators Brochure.

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7.2
Adverse Event Characteristics

CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

For expedited reporting purposes only:  
-
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided.

Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
7.3
Serious Adverse Events
A serious adverse event (SAE) is any AE occurring at any dose that occurs after the initial dose 
of study treatment, during treatment, or within 30 days of the last dose of treatment that results in 
any of the following outcomes:

Death

Is life-threatening

Requires inpatient hospitalization ≥ 24 hours

Requires prolongation of existing hospitalization

A persistent or significant disability or incapacity or substantial disruption of 
the ability to conduct normal life functions

A congenital anomaly or birth defect
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization. 
Note that hospitalization is defined as admission to treat a clinical adverse event. 
The following events would not be considered hospitalizations for SAE reporting purposes: 

<24-hour hold for observation, admission to a hospice facility or nursing home, respite 

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care, outpatient surgery, social admission (e.g., a homeless patient) or admission not 
associated with a precipitating clinical adverse event (e.g., elective or pre-planned 
surgery, or in-patient administration of subsequent chemotherapy, etc.).

Events of progression of the patient’s underlying cancer as well as events clearly related 
to progression of the patient’s cancer (signs and symptoms of progression) should not be 
reported as a serious adverse event unless the outcome is fatal within the safety reporting 
period. If the event has a fatal outcome within the safety reporting period, then the event 
of Progression of Disease must be recorded as an important medical event and as a SAE 
with CTC Grade 5 (fatal outcome) indicated. 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to ImmunoGen and Merck in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are considered 
serious for collection purposes.

Is a new cancer (that is not a condition of the study);

Is associated with an overdose
7.4
Adverse Event Reporting to Overall PI
7.4.1
In the event of an unanticipated problem or life-threatening complications treating 
investigators must immediately notify the Overall PI.
7.4.2
Investigators must report within 1 business day of investigator awareness to the Overall 
PI any serious adverse event (SAE) that occurs from the time that the subject provides 
informed consent, through and including the 30 calendar days after the last administration 
of study treatment.
7.4.3
Adverse Event Reporting Guidelines
All participating sites will report AEs to the Sponsor-Investigator per DF/HCC 
requirements, and the IRB of record for each site as applicable per IRB policies. The 
table below indicates which events must be reported to the Overall PI.
Table 9: DF/HCC Reportable Adverse Events (AEs)
DF/HCC Reportable Adverse Events(AEs)
Attribution
Gr. 2 & 3 AE
Expected
Gr. 2 & 3 AE 
Unexpected
Gr. 4 AE Expected
Gr. 4 AE
Unexpected
Gr. 5 AE 
Expected or 
Unexpected
Unrelated
Unlikely
Not required
Not required
5 calendar days#
5 calendar days
24 hours*
Possible
Probable
Definite
Not required
5 calendar days
5 calendar days#
5 calendar days
24 hours*
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported.
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 1 business day of learning of the event.

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7.5
Reporting Period
For the time period beginning when the consent form is signed until 30 days following cessation 
of treatment, any serious adverse event, or follow up to a serious adverse event, including death 
due to any cause whether or not related to the study products, must be reported within 24 hours 
to the Overall PI. 
All participants with serious adverse events must be followed up for outcome.
7.6
Adverse Event Reporting to ImmunoGen
The following events will be reported to ImmunoGen:

Any serious adverse event (SAE), considered by an investigator who is a qualified 
physician to be related to mirvetuximab soravtansine (Section 7.6.1)

Any new cancers or overdose of mirvetuximab soravtansine (Section 7.6.1)

Pregnancy or Lactation (Section 7.6.2)

Events of Special/Clinical Interest (Section 7.6.3)
7.6.1
Serious Adverse Event Reporting to ImmunoGen
For SAE reporting, including those that are expedited, the MedWatch (MW) format is 
preferred.  A line listing is acceptable for non-expedited cases and should be sent within 2 
working days to ImmunoGen using: IMGNPVGSAFETY@immunogen.com (CC ).
IND Safety Reports (final MedWatch only) must be sent, upon submission to FDA, to:   
IMGNPVGSAFETY@immunogen.com
In addition to SAE, any new cancer (that is not a condition of the study) or overdose of 
mirvetuximab soravtansine will be reported to ImmunoGen the same timeframe as SAEs using 
the procedure for SAEs. 
7.6.2
Reporting a Pregnancy and Lactation to ImmunoGen
Pregnancy and lactation are exclusion criteria.  The Overall PI and ImmunoGen must be 
immediately notified (within 24 hours) in the event of a pregnancy occurring during the course 
of the study and through 120 days after a patient’s last dose of mirvetuximab soravtansine 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 for SAE will be followed.  Pregnancy outcomes listed above are also reportable to 
ImmunoGen in the same timeframe as SAEs.  If the pregnancy continues to term, the outcome 

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(health of infant) must also be reported.
7.6.3
Reporting Adverse Events of Special Interest (AESI) to ImmunoGen
An adverse event of special interest (AESI) (serious or non-serious) is one of scientific and 
medical concern specific to the ImmunoGen product for which ongoing monitoring and rapid 
communication by the investigator to ImmunoGen could be appropriate.   These are reportable to 
ImmunoGen in the same timeframe as SAEs.
Mirvetuximab soravtansine: 

AESI: pneumonitis.
Any symptom or sign potentially suggestive of pneumonitis should be promptly reported to 
ImmunoGen as for SAE, even if non-serious and/or unrelated to mirvetuximab soravtansine. If it 
meets requirements for expedited reporting it will be reported to the IRB and FDA per guidelines 
as well.  These AESIs are to be reported to ImmunoGen expeditiously within 48 hours of 
knowledge of the event, during the study through 30 days after receiving the last dose of study 
treatment. It is important that the investigator provide an assessment of relationship of the SAE 
or AESI to study treatment at the time of the initial report. The Sponsor-Investigator’s study-
specific Serious Adverse Event (SAE)/Adverse Events of Special Interest (AESI) Report Form 
(MW) must be used for reporting SAEs and AESIs. The contact information for reporting of 
SAEs and AESIs can be found on the SAE/AESI Reporting Form and Pregnancy Report Forms.
Radiologic findings suggestive of pneumonitis include new onset of any of the following:

Pulmonary consolidation

Pulmonary infiltrate

Reticular infiltrate

Nodular infiltrate

Reticulo-nodular infiltrate

Ground-glass pulmonary infiltrate

Increased interstitial markings

Interstitial infiltrate

Honeycomb’s appearance
7.7
Adverse Event Reporting to Merck
The following events will be reported to Merck & Co., Inc.:

Any serious adverse event (SAE), considered by an investigator who is a qualified 
physician to be related to pembrolizumab (Section 7.7.1)

Any new cancers (Section 7.7.1) or overdose of pembrolizumab (Section 7.7.2)

Pregnancy and Lactation (Section 7.7.3)

Events of Special/Clinical Interest (Section 7.7.4)
7.7.1
Serious Adverse Event Reporting to Merck

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Any serious adverse event, considered by an investigator who is a qualified physician to be 
related to Merck 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 Merck Global Safety.
SAE reports and any other relevant safety information are to be reported within 24 hours to 
the Overall PI and forwarded within 2 working days to Merck Global Safety (Attn: Worldwide 
Product Safety; FAX 215-661-6229).  Following submission to Merck Global Safety, forward 
the SAE report and a copy of the fax confirmation to .
In addition to SAE, any new cancer (that is not a condition of the study) will be reported to 
Merck within the same timeframe as SAEs, using the procedure for SAEs. 
7.7.2
Reporting of Pembrolizumab Overdose to Merck
For purposes of this study, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, the participant should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met.
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported to Merck 
as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 
hours to the Overall PI and within 2 working days hours to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215-661-6229)
7.7.3
Reporting of Pregnancy and Lactation to Merck
Although pregnancy and infant exposure during breast-feeding are not considered adverse 
events, it is the responsibility of investigators or their designees to report any pregnancy or 
lactation in a participant (spontaneously reported to them) that occurs during the study.
Pregnancies and infant exposures during breastfeeding that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if they cause 
the participant to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment 
or a procedure.  

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Pregnancies and infant exposures during breastfeeding that occur from the time of treatment 
allocation/randomization through 120 days following cessation of pembrolizumab, or 30 days 
following cessation of treatment if the participant initiates new anticancer therapy, whichever is 
earlier, must be reported by the investigator.  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). If the pregnancy 
continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Overall PI and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215-661-6229)
7.7.4
Reporting Events of Clinical Interest to Merck
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be reported within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215-661-6229).
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any participant must be 
reported within 2 working days to Merck Global Safety if it causes the participant to be excluded 
from the trial, or is the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the participant initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to Merck product, must be reported within 2 working days to Merck Global Safety.
Events of clinical interest for this trial include:
1. an overdose of Merck product, as defined in Section 7.7.2, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing,* whether or not related to Merck product
*Note:  These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. 
7.8
Reporting to the Food and Drug Administration (FDA)

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The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA.
7.9
Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant 
safety reports, sentinel events or unanticipated problems that require reporting per institutional 
policy. 
7.10
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions.
PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in Section 7.1.
8.1
Mirvetuximab Soravtansine (IMGN 853)
8.1.1
Description
Mirvetuximab soravtansine is an antibody-drug conjugate 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).
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. 
Figure 1: Mirvetuximab soravtansine

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      48
S
NH
O
S
O
O
OH
MeO
Cl
N
O
O
O
NH
O
O
MeO HO
N
O
O
S
Ab
3-4
PK studies demonstrated the stability of mirvetuximab soravtansine 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.  
8.1.2
Form
The investigational study drug, mirvetuximab soravtansine, 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 Type I glass vial with 20 mL deliverable volume. 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.
8.1.3
Storage and Stability
Mirvetuximab soravtansine should be stored upright in the carton supplied, protected from light, 
refrigerated at 2-8C (36 to 46°F) until the time of preparation and should not be shaken or 
frozen. 
Table 3 specifies the cumulative allowable time limits for specific temperature ranges and 
reporting requirements for IMGN853 while in storage. The total cumulative temperature 
excursion time for vials must be documented by the pharmacy in the applicable drug 
accountability logs. 
Table 1: IMGN853 Storage, Temperature Excursion Allowance, and Reporting 
Requirements
Temperature 
Range
Time Duration
Allowable?
Comments
< -5.4C
Any
No
Investigative sites to quarantine product 

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      49
and report excursion to sponsor-
investigator.
-5.4 to 1.4C
Up to 24 hours 
(1,440 minutes) 
cumulative
Yes
IMGN853 can be used 
Investigative sites to check cumulative 
time. If less than or equal to 24 hours 
(1,440 minutes) then no reporting 
required.
1.5 to 8.4C
Any
Yes
IMGN853 can be used.
8.5 to 25.4C
More than 6 
hours (360 
minutes) 
cumulative
Yes
IMGN853 can be used. 
Investigative sites to check cumulative 
time. If less than or equal to 6 hours 
(360 minutes) then no reporting 
required.
8.5 to 25.4C
More than 6 
hours (360 
minutes) 
cumulative
No
Investigative sites to quarantine product 
and report excursion and cumulative 
time to sponsor-investigator. 
*Use may be permitted upon review.
> 25.4C
Any
No
Investigative sites to quarantine product 
and report excursion to sponsor-
investigator.
Note: The temperature excursion allowances for onsite storage of IMGN853 do not apply during 
the shipment period. Any excursion outside of 2 to 8ºC (36 to 46 ºF) experienced during transit 
must be reported.
8.1.4
Compatibility
IMGN853 is NOT compatible with saline (0.9% sodium chloride). Therefore, dilutions must be 
made in 5% dextrose and 5% D-glucose. Other diluents have not been tested, and therefore, 
cannot be deemed compatible. 
Any combination of the materials used in the fluid contact pathways (e.g., infusion bag, syringe, 
needle, infusion set, closed system transfer device, filter, or catheter materials) listed below are 
acceptable for use:

Acetyltributylcitrate (ATBC)

Acrylonitrile-butadiene-styrene copolymer (ABS)

Diethylhydroxylamine (DEHA)

Diisononyl ester (DINCH)

Dioctyl terephthalate (DEHT or DOTP)

Ethylene Vinyl Acetate (EVA)

Fluorinated ethylene propylene (FEP) 

Polyacetal

Polycarbonate

Polyethersulfone (PES)

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
Polyethylene 

Polyisoprene 

Polyolefin (e.g., polymer of ethylene and/or propylene)

Polypropylene (PP)

Polytetrafluoroethylene (PTFE), Acrylic

Polytetrafluoroethylene (PTFE)

Polyurethane (PUR) 

Polyvinyl chloride (PVC) plasticized with Di-2-ethyl-hexylphthalate (DEHP)

Polyvinyl chloride (PVC) plasticized without Di-2-ethyl-hexylphthalate (non- DEHP)

Silicone

Stainless steel

Thermoplastic elastomer (TPE)

Trioctyl Trimellitate (TOTM or TETM)
Contact Sponsor-Investigator for materials not listed above.
8.1.5
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment. 
8.1.6
Availability 
Each site is responsible for requesting the investigational products from ImmunoGen.
8.1.7
Preparation
The total dose of IMGN853 will be based upon the adjusted ideal body weight (AIBW) using the 
following formula:
Adjusted Ideal Body Weight (AIBW)
IBW1 + 0.4 ( Actual weight – IBW1)
Where:
Ideal Body Weight (IBW)
IBW1 (male) = 0.9H1-88
IBW1 (female) = 0.9H1-92
(1H=height in cm; W=weight in kg)
The patient’s weight will be collected at each cycle. Dosing will be based off the wight at 
baseline prior to C1D1 unless current weight is > 10% different (not influenced by weight gain 

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or loss attributed to fluid retention). If required per institutional policy, it is acceptable to 
recalculate AIBW at each cycle using the patient’s current weight. Sites must clearly document 
the weight used to calculate dose at each cycle.
Prior to preparation, the lot expiry date should be verified via the Certificate of Analysis (CoA) 
or label. A visual inspection for cracks, leaks or any other damage should be done before use 
and any damage must be reported to the Sponsor-Investigator and ImmunoGen at 
IMGNdrugresupply@immunogen.com.
Infusion bags must be labeled with the protocol number, subject number (patient ID), storage 
temperature, dose, and volume of IMGN853 in the bag, or according to Institutional protocol.
If necessary, study drug from different drug lots may be mixed in a single-dose 
administration.

Remove the required number of vials from the refrigerator 25 minutes before preparation 
to allow IMGN853 solution for injection to reach ambient temperature (18 to 25°C) 

Keep IMGN853 vials protected from direct light

Gently invert vials (without shaking) 8 to 10 times before withdrawing the drug 

Withdraw the required volume aseptically using an appropriate syringe and needle or 
CSTD (closed system transfer device)

Choose a suitable infusion bag based on final volume for infusion. 

Dilute the drug with 5% dextrose or 5% D-glucose to a final concentration of 1 mg/mL to 
2 mg/mL
o
Important: IMGN853 is NOT compatible with saline (0.9% sodium chloride). 
Therefore, dilutions must be made in 5% dextrose or 5% D-glucose.

IMGN853 does not contain a preservative. Prepared study drug:
o
May be stored at room temperature but infusion must be completed within 8 hours 
after preparation
o
May be stored at 2 to 8ᴼC for up to 24 hours, and once removed from the fridge it 
may be stored at room temperature, but the infusion must be completed within 8 
hours

If the prepared study drug is stored at 2 to 8 °C, it should be removed from the 
refrigerator at least 30 to 60 minutes prior to administration, to allow the solution to reach 
room temperature. Allow the prepared study drug to reach room temperature without 
warming methods.

The total time at room temperature may not exceed 8 hours, inclusive of infusion time.
Light protection is not required for prepared IMGN853. Ensure that in-line filter of 0.2 or 
0.22 µm is used to filter diluted IMGN853 from the bag during administration
8.1.8
Administration
During combination treatment, mirvetuximab soravtansine should be administered first, followed 
by pembrolizumab. 

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
IMGN853 should be administered IV, using an IV tubing administration set with a 0.2 
µm or 0.22 µm in-line filter.

The infusion tubing may be primed with 5% dextrose (or 5% D-glucose) or may be 
primed with IMGN853, ensuring that no drug is wasted in the process.

Following the infusion, the IV line should be flushed with 5% dextrose, or 5% D-glucose 
as required to ensure delivery of the full dose. 
Infusion Rate: Initially IMGN853 should be administered at a rate of 1 mg/min; after a 
continuous 30 minutes of infusion, the rate can be increased to 3 mg/min if well tolerated. If well 
tolerated after a continuous 30 minutes of infusion at 3 mg/min the rate may be increased to 5 
mg/min. Subsequent infusions may be delivered at the highest tolerated rate. 
Duration of infusion: The overall length of infusion will vary depending on dose and patient 
tolerability. Patients will remain in the clinic under observation for 2 hours after the first 
infusion, and for at least 1 hour after each subsequent infusion of MIRV, during which 
pembrolizumab infusion can be administered. While in the treatment area, patients are closely 
monitored for AEs.
Details of the dose level and total dose administered should be documented in the source records 
as noted below:

Start and stop times for each administration (end of infusion should be the time of 
completion of the post-dose 5% dextrose or 5% D-glucose flush)

Infusion rate(s)

Total calculated dose (in mg)

Total calculated volume (in mL)

Total volume administered (in mL)

Times for any interruptions

Reason if any administration is stopped prematurely or interrupted and volume 
administered prior to interruption.
8.1.9
Ordering
Investigative sites will order their own supply of mirvetuximab soravtansine.
8.1.10 Accountability 
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.)
8.1.11 Destruction and Return

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Expired investigational product will be destroyed at the site per institutional policy.  Upon 
completion or termination of the study, all unused and/or partially used investigational product 
will be destroyed at the site per institutional policy. 
8.2
Pembrolizumab
8.2.1
Description
Pembrolizumab is a highly selective humanized mAb designed to block the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2.  Pembrolizumab is an IgG4/kappa isotype with a 
stabilizing sequence alteration in the Fc region.  The theoretical molecular weights of the heavy 
and light chains derived from the amino acid sequences, excluding glycosylation, are 49.4 
kiloDaltons (KDa) and 23.7 KDa, respectively.  The antibody is heterogeneously glycosylated at 
asparagine 297 within theFc domain of each heavy chain, yielding a molecular weight of 
approximately 149 KDa for intact pembrolizumab.
8.2.2
Form
Pembrolizumab Solution for Infusion is a sterile, non-pyrogenic clear to slightly opalescent, 
colorless to slightly yellow aqueous solution supplied in single-use Type I glass vial containing 
100 mg/ 4 mL of pembrolizumab. The drug product is manufactured using facilities and 
practices under Good Manufacturing Practice (GMP) requirements. 
Pembrolizumab Solution for Infusion 100 mg/ 4 mL vial is a liquid DP (manufactured using the 
fully formulated DS with L-histidine as a buffering agent, polysorbate 80 as a surfactant, and 
sucrose as a stabilizer/tonicity modifier, and Water for Injection as Solvent). Pembrolizumab 
Solution for Infusion vials are filled to a target of 4.25mL (106.25mg) to ensure recovery of 
4.0mL (100mg). At the point of use, Pembrolizumab Solution for Infusion is diluted with 0.9% 
Sodium Chloride Injection, USP (normal saline) or regional equivalent or 5% Dextrose Injection, 
USP (5% dextrose) or regional equivalent to 1-10 mg/mL before intravenous (IV) administration 
through an infusion filter.
8.2.3
Storage and Stability
Pembrolizumab Solution for Infusion 100 mg/ 4 mL vial should be stored under refrigerated 
conditions 2°C to 8°C (36-46 °F). Vials should be stored in the original box to ensure the drug 
product is protected from light. Do not shake and do not freeze.
Store the diluted solution from KEYTRUDA 100 mg/vial either

At room temperature for no more than 6 hours from the time of dilution. This includes 
room temperature storage of the diluted solution, and the duration of infusion.

Under refrigeration at 2°C to 8°C (36-46 °F) for no more than 96 hours from the time of 
dilution. If refrigerated, allow the diluted solution to come to room temperature prior to 
administration. Do not shake.

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Discard after 6 hours at room temperature or after 96 hours under refrigeration.
Do not freeze.
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label. Receipt and dispensing of trial medication must be recorded by an 
authorized person at the trial site. Clinical supplies may not be used for any other purpose other 
than that stated in the protocol.
8.2.4
Compatibility
Pembrolizumab should be prepared in 0.9% Sodium Chloride Injection, USP (normal saline) or 
regional equivalent or 5% Dextrose Injection, USP (5% dextrose) or regional equivalent. The 
final concentration of pembrolizumab in the infusion solutions should be between 1 mg/mL and 
10 mg/mL. Pembrolizumab SHOULD NOT BE MIXED WITH OTHER DILUENTS. 
See section 8.2.7 for infusion bag material compatibility.
8.2.5
Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.
8.2.6
Availability 
 Each site is responsible for requesting the investigational products from Merck. 
8.2.7
Preparation
Aseptic technique must be strictly observed throughout the preparation procedure. Use of a 
biosafety cabinet is preferred since no anti-microbial preservative is present in the product; 
however, it is not mandatory unless specified by site standard operating procedure.
The preferred method of dose preparation is the volumetric method. The Sponsor recommends 
reconstitution and administration of pembrolizumab that follows the parameters in the Pharmacy 
Manual, however if use of gravimetric preparation is mandatory due to local site procedures, the 
following requirements must be satisfied and documented:

Draw the required volume up to 4.0 mL (100 mg) of pembrolizumab from each vial

Limit the number of punctures of each vial to one

For gravimetric preparation method using density of pembrolizumab solution, a value of 
1.03 g/mL should be used 
Use of spikes or other CSTDs (closed system transfer devices) are permitted as long as the 
pharmacist is aware of the hold-up volume (volume of fluid that is left in the device) and that the 
contact time is ≤ 30 min. HQ approval is only needed for spikes/ CSTDs with contact time 

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greater than 30 min to ensure compatibility of the device. Please note that as long as the CSTD 
or spike does not come into contact with the drug product during infusion, then 30 mins does not 
count in infusion time.
Sites may choose to select an infusion bag size based on their institutional practice provided the 
following conditions are met:

Concentration of pembrolizumab is between 1 mg/mL and 10 mg/mL

The infusion volume to bag capacity ratio should not be less than 0.3. In other words, the 
bag must be filled to at least 30% capacity.
A suitable infusion bag material must be chosen. The bag may be empty, or it may contain 
normal saline. The following infusion bag materials are compatible with pembrolizumab:

PVC plasticized with DEHP

PVC, DEHP free
o
Since it is still a PVC set, DEHP must be replaced with another plasticizer. If the 
alternate plasticizer is DEHT or TOTM then it is ok. 

Non-PVC (polyolefin)

Ethylene-vinyl acetate (EVA)

Polyethylene (PE) lined polyolefin

Polypropylene (PP) 

Low density poly ethylene (LDPE)

Clear Polyurethane (PVC Free, DEHP Free)

Acrylic

Polymethylmethacrylate,

Silicone rubber with Fluorosilicone

Polyethylene terephthalate (PET)

Stainless steel

Polybutadiene

Polycarbonate (PC)

Isoprene rubber

Polyvinyl chloride

Polyethersulfone (membrane pore size 0.2μm) non-PVC multilayer co-extrusion infusion 
bag: three layers co-extrusion infusion bag; polypropylene/ polypropylene/ polypropylene

Acrylonitrile butadiene styrene (ABS)

Polytetrafluoroethylene

Dioctyl terephthalate (DOTP)
*Contact Sponsor-Investigator for materials not listed above
To prepare the pembrolizumab infusion bag:
1. Calculate the volume of pembrolizumab and normal saline required to prepare the 
infusion (admixture) bag. The dose of pembrolizumab used in this trial is 200mg.

Volume of pembrolizumab (mL) = required dose amount (mg) / 25 (mg/mL)

Volume of normal saline = total infusion volume – volume of pembrolizumab from 

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above

If a bag pre-filled with normal saline is being used, remove the excess volume of 
normal saline using a sterile syringe (Polypropylene, latex-free) attached to a suitable 
needle. Keep in consideration the excess bag fill volume as well as the volume of 
pembrolizumab to be added to the bag to prepare the infusion solution. This helps 
ensure that the concentration in the bag can be accurately calculated and falls within 
the acceptable range of 1 mg/mL to 10 mg/ml. If the site would like to proceed 
without removing excess saline they must ensure that the concentration of 
pembrolizumab would still fall within acceptable range.

If an empty bag is being used, withdraw the necessary volume of normal saline from 
another appropriate bag and inject into the empty bag. Keep in consideration the 
volume of pembrolizumab to be added to the bag to prepare the infusion solution.
2. Withdraw the required volume of pembrolizumab from the vial(s) (up to 4 mL from each 
vial) using a sterile syringe attached to a suitable needle. The vial(s) may need to be 
inverted to remove solution.

Volume of pembrolizumab (mL) = required dose amount (mg) / 25 (mg/mL)

Note: If it is necessary to use several vials, it is advisable to withdraw from several vials 
into a suitable size single use syringe using a new needle for each vial.

Discard any unused portion left in the vial as the product contains no preservative.
3. Add the required pembrolizumab into the infusion IV bag containing normal saline and 
gently invert the bag 10-15 times to mix the solution.

From a microbiological point of view, diluted solution should be used as soon as possible 
after preparation

Pembrolizumab solutions may be stored at room temperature for a cumulative time of up 
to 6 hours. This includes room temperature storage of admixture solutions in the IV bags 
and the duration of infusion. 

IV bags may be stored under refrigeration at 2 °C to 8 °C (36 °F to 46 °F), total 
cumulative storage time at room temperature and refrigeration should not exceed 24 
hours. (96 hours is acceptable dependent upon country approved commercial 
Keytruda label).    
If the infusion bag is excessively handled or shaken, particulates may form. If this occurs, 
discard the bag and create a new bag taking care not to shake. Please contact your HQ clinical 
study team if particulates are noticed for further instructions. Be prepared to provide the 
following information:

IV bag manufacture, lot and expiry 

Target volume of admixture solution in the IV bag (e.g. 100 mL, 200 mL etc.) 

Amount of drug product (mL or mg) added to the bag 

Drug product lot 

Brief description of the nature of visible particles (color, shape, size, numbers etc.).
To prevent the formation of particulates:

Minimize agitation

Ensure dilution of admixture solution is 1mg/mL to 10 mg/mL

Minimization of headspace (empty space over the liquid) in syringes and admixture bags

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
Avoid siliconized products during preparation (Please note there is particulate formation 
when there is over agitation of the product and when concentrations are less than 1 
mg/mL)
If particles are seen in the vials, these will need to be reported as clinical supply complaints per 
GCD 104. If particles are seen in the admixture solution, these need to be reported to the HQ 
clinical study team for further consultation with the pharmacy manual owner. 
8.2.8
Administration
See Section 5.3.2. During combination treatment, mirvetuximab soravtansine should be 
administered first, followed by pembrolizumab. Details of the dose level and total dose 
administered should be documented in the source records
Pembrolizumab administration will be monitored to ensure compliance and proper 
documentation of the infusion procedure as well as management of infusion reactions should 
they occur.
8.2.9
Ordering
 Investigative sites will order their own supply of pembrolizumab.
8.2.10 Accountability 
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.)
8.2.11 Destruction and Return 
Expired investigational product will be destroyed at the site per institutional policy. Upon 
completion or termination of the study, all unused and/or partially used investigational product 
will be destroyed at the site per institutional policy.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
9.1
Biomarker Studies
9.1.1
FRα Expression - Integral Biomarker
All patients must submit archived or new biopsy tumor tissue, or formalin-fixed, paraffin 
embedded (FFPE) block of sufficient size to allow for sectioning of ten 5-micron tissue sections 
or five unstained slides for central analysis of FRα expression prior to enrollment.  

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The tumor samples will be analyzed centrally for FRα expression by Immunohistochemistry 
(IHC) in the Companion Diagnostics Pharma Services CAP-accredited and CLIA-certified 
laboratory and Pathology Services at Ventana Medical Systems, Inc. 
Only patients with confirmation of FRα positivity by the Ventana FOLR2.1 IHC assay (Ventana 
Medical Systems. Tucson, AZ) will be eligible to enroll in the study.  
Samples will be shipped Monday – Thursday to (address below):
CDx CAP/CLIA Laboratory
Ventana Medical Systems, Inc.
Attn: CDx CAP/CLIA Laboratory
1910 E. Innovation Park Drive
Tucson, AZ 85755
9.1.2
Microsatellite Stability – Integral Biomarker
Prior to enrollment, patients must have documented MSS by routine methods including MMR 
IHC, MSI PCR or MSI by Next Generation Sequencing (NGS). Only patients with intact 
expression of all four MMR proteins by IHC, or MSS by PCR or NGS from a CLIA-certified 
laboratory will be eligible to enroll. 
9.2
Laboratory Correlative Studies (FFPE Tumor Tissue)
Correlative studies may be performed in the Immune Oncology and DNA Repair Centers here at 
DFCI or Ventana Medical Systems. Depending on funding availability these studies may include: 
i) determination of CD3+, CD8+ TILs, CD8+/CD4+FOXP3+ TIL ratio, CD137+CD8+ TILs, 
CD137+CD8+/CD4+FOXP3+ TIL ratio, peritumoral lymphocytes and correlation with response; 
ii) expression of immune checkpoints including TIM-3, LAG-3, CTLA-4, PD-L2, PD-L1, PD-1, 
IDO and correlation with response; iii) targeted next generation sequencing (OncoPanel) to 
determine specific genetic alterations and correlate with response.  Where OncoPanel sequencing 
has already been performed on patient samples clinically or through DF/HCC protocols 11-104, 
17-000, and 20-000, we may plan to access these results.  Additionally, we will characterize the 
FOLR1 expression in uterine serous cancers and overlap with other potential targets of interest, 
which may include but is not limited to HER2 and Trop2.
If archival tumor tissue in the form of unstained slides are used for central analysis of FRα 
expression prior to enrollment, the remaining five unstained slides should be shipped to the DFCI 
coordinating center along with the manifest form provided to each site.  Please send the samples 
to:
Sandy Elias
Dana-Farber Cancer Institute
450 Brookline Ave, DA-122
Boston, MA 02215
Email contact: Sandy_Elias@dfci.harvard.edu; Martin_Hayes@dfci.harvard.edu 

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STUDY CALENDAR
Baseline screening evaluations are to be conducted within 14 days prior to start of protocol 
therapy.  Scans and x-rays  must be done <4 weeks prior to the start of therapy.  In the event that 
the participant’s condition is deteriorating, laboratory evaluations should be repeated within 48 
hours prior to initiation of the next cycle of therapy.
Assessments must be performed prior to administration of any study agent. Study assessments 
and agents should be administered within + 3 days of the protocol-specified date, unless 
otherwise noted.
Cycle 1
Cycle 2 and beyond
Pre-Study
Day 1
Day 8
Day 15
Day 1 
Off-treatment visite
Mirvetuximab Soravtansine
X
X
Pembrolizumab
X
X
Archival FFPE sample
X
Collection of MSS 
documentation
X
Demographics
X
Medical history
X
Concurrent medications
X
X---------------------------------------------------------------------------------------------------------------X
Physical exam
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
Pulse Oximetry
X
X
X
X
X
ECOG Performance status
X
X
X
X
X
CBC w/diff, plts
X
X
X
X
X
X
Serum chemistrya
X
X
X
X
X
X
TSH
X
X
X
X
PT/INR/PTT
X
X
EKG (as indicated)
X
X
Pulmonary Function Testsc
X
Ophthalmic examinationsd
X
Every other cycle (from time toxicity first reported, until resolved to baseline or ≤Grade 1)
Schirmer Testd
X
For patients who experience treatment-emergent eye disorders, 
the Schirmer Test will be repeated at the first on-study 
ophthalmic examination and at subsequently if clinically 
indicated
Ocular Symptom 
Assessmentd
X
X
X
X
Adverse event evaluation
X---------------------------------------------------------------------------------------------------------------X
Tumor measurements
X
Tumor measurements are repeated every 2 cycles (6 weeks, ± 1 
week).  Documentation (radiologic) must be provided for 

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participants removed from study for progressive disease.
B-HCG
Xb
Lubricating artificial tears 
administration
Daily as directedf
Xg
Corticosteroid eye drop 
administration
Six times daily on Days 1-4 and four times daily on Days 5-8 of 
each cyclef
Xg
a.
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium.
b.
Serum pregnancy test (women of childbearing potential) should be done within 3 days of the first dose of study 
treatment.
c.
Pulmonary function tests (PFTs) should include spirometry, diffusion capacity, and lung volumes. PFTs will be 
performed at screening and in the event of pulmonary symptoms as clinically indicated
d.
Baseline ophthalmic exams will be performed by a board-certified ophthalmologist and will include the 
following: visual acuity, indirect fundoscopy, slit lamp examination under dilatation, intraocular pressure 
measurement, and corneal photography. A Schirmer test will be performed at baseline for all patients, and for 
patients who experience ocular symptoms, it will be repeated at the first on-study ophthalmic examination and at 
subsequently if clinically indicated. May be performed within 14 days of Cycle 1, Day 1. Ocular symptom 
assessment will be performed prior to the start of each cycle by the treating physician or other qualified 
individual. If the subject reports ocular symptoms then IMGN853 will be stopped and the subject will then be 
referred to an ophthalmologist for a complete examination (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 who experience ocular toxicity will be followed until 
resolution.
e.
Off-treatment evaluation. Off-treatment visit will occur within 7 days of the decision to discontinue study 
treatment. Participants will be followed for 30 days after the last dose of study drug for adverse events. 
Participants will be followed for 3 years by phone after removal from study or until death, whichever occurs 
first. Survival status should be checked every 6 months during that time
f.
See Appendix D. The patient should continue use of the corticosteroid eye drops per the ophthalmologist 
recommendation after discontinuation of mirvetuximab soravtansine. The patient should continue the lubricating 
eye drops for 4 weeks following discontinuation of mirvetuximab soravtansine. 

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MEASUREMENT OF EFFECT
Measurement of effect will be assessed by both the Response Evaluation Criteria in Solid 
Tumors (RECIST) Version 1.1 and by the Immune-related Response Criteria Derived from 
RECIST 1.1 (irRECIST).
11.1
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Guidelines
11.1.1 Categorizing Lesions at Baseline
Measurable Lesions

Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10mm or greater 
when assessed by CT or MRI (slice thickness 5-8mm).

Lesions with longest diameter at least 20mm when assessed by Chest X-ray.

Superficial lesions with longest diameter 10mm or greater when assessed by caliper.

Malignant lymph nodes with the short axis 15mm or greater when assessed by CT.
Note: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for 
all other measurable lesions.
Note: Tumor lesions that are situated in a previously irradiated area will be considered 
measurable if there has been progression of disease at that site since radiation occurred.
Normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should not 
be recorded either as target or non-target disease. Cystic lesions thought to represent 
cystic metastases can be measurable lesions, if they meet the specific definition above.

If non-cystic lesions are also present, these are preferred as target lesions.

Normal nodes: Nodes with short axis <10mm are considered normal and should not be 
recorded or followed either as measurable or non-measurable disease.
11.1.2 Recording Tumor Assessments
All sites of disease must be assessed at baseline. Baseline assessments should be done as close as 
possible prior to study start. For an adequate baseline assessment, all required scans must be 
done within 28 days prior to treatment and all disease must be documented appropriately. If 
baseline assessment is inadequate, subsequent statuses generally should be indeterminate.
Target lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, representative 
of all involved organs, should be identified as target lesions at baseline. Target lesions should be 
selected on the basis of size (longest lesions) and suitability for accurate repeated measurements. 

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Record the longest diameter for each lesion, except in the case of pathological lymph nodes for 
which the short axis should be recorded. The sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions at baseline will be the basis for 
comparison to assessments performed on study. If two target lesions coalesce, the measurement 
of the coalesced mass is used. If a large target lesion splits, the sum of the parts is used. 
Measurements for target lesions that become small should continue to be recorded. If a target 
lesion becomes too small to measure, 0mm should be recorded if the lesion is considered to have 
disappeared; otherwise a default value of 5mm should be recorded.
Note: When nodal lesions decrease to <10mm (normal), the actual measurement should still be 
recorded.
Non-target disease
All non-measurable disease is non-target. All measurable lesions not identified as target lesions 
are also included as non-target disease. Measurements are not required but rather assessments 
will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT INCREASED, 
INCREASED. Multiple non-target lesions in one organ may be recorded as a single item on the 
case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’).
11.1.3 Objective Response Status at Each Evaluation
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning. If a change needs to be made the case must be 
discussed with the radiologist to determine if substitution is possible. If not, subsequent objective 
statuses are indeterminate.
Target disease

Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease. All target nodes must decrease to normal size (short axis 
<10mm). All target lesions must be assessed.

Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum 
of diameters of all target measurable lesions. The short diameter is used in the sum for 
target nodes, while the longest diameter is used in the sum for all other target lesions. All 
target lesions must be assessed.

Stable: Does not qualify for CR, PR or Progression. All target lesions must be assessed. 
Stable can follow PR only in the rare case that the sum increases by less than 20% from 
the nadir, but enough that a previously documented 30% decrease no longer holds.

Objective Progression (PD): 20% increase in the sum of diameters of target measurable 
lesions above the smallest sum observed (over baseline if no decrease in the sum is 
observed during therapy), with a minimum absolute increase of 5mm.

Indeterminate. Progression has not been documented, and 
o
One or more target measurable lesions have not been assessed;
or

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o
Assessment methods used were inconsistent with those used at baseline;
or
o
One or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure);
or
o
One or more target lesions were excised or irradiated and have not reappeared or 
increased.
Non-target disease

CR: Disappearance of all non-target lesions and normalization of tumor marker levels. 
All lymph nodes must be ‘normal’ in size (<10mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level above 
the normal limits.

PD: Unequivocal progression of pre-existing lesions. Generally the overall tumor burden 
must increase sufficiently to merit discontinuation of therapy. In the presence of SD or

PR in target disease, progression due to unequivocal increase in non-target disease should 
be rare.

Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at baseline.
New Lesions
The appearance of any new unequivocal malignant lesion indicates PD. If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology. If 
repeat assessments confirm the lesion, then progression should be recorded on the date of the 
initial assessment. A lesion identified in an area not previously scanned will be considered a new 
lesion. Supplemental Investigations If CR determination depends on a residual lesion that 
decreased in size but did not disappear completely, it is recommended the residual lesion be 
investigated with biopsy or fine needle aspirate. If no disease is identified, objective status is CR. 
If progression determination depends on a lesion with an increase possibly due to necrosis, the 
lesion may be investigated with biopsy or fine needle aspirate to clarify status.
Objective/Subjective
Patients requiring discontinuation of treatment without objective evidence of disease progression 
should not be reported as PD on tumor assessment CRFs. This should be indicated on the end of 
treatment CRF as off treatment due to Global Deterioration of Health Status. Every effort should 
be made to document objective progression even after discontinuation of treatment.
For Participants with Measurable Disease (i.e., Target Disease)
Table 10: Best Overall Response for Measurable Disease (Target Disease) 
Target 
Non-Target 
New 
Overall 
Best Overall Response when 

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Lesions
Lesions
Lesions
Response
Confirmation is Required*
CR
CR
No
CR
>4 wks Confirmation**
CR
Non-CR/Non-
PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
>4 wks Confirmation**
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks from baseline**
PD
Any
Yes or No
PD
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR

See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**        Only for non-randomized trials with response as primary endpoint.
***      In exceptional circumstances, unequivocal progression in non-target lesions may be
            accepted as disease progression.
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment.
Determination of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest sum on 
study). For CR and PR, the patient’s best response assignment will depend on the achievement of 
both measurement and confirmation criteria. CR and PR must be confirmed by 2 measurements 
at least 4 weeks apart. In the case of SD, follow up measurements must have met the SD criteria 
at least once after study entry at a minimum interval of 6 weeks.
11.2
Immune-related Response Criteria Derived from RECIST 1.1 (irRECIST)
Increasing clinical experience indicates that traditional response criteria may not be sufficient to 
fully characterize activity in this new era of targeted therapies and/or biologics. 
This is particularly true for immunotherapeutic agents such as anti-CTLA-4 and anti-PD-1 / anti 
PD-L1 which exert the antitumor activity by augmenting activation and proliferation of T-cells, 
thus leading to tumor infiltration by T-cells and tumor regression rather than direct cytotoxic 
effects [31, 32]. Clinical observations of patients with advanced melanoma treated with 
ipilimumab, for example, suggested that conventional response assessment criteria such as 
Response Evaluation Criteria in Solid Tumors (RECIST) and WHO criteria are not sufficient to 
fully characterize patterns of tumor response to immunotherapy because tumors treated with 

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immunotherapeutic agentsmay show additional response patterns that are not described in these 
conventional criteria [33, 34]. 
Furthermore, the conventional tumor assessment criteria (RECIST and WHO criteria) have been 
reported as not capturing the existence of a subset of patients who have an OS similar to those 
who have experienced CR or PR but were flagged as PD by WHO criteria [34, 35].
On these grounds, a tumor assessment system has been developed that incorporates these delayed 
or flare-type responses into the RECIST 1.1 criteria (irRECIST) [33].
For irRECIST, only target and measurable lesions are taken into account. In contrast to the
RECIST 1.1, the irRECIST criteria:

require confirmation of both progression and response by imaging at least 4 weeks from 
the date first documented, and

do not necessarily score the appearance of new lesions as progressive disease if the sum 
of lesion diameters of target lesions (minimum of 10 mm per lesion, maximum of 5 target 
lesions, maximum of 2 per organ) and measurable new lesions does not increase by >= 
20%.
The same method of assessment and the same technique should be used to characterize each 
identified and reported target lesion(s) at baseline and throughout the trial.
irRECIST criteria are defined as follows:

Overall immune-related complete response (irCR): Complete disappearance of all lesions 
(whether measurable or not) and no new lesions. All measurable lymph nodes also must 
have a reduction in short axis to <10 mm.

Overall immune-related partial response (irPR): Sum of the diameters (longest for 
nonnodal lesions, shortest for nodal lesions) of target and new measurable lesions 
decreases >= 30%.

Overall immune-related stable disease (irSD): Sum of the diameters (longest for 
nonnodal lesions, shortest for nodal lesions) of target and new measurable lesions neither 
irCR, irPR, (compared to baseline) or immune-related progressive disease (irPD, 
compared to nadir).

Overall immune-related progressive disease (irPD): Sum of the diameters (longest for 
non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions 
increases >= 20% (compared to nadir), confirmed by a repeat, consecutive observation at 
least 4weeks from the date first documented.
New measurable lesions: Incorporated into tumor burden (ie, added to the target lesion 
measurements). A lymph node has to be >= 15 mm in short axis to be a measurable new lesion 
and its short axis measurement is included in the sum. Up to 2 new lesions per organ and up to 5 
new lesions in total can be added to the measurements.
New non-measurable lesions: Do not define progression but preclude irCR.

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Overall responses derived from changes in index, non-index, and new lesions are outlines in the 
table.
Table 11: Overall Response for irRECIST Derived from Changes in Index, Non-index and 
New Lesions
Measurable Response
Non-measurable response
Overall Response 
using irRECISTb
Index and New 
Measurable Lesions 
(Tumor Burden)a
Non-Index Lesions
New non-
measurable lesions
Decrease 100%
Absent
Absent
irCR
Decrease 100%
Stable
Any
irPR
Decrease 100%
Unequivocal progression
Any
irPR
Decrease ≥ 30%
Absent / stable
Any
irPR
Decrease ≥ 30%
Unequivocal progression
Any
irPR
Decrease < 30% and 
increase <20%
Absent/ stable
Any
irSD
Decrease < 30% and 
increase <20%
Unequivocal progression
Any
irSD
Increase ≥ 20%
Any 
Any
irPD
a. Decrease assessed relative to baseline. Increase assessed relative to nadir.
b. Response (irCR and irPR) and progression (irPD) must be confirmed by a second, consecutive
assessment at least 4 weeks apart.
11.3
Methods for Evaluation of Disease
All measurements should be taken and recorded in metric notation using a ruler, calipers, or a 
digital measurement tool.  All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 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. 
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung; however, CT is preferable. 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT thickness is 5mm or less. If CT scans have slice thickness greater than 

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5 mm, the minimum size of a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible.
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible “new” disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.
(b) No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD.
(c) FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity.
Note:  A “positive” FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.
PET-CT. At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.  

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Tumor markers. Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a participant to be considered in complete 
clinical response.
DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements).
12.1
Data Reporting
12.1.1 Method
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the data 
for this study.
12.1.2 Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data 
forms to the Office of Data Quality (ODQ) in accordance with DF/HCC policies.
12.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of medical oncologists, research 
nurses, pharmacists and biostatisticians with direct experience in cancer clinical research.  
Information that raises any questions about participant safety will be addressed with the Overall 
PI and study team.
The DSMC will review each protocol up to four times a year with the frequency determined by 
the outcome of previous reviews. Information to be provided to the committee may include: up-
to-date participant accrual; current dose level information; DLT information; all grade 2 or 
higher unexpected adverse events that have been reported; summary of all deaths occurring 
within 30 days of intervention for Phase I or II protocols; for gene therapy protocols, summary of 
all deaths while being treated and during active follow-up; any response information; audit 
results, and a summary provided by the study team. Other information (e.g. scans, laboratory 
values) will be provided upon request. 
12.2
Multi-Center Guidelines
This protocol will adhere to DF/HCC Policy MULTI-100 and the requirements of the DF/HCC 
Multi-Center Data and Safety Monitoring Plan. The specific responsibilities of the Sponsor-
Investigator, Coordinating Center, and Participating Institutions and the procedures for auditing 
are presented in Appendix B.

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STATISTICAL CONSIDERATIONS
This is an open label, two-stage, non-randomized phase 2 trial examining mirvetuximab 
soravtansine (IMGN853) and pembrolizumab in participants with advanced or recurrent serous 
endometrial cancer (EC). The combination will be tested in patients with microsatellite stable 
(MSS) and FRα positive tumors. 
Enrollment will follow a standard Simon two-stage optimal design for a single cohort to inform 
whether the combination has significant clinical activity worthy of further evaluation. Statistical 
considerations are developed for a co-primary objectives to evaluate the objective response rate 
(ORR) and rate of progression-free survival at 6 months (PFS6), with a two-stage design that 
allows for early stopping for futility. 
Target enrollment is a maximum of 35 patients. Up to 19 patients of the total cohort may have 
received prior therapy targeting the PD-1/PD-L1 pathway.  
13.1
Study Design/Endpoints
Primary Endpoints
To assess the activity of mirvetuximab soravtasine in combination with pembrolizumab in 
patients with recurrent or persistent MSS and FRα positive endometrial cancer by evaluating the 
frequency of patients who survive progression-free for at least 6 months (PFS6) after initiating 
therapy or have objective tumor response.
Statistical considerations are developed for co-primary objectives to evaluate the objective 
response rate (ORR) by RECIST 1.1 and rate of progression-free survival at 6 months (PFS6), 
with a two-stage design that allows for early stopping for futility.
A two-stage test was constructed using the method of Sill, Rubinstein, Litwin and Yothers [36] 
with the goal of stopping early for futility to limit patient exposure to an inactive agent while 
restricting the probabilities of type I and type II errors to approximately 10% and 15%, 
respectively. For the co-primary endpoints, a true ORR of 5% or less and a rate of progression-
free survival at 6 months of (PFS6) 10% or less would not be of clinical interest (H0: πOR ≤ 5% 
AND π PFS6 ≤ 10%), whereas an improvement to a 20% objective response rate or 30% PFS6 rate 
would warrant further investigation of the study treatment. In the first stage, 16 patients will be 
enrolled and accrual will pause. If there are at least two objective responses or two patients 
progression-free at 6 months among the first 16 patients, the second stage of accrual will 
commence where an additional 19 patients will be enrolled. If at the end of the trial there are at 
least 4 treated patients with an objective response or 8 patients progression-free at 6 months, the 
study treatment will be considered worthy of further study. Specifically, analysis of historical 
data (GOG129 and GOG229 series) based on similar population of patients with endometrial 
cancer where the levels of activity were believed to be inactive to modestly active shows that an 
unacceptable rate for objective response (πOR) is 5% and for PFS6 (π PFS6) is 10%, respectively. 
A bivariate test of the co-primary endpoints is constructed as follows:
H0: πOR ≤ 5% AND πPFS6 ≤ 10%

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vs.
H1: πOR > 5% OR π PFS6 > 10%
Targeted alternative hypothesis: An absolute improvement in the rate of OR by 15% or PFS6 by 
20% would be of clinical interest. Power is determined under two specific hypotheses (Hr: πOR =
20%, π PFS6 = 10%) and (Hs: πOR = 5%, π PFS6 = 30%) where sufficient activity is seen in only 
each endpoint, respectively. Sample size is selected to have sufficient power to reject the null 
under cases that assume either (a) independence or (b) dependence among the co-primary 
endpoints. The decision rules and operating characteristics of the two-stage design are 
summarized in the Table below:
Table 12: Decision rules and operating characteristics of the two-stage design
Endpoint
Objective 
Response
PFS6
Null hypothesis
5%
10%
Alternative Hypothesis
20%
30%
Number of Patients
16
Minimum number of 
events to continue to 
Stage 2
2
2
PET (Independence)
0.417
Stage 1
PET (Dependence)
0.502
Number of Patients
35
Minimum number of 
events to reject the null 
hypothesis
4
8
Alpha (Independence)
0.098
Alpha (Dependence)
0.88
Power (Independence)
0.889
0.873
Stage 2
Power (Dependence)
0.846
0.862
13.2
Sample Size, Accrual Rate and Study Duration
Table 13: Accrual Target Demographics
Accrual Targets
Sex/Gender
Ethnic Category
Females
Males
Total
Hispanic or Latino
5
+
0
=
5
Not Hispanic or Latino
30
+
0
=
35
Ethnic Category: Total of all subjects
35
+
0
=
35
Racial Category
American Indian or Alaskan Native
0
+
0
=
0
Asian
5
+
0
=
5

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Black or African American
3
+
0
=
3
Native Hawaiian or other Pacific 
Islander
0
+
0
=
0
White
27
+
0
=
27
Racial Category: Total of all subjects
35
+
0
=
35
35
0
35
13.3
Stratification Factors
N/A
13.4
Interim Monitoring Plan
See Section 13.1
13.5
Analysis of Primary Endpoints
See Section 13.1
13.6
Analysis of Secondary Endpoints
The distributions of progression-free- and overall survival times will be estimated by using 
Kaplan-Meier analysis. Immune-related objective response rate will be estimated as described in 
Section 11.2. Immune-related progression-free survival (irPFS) rate is defined as time from 
treatment initiation to death or to immune-related progression of disease (irPD) as defined in 
Section 11.2. Duration of response (DoR) is defined as time from best overall response to the 
time of disease progression, where best overall response and disease progression are as defined 
in Section 11.1.
Exploratory endpoints are not specifically planned but could include biomarker expression and 
immune population analysis, and descriptive statistics including the mean, standard deviation, 
median, minimum, and maximum values, for the cohort. For baseline categorical data, the 
number and percentage of patients in each category will be collected. Appropriate statistical 
methods may be used to investigate any possible relationship of biomarker levels with response 
to baseline characteristics and response to study treatment. 
An additional exploratory endpoint includes a comparison of the assessment of activity of 
mirvetuximab soravtansine in combination with pembrolizumab as described in Section 13.1 
between patients with and without prior exposure to IO therapy targeting the PD-1/PD-L1 
pathway.  If at least 6 of the 19 patients meet the endpoint of either OR and/or PFS6 (i.e. exhibit 
clinical benefit), this would generate a 95% binomial coefficient of 12.6% - 56.5%, which would 
exclude the possibility that clinical benefit with this regimen is <10% in the IO-exposed patients.
13.7
Reporting and Exclusions

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13.7.1 Evaluation of Toxicity
All participants will be evaluable for toxicity from the time of their first treatment.
13.7.2 Evaluation of the Primary Efficacy Endpoint
All participants included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible. Each participant should be 
assigned one of the following categories: 1) complete response, 2) partial response, 3) stable 
disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from 
toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient data). 
By arbitrary convention, category 9 usually designates the “unknown” status of any type of data 
in a clinical database. 
All participants who have measurable disease present at baseline, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
response. Participants in response categories 5-9 will not be considered evaluable but will remain 
within the intention to treat analysis.
Patients who develop brain metastasis on study, but continue on study after definitive treatment 
of their cranial disease, will be considered to have had progressive disease at the point of the 
diagnosis of the initial brain metastasis. 
All conclusions should be based on all evaluable participants. Subanalyses may then be 
performed on the basis of a subset of participants, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early discontinuation of 
treatment, major protocol violations, etc.). However, these subanalyses may not serve as the 
basis for drawing conclusions concerning treatment efficacy, and the reasons for excluding 
participants from the analysis should be clearly reported. The 95% confidence intervals should 
also be provided.
PUBLICATION PLAN
Publication guidelines exist within the DF/HCC Gynecologic Oncology Program. The study 
principal investigator will be responsible for collection of data, interpretation of data, monitoring 
of toxicities, and publication of abstracts and final manuscripts. The principal investigator 
chooses the different authorship slots per the DF/HCC gynecologic oncology program 
guidelines.
The information obtained during the conduct of this clinical study is confidential, and disclosure 
to third parties other than those noted below is prohibited. All information concerning the 
product as well as any matter concerning the operation of the Sponsor, such as clinical 
indications for the drug, its formula, methods of manufacture and other scientific data relating to 
it, that have been provided by the Sponsor and are unpublished, are confidential and must remain 
the sole property of the Sponsor. The Investigator will agree to use the information only for the 

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purposes of carrying out this study and for no other purpose unless prior written permission from 
the Sponsor is obtained.
Information obtained during the conduct of this study will be used by ImmunoGen in connection 
with the development of the study drug. The study Investigator is obliged to provide 
ImmunoGen with complete test results and all data developed in this study. This information 
may be disclosed to other physicians who are conducting similar studies and to the FDA, as 
deemed necessary by the Sponsor. Patient-specific information may be provided to other 
appropriate medical personnel related to the care of that patient only with patient's prior consent. 
The Investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with 
ImmunoGen, provided ImmunoGen a copy of the draft document intended for publication, and 
obtained ImmunoGen’s written consent for such publication. All information obtained during the 
conduct of this study will be regarded as confidential. ImmunoGen will use the information for 
registration purposes and for the general development of the drug.
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study. 

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Thigpen, J.T., et al., Phase III trial of doxorubicin with or without cisplatin in advanced 
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Fleming, G.F., et al., Phase III randomized trial of doxorubicin + cisplatin versus 
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Fleming, G.F., et al., Phase III trial of doxorubicin plus cisplatin with or without 
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Bradford, L.S., et al., Advances in the management of recurrent endometrial cancer. Am 
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Fleming, G.F., Second-Line Therapy for Endometrial Cancer: The Need for Better 
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Aghajanian, C., et al., Phase II trial of bevacizumab in recurrent or persistent 
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Moore, K.N., et al., Safety and Activity of Mirvetuximab Soravtansine (IMGN853), a 
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Cancer Genome Atlas Research, N., et al., Integrated genomic characterization of 
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Howitt, B.E., et al., Association of Polymerase e-Mutated and Microsatellite-Instable 
Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, 
and Expression of PD-1 and PD-L1. JAMA Oncol, 2015. 1(9): p. 1319-23.
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Le, D.T., et al., PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J 
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Diaz, L.A., et al., Programmed death-1 blockade in mismatch repair deficient cancer 
independent of tumor histology, 2016, American Society of Clinical Oncology.
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Ott, P.A., et al., Safety and Antitumor Activity of Pembrolizumab in Advanced 
Programmed Death Ligand 1-Positive Endometrial Cancer: Results From the 
KEYNOTE-028 Study. J Clin Oncol, 2017. 35(22): p. 2535-2541.
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Senol, S., et al., Folate receptor alpha expression and significance in endometrioid 
endometrium carcinoma and endometrial hyperplasia. Int J Clin Exp Pathol, 2015. 8(5): 

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p. 5633-41.
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Brown Jones, M., et al., Rationale for folate receptor alpha targeted therapy in "high 
risk" endometrial carcinomas. Int J Cancer, 2008. 123(7): p. 1699-703.
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Martin, L., et al. Phase I expansion study of mirvetuximab soravtansine, a folate receptor 
alpha (FRalpha)-targeting antibody-drug conjugate (ADC), in patients with endometrial 
cancer. in European Society for Gynecologic Oncology. 2017.
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Muller, P., et al., Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly 
susceptible to CTLA-4/PD-1 blockade. Sci Transl Med, 2015. 7(315): p. 315ra188.
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Muller, P., et al., Microtubule-depolymerizing agents used in antibody-drug conjugates 
induce antitumor immunity by stimulation of dendritic cells. Cancer Immunol Res, 2014. 
2(8): p. 741-55.
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Skaletskaya, A., et al., Treatment of Tumor Cells with Mirvetuximab Soravtansine, a FR-
alpha-Targeting Antibody-Drug Conjugate (ADC), Activates Monocytes Through Fc-Fc 
gamma R Interaction and Immunogenic Cell Death, in Society for the Immunotherapy of 
Cancer2016.
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O'Malley, D.M., et al. Safety findings from FORWARD II: A phase 1b study evaluating 
the folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC) mirvetuximab 
soravtansine (IMGN853) in combination with bevacizumab, carboplatin, pegylated 
liposomal doxorubicin (PLD), or pembrolizumab in patients (pts) with ovarian cancer. in 
ASCO. 2017.
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Ascierto, P.A., Ipilimumab in the treatment of metastatic melanoma: a summary of recent 
studies. Tumori, 2013. 99(6): p. 302e-5e.
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Herbst, R.S., et al., Predictive correlates of response to the anti-PD-L1 antibody 
MPDL3280A in cancer patients. Nature, 2014. 515(7528): p. 563-7.
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Garon, E.B., et al., Pembrolizumab for the treatment of non-small-cell lung cancer. N 
Engl J Med, 2015. 372(21): p. 2018-28.
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Borghaei, H., et al., Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-
Cell Lung Cancer. N Engl J Med, 2015. 373(17): p. 1627-39.
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Brahmer, J., et al., Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-
Cell Lung Cancer. N Engl J Med, 2015. 373(2): p. 123-35.
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Rizvi, N.A., et al., Cancer immunology. Mutational landscape determines sensitivity to 
PD-1 blockade in non-small cell lung cancer. Science, 2015. 348(6230): p. 124-8.
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Snyder, A., et al., Genetic basis for clinical response to CTLA-4 blockade in melanoma. 
N Engl J Med, 2014. 371(23): p. 2189-2199.
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Hodi, F.S., et al., Immunologic and clinical effects of antibody blockade of cytotoxic T 
lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl 
Acad Sci U S A, 2008. 105(8): p. 3005-10.
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Hoos, A., et al., Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst, 
2010. 102(18): p. 1388-97.
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Nishino, M., et al., Optimizing immune-related tumor response assessment: does 
reducing the number of lesions impact response assessment in melanoma patients treated 
with ipilimumab? J Immunother Cancer, 2014. 2: p. 17.
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Wolchok, J.D., et al., Guidelines for the evaluation of immune therapy activity in solid 
tumors: immune-related response criteria. Clin Cancer Res, 2009. 15(23): p. 7412-20.
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Nishino, M., et al., Personalized tumor response assessment in the era of molecular 
medicine: cancer-specific and therapy-specific response criteria to complement pitfalls of 

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RECIST. AJR Am J Roentgenol, 2012. 198(4): p. 737-45.
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Sill, M.W., et al., A method for utilizing co-primary efficacy outcome measures to screen 
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95.

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APPENDIX A
ECOG PERFORMANCE STATUS
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, but ambulatory.  
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).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
2
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.

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APPENDIX B: DANA-FARBER/HARVARD CANCER CENTER MULTI-CENTER 
DATA AND SAFETY MONITORING PLAN

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TABLE OF CONTENTS
1.
INTRODUCTION ...............................................................................................................4
1.1.
Purpose.....................................................................................................................4
2.
GENERAL ROLES AND RESPONSIBILITIES ...............................................................4
2.1.
Coordinating Center.................................................................................................4
2.2.
External Site.............................................................................................................5
3.
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS ...............................6
3.1.
Protocol Revisions and Closures .............................................................................6
3.2.
Informed Consent Requirements .............................................................................6
3.3.
IRB Re-Approval.....................................................................................................6
3.4.
DF/HCC Multi-Center Protocol Confidentiality .....................................................7
3.5.
Participant Registration and Randomization ...........................................................7
3.6.
Initiation of Therapy ................................................................................................8
3.7.
Eligibility Exceptions...............................................................................................8
3.8.
Data Management....................................................................................................8
3.9.
Protocol Reporting Requirements............................................................................8
4.
MONITORING: QUALITY CONTROL............................................................................9
4.1.
Ongoing Monitoring of Protocol Compliance.........................................................9
4.2.
Monitoring Reports................................................................................................10
4.3.
Accrual Monitoring................................................................................................10
5.
AUDITING: QUALITY ASSURANCE ...........................................................................11
5.1.
DF/HCC Internal Audits........................................................................................11
5.2.
Audit Notifications.................................................................................................11
5.3.
Audit Reports.........................................................................................................11
5.4.
External Site Performance .....................................................................................11

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1. INTRODUCTION
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP serves as a reference for any sites external to DF/HCC that 
are participating in a DF/HCC clinical trial. 
1.1.
Purpose
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-
Center protocol will comply with Federal Regulations, Health Insurance Portability and 
Accountability Act (HIPAA) requirements and applicable DF/HCC Policies and 
Operations..       
2. GENERAL ROLES AND RESPONSIBILITIES
For DF/HCC Multi-Center Protocols, the following general responsibilities apply, in 
addition to those outlined in DF/HCC Policies for Sponsor-Investigators: 
2.1.
 Coordinating Center 
The general responsibilities of the Coordinating Center may include but are not limited to:

Assist in protocol development. 

Maintain FDA correspondence, as applicable.

Review registration materials for eligibility and register participants from 
Participating Institutions in the DF/HCC clinical trial management system 
(CTMS).

Distribute protocol and informed consent document updates to External Sites as 
needed.

Oversee the data collection process from External Sites.

Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violation submitted by External Sites and provide to the DF/HCC 
Sponsor for timely review and submission to the IRB of record, as necessary. 

Distribute serious adverse events reported to the DF/HCC Sponsor that fall under 
the reporting requirements for the IRB of record to all External Sites.

Provide External Sites with information regarding DF/HCC requirements that they 
will be expected to comply with.

Carry out plan to monitor External Sites either by on-site or remote monitoring. 

Maintain Regulatory documents of all External Sites which includes but is not 
limited to the following: local IRB approvals/notifications from all External Sites, 
confirmation of Federalwide Assurances (FWAs) for all sites, all SAE 
submissions, Screening Logs for all sites, IRB approved consents for all sites

Conduct regular communications with all External Sites (conference calls, emails, 
etc) and maintain documentation all relevant communications.

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2.2.
 External Site
An External Site is an institution that is outside the DF/HCC and DF/PCC consortium that 
is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC investigator.  
The External Site acknowledges the DF/HCC Sponsor as having the ultimate authority and 
responsibility for the overall conduct of the study. 
Each External Site is expected to comply with all applicable DF/HCC requirements stated 
within this Data and Safety Monitoring Plan and/or the protocol document.. 
The general responsibilities for each External Site may include but are not limited to:

Document the delegation of research specific activities to study personnel.

Commit to the accrual of participants to the protocol.

Submit protocol and/or amendments to their IRB of record. For studies under a 
single IRB, the Coordinating Center will facilitate any study-wide submissions..

Maintain regulatory files as per ICH GCP and federal requirements.

Provide the Coordinating Center with regulatory documents or source documents as 
requested.

Participate in protocol training prior to enrolling participants and throughout the trial 
as required.

Update Coordinating Center with research staff changes on a timely basis.

Register participants through the Coordinating Center prior to beginning research 
related activities when required by the sponsor. 

Submit Serious Adverse Event (SAE) reports to sponsor, Coordinating Center, and 
IRB of record as applicable, in accordance with DF/HCC requirements. 

Submit protocol deviations and violations to the Sponsor, Coordinating Center, and 
IRB of record as applicable..

Order, store and dispense investigational agents and/or other protocol mandated 
drugs per federal guidelines and protocol requirements.

Participate in any quality assurance activities and meet with monitors or auditors at 
the conclusion of a visit to review findings.

Promptly provide follow-up and/or corrective action plans for any monitoring 
queries or audit findings.

Notify the sponsor immediately of any regulatory authority inspection of this 
protocol at the External Site.
3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS
Certain DF/HCC Policy requirements apply to External Sites participating in DF/HCC 
research. The following section will clarify DF/HCC requirements and further detail the 
expectations for participating in a DF/HCC Multi-Center protocol. 
3.1.
 Protocol Revisions and Closures

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The External Sites will receive notification of protocol revisions and closures from the 
Coordinating Center.  When under a separate IRB, it is the individual External Site’s 
responsibility to notify its IRB of these revisions.

Protocol revisions: External Sites will receive written notification of protocol 
revisions from the Coordinating Center. All protocol revisions should be IRB 
approved and implemented within a timely manner from receipt of the notification.

Protocol closures and temporary holds: External Sites will receive notification of 
protocol closures and temporary holds from the Coordinating Center. Closures and 
holds will be effective immediately.  In addition, the Coordinating Center, will 
update the External Sites on an ongoing basis about protocol accrual data so that 
they will be aware of imminent protocol closures.
3.2.
 Informed Consent Requirements
The DF/HCC approved informed consent document will serve as a template for the 
informed consent for External Sites. The External Site consent form must follow the consent 
template as closely as possible and should adhere to specifications outlined in the DF/HCC 
Guidance Document on Model Consent Language for Investigator-Sponsored Multi-Center 
Trials.  This document will be provided separately to each External Site upon request.
External Sites must send their version of the informed consent document to the Coordinating 
Center for sponsor review and approval. If the HIPAA authorization is a separate document, 
please submit to the sponsor for the study record. Once sponsor approval is obtained, the 
External site may submit to their IRB of record, as applicable. In these cases, the approved 
consent form must also be submitted to the Coordinating Center after approval by the local 
IRB for all consent versions.
The Principal Investigator (PI) at each External Site will identify the appropriate members 
of the study team who will be obtaining consent and signing the consent form for protocols. 
External Sites must follow the DF/HCC requirement that for all interventional drug, 
biologic, or device research, only attending physicians may obtain initial informed consent 
and any re-consent that requires a full revised consent form.  
3.3.
 IRB Re-Approval
Verification of IRB re-approval for the External Sites is required in order to continue 
research activities.  There is no grace period for continuing approvals.
The Coordinating Center will not register participants if a re-approval letter is not received 
for the External Site on or before the anniversary of the previous approval date.  
3.4.
 DF/HCC Multi-Center Protocol Confidentiality

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All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should 
be de-identified. It is recommended that the assigned protocol case number be used for all 
participant specific documents. Participant initials may be included or retained for cross 
verification of identification. 
3.5.
 Participant Registration
Refer to Section 4 of the protocol for the participant registration process.
3.6.
 Initiation of Therapy
Participants must be registered with the DF/HCC CTMS before the initiation of treatment 
or other protocol-specific interventions. Treatment and other protocol-specific interventions 
may not be initiated until the External Site receives confirmation of the participant’s 
registration from the Coordinating Center. The DF/HCC Sponsor and IRB of record must 
be notified of any violations to this policy.
3.7.
 Eligibility Exceptions
No exceptions to the eligibility requirements for a protocol without IRB approval will be 
permitted. All External Sites are required to fully comply with this requirement. The process 
for requesting an eligibility exception is defined below.
3.8.
 Data Management
DF/HCC develops case report forms (CRF/eCRFs), for use with the protocol.  These forms 
are designed to collect data for each study. DF/HCC provides a web-based training for all 
eCRF users.
  
3.8.1. Data Forms Review
Data submissions are monitored for timeliness and completeness of submission. If study 
forms are received with missing or questionable data, the submitting institution will receive 
a written or electronic query from the DF/HCC Office of Data Quality, Coordinating Center, 
or designee. 
Responses to all queries should be completed and submitted within 14 calendar days.  
If study forms are not submitted on schedule, the External Sites will receive a Missing Form 
Report from the Coordinating Center noting the missing forms.  These reports are 
distributed by the Coordinating Center on a monthly basis.

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3.9.
 Protocol Reporting Requirements
3.9.1. Protocol Deviations, Exceptions and Violations
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review 
and approval, except when necessary to eliminate apparent immediate hazards to the 
participant. DF/HCC requires all departures from the defined procedures set forth in the 
IRB approved protocol to be reported to the DF/HCC Sponsor and to the IRB of record.
3.9.2. Reporting Procedures
Requests to deviate from the protocol require approval from the IRB of record and the 
sponsor. 
All protocol violations must be sent to the Coordinating Center in a timely manner. The 
Coordinating Center will provide training for the requirements for the reporting of 
violations. 
3.9.3. Guidelines for Processing IND Safety Reports 
The DF/HCC Sponsor will review all IND Safety Reports per DF/HCC requirements, and 
ensure that all IND Safety Reports are distributed to the External Sites as required by 
DF/HCC Policy. External Sites will review/submit to the IRB according to their 
institutional policies and procedures.
4. MONITORING: QUALITY CONTROL
The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, provides 
quality control oversight for the protocol.
4.1.
 Ongoing Monitoring of Protocol Compliance
The External Sites may be required to submit participant source documents to the 
Coordinating Center for monitoring. External sites may also be subject to on-site 
monitoring conducted by the Coordinating Center.
The Coordinating Center will implement ongoing monitoring activities to ensure that 
External Sites are complying with regulatory and protocol requirements, data quality, and 
participant safety. Monitoring practices may include but are not limited to source data 
verification, and review and analysis of eligibility requirements, informed consent 
procedures, adverse events and all associated documentation, review of study drug 
administration/treatment, regulatory files, protocol departures reporting, pharmacy 
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External Sites will be required to participate in Coordinating Center initiated 
teleconferences, as scheduled. The Coordinating Center will keep in close touch with the 
External Sites via email and phone.
Remote Monitoring: The Coordinating Center will request source documentation from 
Participating Institutions as needed to complete monitoring activities.  Participating 
Institutions will be asked to forward de-identified copies of participants’ medical record and 
source documents to the Coordinating Center to aid in source data verification.
4.2.
 Monitoring Reports
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. 
The DF/HCC Sponsor may increase the monitoring activities at External Sites that are 
unable to comply with the protocol, DF/HCC Sponsor requirements or federal and local 
regulations. 
4.3.
 Accrual Monitoring
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish 
accrual requirements for each External Site. Accrual will be monitored for each External 
Site by the DF/HCC Sponsor or designee. Sites that are not meeting their accrual 
expectations may be subject to termination.
A minimum of 3 participants per site annually is recommended for Phase II trials.
5. AUDITING: QUALITY ASSURANCE
5.1.
 DF/HCC Internal Audits
 
All External Sites are subject to audit by the DF/HCC Office of Data Quality (ODQ). 
Typically, approximately 3-4 participants would be audited at the site over a 2-day period. 
If violations which impact participant safety or the integrity of the study are found, more 
participant records may be audited. 
5.2.
 Audit Notifications
It is the External Site’s responsibility to notify the Coordinating Center of all external audits 
or inspections (e.g., FDA, EMA, NCI) that involve this protocol. All institutions will 
forward a copy of final audit and/or re-audit reports and corrective action plans (if 
applicable) to the Coordinating Center, within 12 weeks after the audit date. 
5.3.
 Audit Reports 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if 
applicable. The Coordinating Center, must forward any reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. For unacceptable audits, the 

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DF/HCC Audit Committee would forward the final audit report and corrective action plan 
to the IRB as applicable.
5.4.
 External Site Performance
The DF/HCC Sponsor and the IRB of record are charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol.
External Sites that fail to meet the performance goals of accrual, submission of timely and 
accurate data, adherence to protocol requirements, and compliance with state and federal 
regulations, may be put on hold or closed. 

87
APPENDIX C
CTCAE VERSION 5.0 GRADING FOR SELECTED ADVERSE EVENTS
Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0; National Cancer Institute; November 27, 
2017; https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
Grade
Adverse 
Event
1
2
3
4
5
Pneumonitis
Asymptomatic; 
clinical or 
diagnositic 
observations only; 
intervention not 
indicated
Symptomatic; 
medical 
intervention 
indicated; limiting 
instrumental ADL
Severe symptoms; 
limiting self-care 
ADL; oxygen 
indicated 
Life-threatening 
respiratory 
compromise; 
urgent 
intervention 
indicated (e.g., 
tracheotomy or 
intubation) 
Death
Blurred 
vision
Intervention not 
indicated
Symptomatic; 
moderate decrease 
in visual acuity 
(best corrected 
visual acuity 20/40 
and better or 3 lines 
or less decreased 
vision from known 
baseline); limiting 
instrumental ADL 
Symptomatic with 
marked decrease in 
visual acuity (best 
corrected visual 
acuity worse than 
20/40 or more than 
3 lines of decreased 
vision from known 
baseline, up to 
20/200); limiting 
self care ADL 
Best corrected 
visual acuity of 
20/200 or worse 
in the affected 
eye 
-
Dry eye
Asymptomatic; 
clinical or 
diagnostic 
observations only; 
mild symptoms 
relieved by 
lubricants
Symptomatic; 
moderate decrease 
in visual acuity 
(best corrected 
visual acuity 20/40 
and better or 3 lines 
or less decreased 
vision from known 
baseline) 
Symptomatic with 
marked decrease in 
visual acuity (best 
corrected visual 
acuity worse than 
20/40 or more than 
3 lines of decreased 
vision from known 
baseline, up to 
20/200); limiting 
self care ADL 
-

NCI Protocol #: N/A
DF/HCC Protocol #: 18-602
Protocol Version Date:  December 11, 2023
      88
Grade
Adverse 
Event
1
2
3
4
5
Keratitis
Asymptomatic; 
clinical or 
diagnostic 
observations only; 
intervention not 
indicated 
Symptomatic; 
moderate decrease 
in visual acuity 
(best corrected 
visual acuity 20/40 
and better or 3 lines 
or less decreased 
vision from known 
baseline) 
Symptomatic with 
marked decrease in 
visual acuity (best 
corrected visual 
acuity worse than 
20/40 or more than 
3 lines of decreased 
vision from known 
baseline, up to 
20/200); corneal 
ulcer; 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 
instrumental ADL; 
best corrected 
visual acuity 20/40 
and better or 3 lines 
or less decreased 
vision from known 
baseline 
Severe or medically 
significant but not 
immediately sight-
threatening; 
limiting self care 
ADL; decrease in 
visual acuity (best 
corrected visual 
acuity worse than 
20/40 or more than 
3 lines of decreased 
vision from known 
baseline, up to 
20/200) 
Sight-threatening 
consequences; 
urgent 
intervention 
indicated; 
blindness (20/200 
or worse) in the 
affected eye
-
Abbreviations:  Activities of daily living (ADL)

NCI Protocol #: N/A
DF/HCC Protocol #: 18-602
Protocol Version Date:  December 11, 2023
      89
APPENDIX D
SCHEMA FOR ADMINISTRATION OF STUDY-REQUIRED EYE DROPS
Steroid eye drops – 
6 times daily
Lubricating eye 
drops at least 15 
minutes after steroid 
eye drops – daily as 
directed
Steroid eye drops – 
4 times daily
Lubricating eye 
drops at least 15 
minutes after steroid 
eye drops – daily as 
directed
Lubricating eye drops – daily as directed
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Cycle Days
* Lubricating drops are continued if dose is held and/or cycle is delayed.