Phase 1 Safety Run-In and Phase 2 Randomized Clinical Trial of Anetumab Ravtansine and Pembrolizumab (MK-3475) Compared to Pembrolizumab Alone for Mesothelin-Positive Malignant Pleural Mesothelioma
Phase: PHASE1
Conditions: Pleural Malignant Mesothelioma
Sponsor: National Cancer Institute (NCI)

NCI Protocol #: 10107 
Local Protocol #: MC1721 
NCI Version Date: October 25, 2021 
 
i 
 
To: 
CTEP Protocol and Information Office 
From: 
Aaron Mansfield, M.D. 
Date: 
October 25, 2021 
Re: 
Amendment #16 (PVD 25Oct21) for P10107: “Phase 1 Safety Run-In and Phase 2 
Randomized Clinical Trial of Anetumab Ravtansine and MK-3475 
(Pembrolizumab) Compared to MK-3475 (Pembrolizumab) Alone for Mesothelin-
Positive Malignant Pleural Mesothelioma” 
 
 
SUMMARY OF CHANGES: 
Protocol (PVD 10/25/2021) 
 
I.     Response to Request for Rapid Amendment (dated October 4, 2021): 
# 
Section 
Comments 
1. 
7.1.2 
Version 2.5 of CAEPR for pembrolizumab replaced with Version 2.6 (July 15, 2021). Changes 
include: 
Added New Risk:  
o 
Rare but Serious: Hepatobiliary disorders - Other (sclerosing cholangitis) 
• 
Decrease in Risk Attribution: 
o 
Changed to Rare but Serious from Less Likely: Blood and lymphatic system 
disorders - Other (immune thrombocytopenic purpura) 
• 
Provided Further Clarification: 
o 
Thrombotic thrombocytopenic purpura is now reported as Blood and 
lymphatic system disorders - Other (immune thrombocytopenic purpura). 
 

NCI Protocol #: 10107 
Local Protocol #: MC1721 
NCI Version Date: October 25, 2021 
 
1 
 
Phase 1 Safety Run-In and Phase 2 Randomized Clinical Trial of Anetumab Ravtansine 
and Pembrolizumab (MK-3475) Compared to Pembrolizumab Alone for Mesothelin-
Positive Malignant Pleural Mesothelioma 
 
 
Corresponding Organization: LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
 
 
Principal Investigator: 
Aaron Mansfield, M.D. 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
Telephone: (507) 284-2511 
Email: mansfield.aaron@mayo.edu 
 
Co-Investigator: 
Raffit Hassan, M.D. 
National Cancer Institute 
10 Center Drive 
Bethesda, MD 20892 
Telephone: (301) 451-8742 
Email: hassanr@mail.nih.gov 
 
Participating Organizations:  
LAO-11030/ University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043/ City of Hope Comprehensive Cancer Center LAO 
LAO-CT018/ Yale University Cancer Center LAO 
LAO-MD017/ JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-OH007/ Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015/ University of Pittsburgh Cancer Institute LAO 
LAO-TX035/ University of Texas MD Anderson Cancer Center LAO 
LAO-NCI/ National Cancer Institute LAO 
LAO-NC010/ Duke University LAO 
EDDOP/ Early Drug Development Opportunity Program 
CATCHUP / Creating Access to Targeted Cancer Therapy for Underserved Populations 
 
 
 
 
 
 
 

NCI Protocol #: 10107 
Local Protocol #: MC1721 
NCI Version Date: October 25, 2021 
 
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Statistician: 
 
Jun Yin, Ph.D. 
 
 
Mayo Clinic  
 
Telephone: (507) 538-6252 
 
Email: yin.jun@mayo.edu 
 
 
 
 
 
Protocol Manager: 
Elizabeth Mikula 
Mayo Clinic Cancer Center 
Telephone: (507) 538-6232 
Email: mikula.elizabeth@mayo.edu 
 
 
 
 
ClinicalTrials.gov identifier: NCT03126630 
NCI-Supplied Agent(s):   
Anetumab ravtansine (NSC 791065) 
Pembrolizumab (MK-3475) (NSC 776864)  
 
IND Sponsor: DCTD, NCI.   
  
Protocol Type / Version # / Version Date: 
 
Original/ Version 1 / March 9, 2017 
Resubmission / Version 2 / April 29, 2017 
Resubmission / Version 3 / June 13, 2017 
Resubmission / Version 4 / July 14, 2017 
Resubmission / Version 5 / July 28, 2017 
Resubmission / Version 6 / October 10, 2017 
Resubmission / Version 7 / December 13, 2017 
Resubmission / Version 8 / December 29, 2017 
Amendment 1 / Version 9 / May 10, 2018 
Amendment 2 / Version 10 / June 28, 2018 
Amendment 3 / Version 11 / July 20, 2018 
Amendment 4 / Version 12 / December 3, 2018 
Amendment 5 / Version 13 / December 26, 2018 
Amendment 6 / Version 14 / February 15, 2019 
Amendment 7 / Version 15 / May 16, 2019 
Amendment 7 / Version 16 / July 1, 2019 
Amendment 8 / Version 17 / October 2, 2019 
Amendment 9 / Version 18 / November 25, 2019 
Amendment 10 / Version 19 / January 21, 2020 
Amendment 10 / Version 20 / January 31, 2020 
Amendment 11 / Version 21 / February 24, 2020 
Amendment 12 / Version 22 / July 28, 2020 
Amendment 13 / Version 23 / September 25, 2020 
Amendment 14 / Version 24 / December 15, 2020 
Amendment 15 / Version 25 / May 3, 2021 

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NCI Version Date: October 25, 2021 
 
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Amendment 16 / Version 26 / October 25, 2021 
 

NCI Protocol #: 10107 
Local Protocol #: MC1721 
NCI Version Date: October 25, 2021 
 
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SCHEMA – Phase 1 Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Cycle length = 21 days 
 
2. Anetumab ravtansine is to be administered prior to pembrolizumab (MK-3475) when given 
in combination 
 
 
 
 
 
 
 
Registration 
Treatment1,2 
 
All cycles:  
Anetumab ravtansine: Day 1 of each cycle for up to 12 months 
MK-3475 (pembrolizumab): Day 1 of each cycle for up to 24 months 
 
 
Continue until 
A maximum of 2 years or disease progression, unacceptable adverse events or 
patient refusal 

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SCHEMA – Randomized Phase 2 Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Mesothelin expression may be determined while a patient is receiving frontline therapy and 
registration may occur at time of progression.  Submitted tissue must show moderate or 
stronger mesothelin expression in ≥ 30% of the tumor cells for the patient to be eligible for 
and registered to the study.  Submit slides or a tissue block to the central laboratory for the 
mesothelin expression assay as per Section 9.2.1.   
 
2. Cycle length = 21 days 
 
3. Anetumab ravtansine is to be administered prior to pembrolizumab when given in 
combination 
Pre-Registration1 
(Tissue Submission for Mesothelin Expression Assay) 
Registration and Randomization 
(Mesothelin Expression Confirmed) 
Treatment2 
Group 1 
 
All cycles:  
Pembrolizumab (MK-3475): Day 1 of each cycle 
for up to 24 months 
 
 
Continue until 
A maximum of 2 years or disease progression, unacceptable adverse events or 
patient refusal 
Treatment2, 3 
Group 2 
 
All cycles:  
Anetumab ravtansine: Day 1 of each cycle for up to 12 
months 
Pembrolizumab (MK-3475): Day 1 of each cycle for 
up to 24 months 

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NCI Version Date: October 25, 2021 
 
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TABLE OF CONTENTS 
 
 
SCHEMA – Phase 1 Study ..............................................................................................................4 
SCHEMA – Randomized Phase 2 Study .........................................................................................5 
1. 
OBJECTIVES ......................................................................................................................8 
1.1 
Primary Objectives ...................................................................................................8 
1.2 
Secondary Objectives ...............................................................................................8 
1.3 
Correlative Study Objectives ...................................................................................8 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Malignant Pleural Mesothelioma .............................................................................9 
2.2 
CTEP IND Agents ...................................................................................................9 
2.3 
Rationale ................................................................................................................12 
2.4 
Correlative Studies Background ............................................................................15 
3. 
PATIENT SELECTION ....................................................................................................18 
3.1 
Pre-Registration Inclusion Criteria ........................................................................18 
3.2 
Registration Inclusion Criteria ...............................................................................18 
3.3 
Exclusion Criteria ..................................................................................................20 
3.4 
Inclusion of Women and Minorities ......................................................................24 
4. 
REGISTRATION PROCEDURES ...................................................................................24 
4.1 
Investigator and Research Associate Registration with CTEP ..............................24 
4.2 
Site Registration .....................................................................................................25 
4.3 
Patient Registration ................................................................................................28 
4.4 
General Guidelines .................................................................................................29 
5. 
TREATMENT PLAN ........................................................................................................29 
5.1 
Agent Administration .............................................................................................29 
5.2 
Phase 1 Study .........................................................................................................33 
5.3 
Phase 2 Study .........................................................................................................34 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................34 
5.5 
Duration of Therapy ...............................................................................................35 
5.6 
Duration of Follow Up ...........................................................................................35 
5.7 
Criteria for Removal from Study ...........................................................................36 
5.8 
Criteria to Resume Treatment Following a Drug-Related Adverse Event ............36 
5.9 
Treatment Beyond Progression ..............................................................................37 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................38 
6.1 
PRO-CTCAE Data .................................................................................................38 
6.2 
Dose Modifications for Anetumab Ravtansine ......................................................38 
6.3 
Dose Modifications for Pembrolizumab (MK-3475) ............................................41 
6.4 
Continuation of Therapy When One Agent is Held or Discontinued ....................44 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................44 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPRs) ...................44 
7.2 
Adverse Event Characteristics ...............................................................................51 
7.3 
Expedited Adverse Event Reporting ......................................................................51 
7.4 
Routine Adverse Event Reporting .........................................................................55 
7.5 
Secondary Malignancy ...........................................................................................55 

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7.6 
Second Malignancy ................................................................................................56 
7.7 
Pregnancy ...............................................................................................................56 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................56 
8.1 
CTEP IND Agent(s) ...............................................................................................56 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................61 
9.1 
Specimen Requirements for Correlative Studies ...................................................61 
9.2 
Integral Laboratory Studies ....................................................................................64 
9.3 
Integrated Correlative Studies ................................................................................65 
9.4 
Exploratory Correlative Studies .............................................................................72 
9.5 
Patient-Reported Outcomes Versions of the Common Terminology 
Criteria for Adverse Events (PRO-CTCAE) Assessment ......................................74 
10. 
STUDY CALENDAR .......................................................................................................75 
11. 
MEASUREMENT OF EFFECT........................................................................................79 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................79 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................87 
12.1 
Study Oversight .....................................................................................................87 
12.2 
Data Reporting .......................................................................................................88 
12.3 
Data Quality Portal ................................................................................................90 
12.4 
CTEP Multicenter Guidelines ................................................................................91 
12.5 
Collaborative Agreements Language .....................................................................91 
12.6 
Genomic Data Sharing Plan ...................................................................................93 
13. 
STATISTICAL CONSIDERATIONS...............................................................................93 
13.1 
Study Design/Endpoints.........................................................................................93 
13.2 
Analysis Plan .........................................................................................................96 
13.3 
Sample Size/Accrual Rate ......................................................................................97 
13.4 
Stratification Factors ..............................................................................................98 
13.5 
Analysis of Secondary Endpoints ..........................................................................98 
13.6 
Analysis of Exploratory Endpoints ......................................................................100 
13.7 
Data and Safety Monitoring .................................................................................100 
13.8 
Reporting and Exclusions ....................................................................................101 
REFERENCES ............................................................................................................................103 
APPENDIX A: PERFORMANCE STATUS CRITERIA ...........................................................110 
APPENDIX B: PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD ..............................................................................................................................111 
APPENDIX C: PRO-CTCAE QUESTIONNAIRE .....................................................................113 
APPENDIX D: MEDIDATA RAVE ePRO INFORMATION ...................................................117 
APPENDIX E: SOP for Cryo-preservation of PBMCs for Quantification of FcγRs 
& PBMC PK Studies .......................................................................................................123 

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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 Phase 1 Safety Lead-In 
• 
Determine the dose of anetumab ravtansine that is safe in combination with 
pembrolizumab to be used in the randomized phase 2 study. 
 
1.1.2 Randomized Phase 2  
• 
Determine if the overall response rate of the combination of anetumab ravtansine 
and pembrolizumab is superior to pembrolizumab alone. 
 
1.2 
Secondary Objectives 
 
1.2.1 To determine the progression free survival of anetumab ravtansine and pembrolizumab 
compared to pembrolizumab alone. 
 
1.2.2 To evaluate the pharmacodynamic effects of anetumab ravtansine and pembrolizumab on 
soluble megakaryocyte potentiating factor (MPF).    
 
1.2.3 To evaluate the pharmacokinetics of anetumab ravtansine and pembrolizumab. 
 
1.2.4 To evaluate mononuclear phagocyte system (MPS) function, FcɣRs, hormone and 
chemokine mediators as methods to evaluate factors affecting the pharmacokinetics and 
pharmacodynamics of these agents. 
 
1.2.5 To determine the incidence of antibodies directed against anetumab ravtansine. 
 
 
1.3 
Correlative Study Objectives   
 
1.3.1 To determine whether elevations in Bim in TTR predict responses to treatment and 
whether its detection is dynamic with treatment. 
 
1.3.2 To determine whether soluble PD-L1 predicts responses to treatment and whether its 
detection is dynamic with treatment. 
 
1.3.3 To evaluate PD-L1 expression in archival tissue as a predictive marker of response to 
pembrolizumab-based therapy. 
 
1.3.4 To explore the symptomatic adverse events (AE) for tolerability of each treatment group 
using PRO-CTCAE. 
 
 
 

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2. BACKGROUND 
 
2.1 
Malignant Pleural Mesothelioma 
Malignant pleural mesothelioma (MPM) is an inexorably progressive and almost 
universally fatal malignancy.  The vast majority of cases are associated with exposure to 
fibrous minerals, specifically asbestos or erionite fibers.  In addition, prior thoracic 
radiation therapy (1) and germline loss of function BAP1 mutations have been linked to 
the development of MPM (2).  With the continued use of asbestos products in many 
countries, the incidence of MPM continues to rise worldwide causing an estimated 
43,000 deaths annually (3).  
Effective treatment options are largely lacking for MPM.  In fact, there is currently no 
United States Food and Drug Administration (FDA) approved second-line therapy for 
MPM.  The roles of surgery and multi-modality therapy (i.e., chemotherapy followed by 
surgery and radiation) remain controversial and may only benefit highly selected patients 
(4).  Folate antimetabolite based chemotherapy, the current standard of care, has modest 
benefits and has been shown to improve overall survival by approximately three months 
(5).  The addition of bevacizumab to this regimen may further improve survival, but is 
not yet approved by the FDA (6).  Chemotherapy provides even less of a benefit for 
patients with sarcomatoid subtypes of MPM (7).  
 
2.2 
CTEP IND Agents 
 
2.2.1 Anetumab Ravtansine 
Anetumab ravtansine is an IgG1 antibody-drug conjugate that recognizes mesothelin and 
is bound to a potent microtubule inhibitor, DM4.  Mesothelin is a cell surface 
glycoprotein that is exclusively expressed by mesothelial cells under normal homeostasis. 
Mesothelin results from the cleavage of a precursor protein by the protease furin that 
releases megakaryocyte potentiating factor (MPF) from the amino terminus.  Mesothelin 
is also expressed by MPM, pancreatic adenocarcinomas, ovarian adenocarcinomas and 
other malignancies.  In fact, all epithelioid MPMs have been shown to express mesothelin 
to some extent (8).  In a recent phase 1 clinical trial, anetumab ravantansine was 
administered to patients with MPM who had 2+/3+ mesothelin expression by 
immunohistochemistry.  Five of 16 patients (31%) treated at the maximum tolerated dose 
(MTD) experienced a durable partial response to treatment.  For four of these five 
patients the response lasted more than 600 days.  Anetumab ravtansine appears to have a 
very steep dose-response as very few patients with MPM responded at doses lower than 
the MTD.  Some drug-related adverse events included fatigue, nausea, vomiting and 
uniquely, corneal epitheliopathy. 
 
2.2.2 Pembrolizumab (MK-3475) 
 
Pembrolizumab has high affinity and potent receptor-blocking activity for the 
programmed cell death 1 (PD-1) receptor, based on preclinical in vitro data (9).  
Pembrolizumab has an acceptable preclinical safety profile and is being advanced for 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies. 
 

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The importance of intact immune surveillance function in controlling outgrowth of 
neoplastic transformations has been known for decades (10).  Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and 
favorable prognosis in various malignancies.  In particular, the presence of CD8+ T-cells 
and the ratio of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with 
improved prognosis and long-term survival in solid malignancies, such as ovarian, 
colorectal, and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and 
renal cell carcinoma.  Tumor-infiltrating lymphocytes can be expanded ex vivo and re-
infused, inducing durable objective tumor responses in cancers such as melanoma (11, 
12). 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T 
lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively regulate 
antigen receptor signaling upon engagement of its ligands (programmed cell death ligand 
1 [PD-L1] and/or programmed cell death ligand 2 [PD-L2]) (13, 14).   
 
The structure of murine PD-1 has been resolved (15).  PD-1 and family members are type 
I transmembrane glycoproteins containing an Ig Variable–type (IgV type) domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of 
signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor 
tyrosine-based switch motif.  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases, SHP 1 and SHP-2, to the immunoreceptor tyrosine-based switch motif 
within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as 
CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-associated protein 
kinase (ZAP70), which are involved in the CD3 T-cell signaling cascade (16-18).  The 
mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct 
from, that of CTLA-4, because both molecules regulate an overlapping set of signaling 
proteins (19, 20).  As a consequence, the PD-1/PD-L1 pathway is an attractive target for 
therapeutic intervention in mesothelioma. 
 
Programmed cell death 1 ligand 1 (PD-L1, aka B7-H1 and CD274) is a critical mediator 
of peripheral immune tolerance (21).  PD-L1 is expressed by many components of the 
immune system including antigen presenting cells and T cells (21).  PD-L1 is also 
constitutively expressed in immunologically privileged sites such as the eyes and 
placenta.  Many tumors, including mesothelioma also express PD-L1 (22) and its 
expression is a poor prognostic marker in this disease (23).  T cells that express PD-1, the 
receptor for PD-L1, undergo apoptosis when PD-1 and PD-L1 bind and tumors that 
express PD-L1 blunt anti-tumor immunity through T cell apoptosis (24).  Pembrolizumab 
is approved by the FDA for the treatment of non-small cell lung cancer (NSCLC) in the 
first or second line, melanoma and head and neck cancer.  There are many other ongoing 
clinical trials testing its efficacy in many malignancies.  The first preliminary report of 
the activity of pembrolizumab in MPM was presented at the Annual Meeting of the 

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American Association for Cancer Research in 2015.  Patients with MPM whose tumor 
cells had 1% or greater expression of PD-L1 were included as a cohort in a larger phase 1 
clinical.  Responses were measured by standard Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1 every eight weeks.  PD-L1 expression was detected in 38 
patients of 84 who were screened (45%), and 25 of these patients were treated.  There 
were three moderate to severe (grade 3 or higher) drug-related adverse events.  There 
were six responders (24%, including unconfirmed responses) and 13 patients with stable 
disease (52%) for an impressive disease control rate of 76% (25).  An update of this trial 
was presented at the 2016 International Association for the Study of Lung Cancer 
(IASLC) World Conference on Lung Cancer (WCLC) and the confirmed, clinical benefit 
rate (complete responses, partial responses and stable disease for six months or greater) 
was 40%, and the median overall survival was 18 months in this pretreated population 
(26). 
 
Pembrolizumab has also been used in MPM in a larger phase 2 clinical trial with a two-
stage design.  The interim results from this trial were also presented at the 2016 IASLC 
WCLC meeting.  There were important differences between these two trial designs to 
consider, including the eligibility of patients without detectable PD-L1 expression, the 
flat dosing of pembrolizumab, less frequent imaging assessments, and the use of the 
modified pleural RECIST (27).  There were 35 patients who enrolled but one subject 
withdrew.  Two patients died on study because of autoimmune hepatitis and an unknown 
cause.  At the time of the presentation, the median progression free survival (PFS) was 
6.2 months and the median overall survival (OS) had not been reached.  There were 
seven partial responses (21%) and 19 patients with stable disease (56%).  Over half of the 
patients did not have detectable PD-L1 expression yet responses to pembrolizumab were 
seen regardless (28).  Similarly, in the largest trial of PD-1/PD-L1 axis inhibition to date 
in MPM, avelumab, an anti-PD-L1 antibody, demonstrated an overall response rate of 
9.4%, regardless of tumor cell PD-L1 expression (29).  Both pembrolizumab and 
avelumab have been relatively well tolerated by patients with MPM or other cancers; 
however, they are commonly associated with rash and auto-immune-like conditions 
affecting the endocrine system.  Most of these toxicities do not overlap with those of 
anetumab ravtansine.  In contrast to PD-1/PD-L1 axis inhibitors, the CTLA-4 inhibitor 
tremelimumab showed no benefit compared to best supportive care in patients with MPM 
and was poorly tolerated (30).  Overall, inhibition of PD-1/PD-L1 interaction is a 
promising therapeutic strategy in MPM that needs further validation as a single agent, 
and may be synergistic in combination with chemotherapy. 
 
2.2.2.1 
Pembrolizumab Background and Clinical Trials 
 
Pembrolizumab (Keytruda®), a humanized monoclonal antibody against the PD-1 
protein, has been developed by Merck & Co. for the treatment of cancer.  
Pembrolizumab is approved for treatment of melanoma in several countries; in the 
United States (US) and European Union, it is approved for the treatment of advanced 
(unresectable or metastatic) melanoma in adults.  Pembrolizumab has also been 
approved for treatment of NSCLC in several countries; in the US it is indicated for 
the treatment of patients with metastatic NSCLC whose tumors express PD-L1 as 
determined by a Food and Drug Administration (FDA)-approved test and who have 

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disease progression on or after platinum-containing chemotherapy.  Patients with 
NSCLC and epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase 
(ALK) genomic tumor aberrations should also have disease progression on FDA-
approved therapy for these aberrations prior to receiving pembrolizumab.  
Pembrolizumab is approved in the US for the treatment of patients with recurrent or 
metastatic head and neck squamous cell carcinoma (HNSCC) with disease 
progression on or after platinum-containing chemotherapy. 
 
Pembrolizumab has demonstrated initial clinical efficacy in single-arm monotherapy 
trials in patients with NSCLC, HNSCC, urothelial cancer, gastric cancer, triple 
negative breast cancer, and Hodgkin’s Lymphoma as determined by response rate.  
Ongoing clinical trials are being conducted in these tumor types as well as a number 
of other advanced solid tumor indications and hematologic malignancies.  For study 
details please refer to the Investigator’s Brochure (2016).  
 
 
 
2.3 
Rationale 
 
Anetumab ravtansine targets mesothelin and its activity is predicated on its internalization 
for DM4 release.  Accordingly, patients who participate in this trial will be screened for 
high levels (2+/3+) of mesothelin expression.  PD-L1 can be adaptively expressed in 
response to interferon-γ, or constitutively expressed due to signal pathway abnormalities 
that result from mutations such as loss of PTEN (31).  Similarly, PD-L1 expression by 
tumor cells can be induced by chemotherapy (32) or radiotherapy (33) in many different 
cancers.  We have demonstrated that microtubule inhibitors such as vinorelbine, which 
have a similar mechanism of action as the DM4 warhead of anetumab ravtansine, 
upregulate the expression of PD-L1 in MPM cell lines (72) (Figure 1).  The dynamic 
expression of PD-L1 following chemotherapy suggests that there may be a benefit to 
combining chemotherapy with inhibitors of the PD-1/PD-L1 axis.  In fact, combined 
cytotoxic therapy with PD-1 or PD-L1 inhibition has been shown to be synergistic in 
multiple syngeneic murine tumor models (32, 34).  
 

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MPM is a challenging disease to assess and standard RECIST criteria were not designed 
to measure pleural disease.  Modified pleural RECIST (mRECIST) have been adopted by 
mesothelioma experts for the measurement of responses in MPM (27).  The mRECIST 
are the most commonly used response criteria in clinical trials for MPM.  Even though 
the gold standard for oncology outcomes is overall survival, cross-over to subsequent 
therapies and competing risks influence survival outcomes.  In order to assess whether 
responses to treatment correlate with survival outcomes in MPM, we retrospectively 
reviewed the clinical trial that lead to FDA approval of the current standard of care first-
line regimen of cisplatin and pemetrexed (5).  We identified that patients with epithelioid 
MPM who responded to front-line therapy had a significantly longer overall survival (HR 
0.341, 95% CI 0.239-0.486; median 20.6 months, 95% CI: 15.3-not reached) than those 
 
MPM cell lines were cultured with vinorelbine (5.5 µg/ml, blue lines) or 
vehicle control (saline, red lines) for 36-40 hours in vitro. After 
incubation, cells were washed and stained with anti-B7-H1 (PD-L1) 
antibody (clone MIH1, open lines) or isotype control (filled gray lines). 
Histograms are the representative data of three independent experiments.   
Figure 1: Dynamics of PD-L1 expression  

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who did not respond (median 9.4 months, 95% CI: 8.1-11.0).  Similarly patients who 
responded to front-line therapy had a significantly longer progression-free survival (HR 
0.496, 95% CI: 0.234-0.549; median 7.8 months, 95% CI: 6.5-8.5) than those who did not 
respond (median 3.7 months, 95% CI: 2.9-4.3).  Although these findings may not cross-
over to other types of therapy, they are suggestive that a decrease in tumor burden as 
assessed by mRECIST is associated with improved survival outcomes in MPM. 
 
This clinical trial is a phase 2 randomized clinical trial of anetumab ravtansine and 
pembrolizumab compared to pembrolizumab for mesothelin-positive MPM that has been 
designed based on the preliminary data above.  First, both anetumab ravtansine and 
pembrolizumab are active agents in MPM based on the early phase clinical trials that 
have been presented to date.  Second, there is no FDA-approved second-line therapy for 
MPM.  Third, anetumab ravtansine and pembrolizumab do not have significant 
overlapping toxicities; however, there is a steep dose-response with anetumab ravtansine 
which favors a dose de-escalation design.  Fourth, pembrolizumab is an appropriate 
control arm.  There is an ongoing phase 2 registration trial of anetumab ravtansine 
compared to vinorelbine for patients with mesothelin-positive MPM.  The eligibility 
criteria are very similar for this proposed study and the registration study and the same 
companion diagnostic test for mesothelin expression will be used in both studies.  
 
2.3.1 Rationale for Pembrolizumab Dose Selection 
 
The dose of pembrolizumab planned to be studied in this trial is 200 mg administered 
every 3 weeks (q3w).  The dose recently approved in the US and several other countries 
for treatment of melanoma patients is 2 mg/kg q3w.  Information on the rationale for 
selecting 200 mg q3w is summarized below. 
 
The initial phase 1 study of pembrolizumab (KN001) evaluated 5 dose levels (1 mg/kg 
every 2 weeks [q2w], 3 mg/kg q2w, 10 mg/kg q2w, 2 mg/kg q3w, and 10 mg/kg q3w) in 
patients with advanced solid tumors.  All 5 dose levels were well tolerated and no dose-
limiting toxicities (DLTs) were observed.  Pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 
mg/kg, and 10 mg/kg q2w).  No maximum tolerated dose (MTD) has been identified to 
date.  In addition, 2 randomized cohort evaluations of melanoma patients receiving 
pembrolizumab 2 mg/kg or 10 mg/kg q3w have been completed and 1 randomized cohort 
evaluating 10 mg/kg q3w or 10 mg/kg q2w has also been completed.  The clinical 
efficacy and safety data demonstrate a lack of any important differences in efficacy or 
safety profile across doses. 
 
An integrated body of evidence suggests that 200 mg q3w is expected to provide similar 
response to 2 mg/kg q3w, 10 mg/kg q3w, and 10 mg/kg q2w.  Previously, a flat 
pembrolizumab exposure-response relationship for efficacy and safety has been found in 
patients with melanoma in the range of doses between 2 mg/kg and 10 mg/kg.  Exposures 
for 200 mg q3w are expected to lie within this range and will be close to those obtained 
with 2 mg/kg q3w dose. 
 

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The PK profile of pembrolizumab is consistent with that of other humanized monoclonal 
antibodies, which typically have a low clearance and a limited volume of distribution.  A 
population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed.  The distribution of exposures from the 200 
mg fixed dose are predicted to considerably overlap those obtained with the 2 mg/kg dose 
and importantly will maintain individual patient exposures within the exposure range 
established in melanoma as associated with maximal clinical response.  The PK 
properties of pembrolizumab, specifically the weight-dependency in clearance and 
volume of distribution, are consistent with no meaningful advantage to weight-based 
dosing relative to fixed dosing. 
 
In translating to other tumor indications, similarly flat exposure-response relationships 
for efficacy and safety as observed in patients with melanoma can be expected.  As the 
antitumor effect of pembrolizumab is driven through immune system activation rather 
than through a direct interaction with tumor cells, it is rendered independent of the 
specific tumor type.  In addition, available PK results in patients with melanoma, NSCLC 
and other tumor types support a lack of meaningful difference in PK exposures obtained 
at tested doses across tumor types.  Thus, the 200 mg q3w fixed-dose regimen is 
considered an appropriate fixed dose for other tumor indications as well. 
 
A fixed-dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors.  A fixed-dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage.  The 
existing data suggest 200 mg q3w as the appropriate dose for pembrolizumab. 
 
2.3.2 Rationale for anetumab ravtansine dose selection 
 
2.3.2.1 
Phase 1 
In the phase 1 clinical trial anetumab ravtansine appeared to have a very steep dose-
response as very few patients with MPM responded at doses lower than the MTD. In 
the trial the following doses and frequencies of anetumab ravtansine were tested: 1.8 
mg/kg q week; 2.2 mg/kg q week; 6.5 mg/kg q 3 weeks. Furthermore, there seem to 
be very few overlapping toxicities between anetumab ravtansine and Pembrolizumab. 
Accordingly, a dose de-escalation strategy was chosen with anetumab ravtansine 
based on the MTD identified in the phase 1 clinical trial. 
 
2.3.2.2 
Phase 2 
The phase 1 safety run-in and expansion cohort for this trial accrued 13 participants to 
Dose Level 1 (6.5 mg/kg anetumab ravtansine IV with 200 mg pembrolizumab IV 
every 3 weeks), 12 of whom were evaluable for dose-limiting toxicity (DLT). No 
DLTs were observed therefore Dose Level 1 was selected as the Phase 2 dose for this 
trial. 
 
 
 
2.4 
Correlative Studies Background 
 
2.4.1 Megakaryocyte Potentiating Factor (MPF) 
 

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MPF is cleaved from the amino terminus of a precursor protein that leaves mesothelin 
linked to the cell surface by glycophosphatidylinositol.  Accordingly, serum MPF is 
correlated with mesothelin expression and provides a blood-based marker of mesothelin-
positive tumor burden.  In a recently published clinical trial that tested the anti-
mesothelin immunotoxin SS1P in patients with MPM, serum MPF levels correlated with 
radiographic responses.  Accordingly, serum MPF may also correlate with radiographic 
responses to treatment with anetumab ravtansine and pembrolizumab. 
 
2.4.2    Mononuclear Phagocyte System (MPS) 
 
Nanoparticles (NPs), monoclonal antibodies (mAb) and antibody-drug conjugates (ADC) 
are cleared via the mononuclear phagocyte system (MPS) (35, 36).  Variability in MPS 
function has been shown to predict variability in the pharmacokinetics (PK) and 
pharmacodynamics (PD) of NPs such as pegylated liposomal doxorubicin in patients and 
preclinical tumor models (37).  While NPs are cleared via phagocytosis by MPS cells, the 
MPS also serves as a natural mechanism of clearance for antibodies and immune 
complexes via their Fc-gamma-receptors (FcɣR) on MPS cells (38-40).  Myeloid cells 
express various forms of FcɣRs (CD64, CD32 and CD16) that interact with extracellular 
monomeric or aggregated IgGs and therapeutic mAb and ADC (38).  Due to the 
differences in types and affinity in FcɣRs, a variation in receptor expression can lead to 
significant differences in the ability of MPS cells to clear immune complexes from the 
blood.  This also translates to variation in MPS’s ability to take up mAbs/ADCs which 
would affect their PK and PD. 
 
The factors affecting the PK of NPs and mAb/ADCs are very similar and consistent with 
variability in MPS function (41).  As with other NPs, there are very high and clinically 
relevant variability in the PK and PD of mAb and ADCs (42-44).  Consistent with MPS 
mediated clearance, the PK of mAbs and ADCs are characterized by high distribution to 
the liver and spleen, saturable clearance at higher doses, PK differences based on MPS 
factors (gender, body composition, and tumor burden), and faster clearance of ADCs that 
have a greater number of linked drugs (45-48).  In addition, studies suggest that the 
clearance of pertuzumab is greater in patients with gastric cancer compared with breast 
cancer and these results may be due to differences in the immune system and MPS (49-
51).  Moreover, preliminary data from Dr. Zamboni’s lab at UNC show that the 
expression of CD64, CD32 and CD16 FcɣRs on MPS cells is highly variable in healthy 
volunteers and patients with cancer (unpublished). 
 
The high PK variability is important for mAbs, and especially for ADCs, as these agents 
have a narrow therapeutic index (52-55).  Moreover, the combination of ADCs, such as 
anetumab ravtansine, with other mAbs and immune modulators may increase the 
likelihood of drug-drug interactions and altered PK and PD of the ADC as these agents 
are also cleared by and may alter the MPS.  Thus, the MPS pharmacology studies are 
critically important to optimizing the treatment of anetumab ravtansine and other ADCs 
alone and in combination with other agents. 
 
2.4.3    Soluble PD-L1 and Bim in Tumor-Reactive T cells 
Recently, two PD-1 inhibitors and a PD-L1 inhibitor have collectively been approved for 

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the treatment of melanoma, NSCLC, renal cell carcinoma and bladder cancer by the FDA 
(56).  Some of these agents require biomarker assessment of PD-L1 expression, whereas 
others do not.  For example, 50% or greater expression of PD-L1 by tumor cells is 
required to administer the PD-1 inhibitor pembrolizumab for NSCLC, but the other PD-1 
inhibitor nivolumab does not have this requirement for NSCLC.  In contrast, no 
biomarker testing is required to administer these agents to patients with melanoma (56). 
The expression of PD-L1 in NSCLC varies over space and time, challenging the use of 
PD-L1 as a predictive biomarker for PD-1/PD-L1 axis inhibitors (57, 58).  We have 
observed this same phenomenon more recently in MPM: in patients with paired lesions 
from resection of multiple sites of disease, or paired lesions from primary MPM and 
recurrent MPM, half of the cases had discrepant expression of PD-L1 (detectable 
compared to not detectable; abstract to be presented at USCAP 2017).  Thus, it is 
challenging to assign treatment to a patient when the expression of the biomarker is 
dynamic and sampling error may affect its measurement.  
 
Given the heterogeneity and dynamics of PD-L1 expression, tissue-based analysis of PD-
L1 expression has demonstrated conflicting applicability for selecting patients to receive 
PD-1 or PD-L1 inhibitors (56).  Other approaches to assess PD-L1 expression have been 
developed such as soluble PD-L1 (sPD-L1) (59).  Using this assay, sPD-L1 can be 
detected in the supernatants of many PD-L1-positive cell lines and sPD-L1 retains pro-
apoptotic signaling properties to T cells.  Many patients with metastatic melanoma have 
significant elevations in sPD-L1 (60).  With the difficulties detecting PD-L1 in tissue, 
sPD-L1 may represent a detectable circulating marker for PD-L1 expression and provide 
a means to non-invasively assess the dynamics of tissue PD-L1 expression.  Additionally, 
the signaling cascade in T cells that follows PD-1 engagement with PD-L1 may be 
predictive of responses to immunotherapy.  The identification of tumor-reactive T cells 
(TTR) based on the expression of CD8, CD11a and PD-1 (61), and the use of knock-out 
models and blocking antibodies led to the identification of Bim as a downstream 
signaling molecule of the PD-1 pathway.  High levels of Bim in circulating TTR cells 
were prognostic of poor survival in patients with metastatic melanoma who did not 
receive anti–PD-1 therapy and were also predictive of clinical benefit (i.e., response) in 
patients with metastatic melanoma who were treated with the PD-1 inhibitor 
pembrolizumab.  Moreover, this circulating TTR cell population significantly decreased 
after successful anti–PD-1 therapy (62).  Accordingly, sPD-L1 and Bim in TTR may 
provide a non-invasive means of monitoring PD-L1 expression and the effects of PD-1 
blockade on TTR in mesothelioma. 
 
2.4.4 Optional ePatient Outcomes Versions of the Common Terminology Criteria for Adverse 
Events (ePRO-CTCAE) Assessment 
 
Participation in the ePRO-CTCAE assessment is optional for both sites and patients.  
Sites may elect to either participate or decline participation in this correlative.  Sites who 
elect to participate may offer patients optional participation in the PRO-CTCAE 
assessment. 
Missing data are a significant problem, particularly for PRO-CTCAE assessments. Unlike 
data for traditional endpoints, such as survival, PRO-CTCAE data cannot be accurately 
obtained retrospectively. This limits researchers’ ability to accurately perform PRO-

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CTCAE statistical analyses and negatively impacts the clinical relevance of this effort. 
 
Typically, PRO-CTCAE forms are filled out in hardcopy (paper). To provide a more 
convenient method of completing PRO-CTCATE assessments, NCI, Theradex and the 
CTSU are working with Medidata Rave’s ePRO Cloud product that offers patients on this 
study the option of completing their PROs forms electronically using an application (app) 
downloaded to their smart phone or from a tablet that has the ePRO-CTCAE app with 
Internet access.   
 
Appendix D includes information on the Medidata Patient Cloud ePRO app including 
links to the training information for sites.  
 
3. PATIENT SELECTION 
For Phase 2, patients may be pre-registered and provide a tissue sample for testing of 
mesothelin expression prior to, during, or after receipt of frontline chemotherapy. 
 
3.1 
Pre-Registration Inclusion Criteria   
 
3.1.1 Patients must have histologically or cytologically confirmed malignant pleural 
mesothelioma. 
 
3.1.2 Patient is willing to submit a tissue sample to test for expression of mesothelin. 
 
Note: Tissue sample for mesothelin assay may have been collected prior to, during or 
after receipt of the frontline chemotherapy; patients will not be required to submit 
another tissue sample after receipt of the chemotherapy. 
 
3.1.3 Patients must have received platinum based chemotherapy.   
 
3.2 
Registration Inclusion Criteria 
 
3.2.1 For phase 2 only:  
 
3.2.1.1 
Patient has measurable disease per RECIST 1.1 for non-pleural disease or modified 
RECIST 1.1 (mRECIST) for pleural disease.  
 
Note: For pleural disease, this is defined as at least one lesion that can be accurately 
measured perpendicular to the chest wall or mediastinum that is ≥ 10 mm (≥ 1 cm). 
For extra pleural disease, measurable disease is defined as at least one lesion that can 
be accurately measured in at least one dimension (longest diameter to be recorded for 
non-nodal lesions and short axis for nodal lesions) as ≥ 10 mm (≥ 1 cm) for non-nodal 
lesions and ≥ 15 mm (≥ 1.5 cm) for nodal lesions with spiral CT scan, MRI, or 
calipers by clinical exam as per RECIST 1.1. 
 
3.2.1.2 
Tissue submitted for testing at pre-registration shows moderate or stronger mesothelin 
expression in ≥ 30% of the tumor cells.   
 

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3.2.2 For phase 1 and phase 2: 
 
3.2.2.1 
Patients must have received platinum-based therapy with or without bevacizumab. 
 
3.2.2.2 
Age ≥18 years. 
 
Note: Because MPM primarily affects older adults and no dosing or adverse event 
data are currently available on the use of anetumab ravtansine and pembrolizumab in 
patients <18 years of age, children are excluded from this study, but will be eligible 
for future pediatric trials. 
 
3.2.2.3 
ECOG performance status < 2 (Karnofsky ≥ 70%, see Appendix A). 
 
3.2.2.4 
Patients must have normal organ and marrow function as defined below: 
• Leukocytes 
≥ 3,000/mcL 
• Absolute neutrophil count 
≥ 1,500/mcL 
• Platelets 
≥ 100,000/mcL 
• Total bilirubin 
Within normal institutional limits 
• AST (SGOT) AND  
ALT (SGPT) 
≤ 2.5 × institutional upper limit of normal (ULN) 
• Creatinine 
OR 
Creatinine clearance 
Within normal institutional limits 
 
≥ 60 mL/min/1.73 m2 for patients with creatinine 
levels above institutional normal. 
 
3.2.2.5 
International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN AND 
partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN, unless 
patient is on stable dose of anti-coagulation therapy in which case patients will be 
allowed to participate if they have no signs of bleeding or clotting and the INR/PT 
and PTT/aPTT results are compatible with an acceptable risk-benefit ratio as per the 
Investigator’s discretion. 
 
3.2.2.6 
Negative serum pregnancy test for females of child bearing potential. 
 

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Note: Females are considered to not be of child bearing potential if any of the 
following apply: 
• Postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women < 45 years of age, a high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy.  In the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.);  
• Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy 
or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
• Has a congenital or acquired condition that prevents childbearing. 
 
3.2.2.7 
Patient agrees to use one of the following acceptable methods of contraception prior 
to study entry, during study participation, and for at least six months after receiving 
the last dose of study treatment: 
 
Acceptable methods of contraception are: 
Single method (1 of the following is acceptable): 
• Abstinence, if consistently employed as the patient’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and Institutional Review 
Boards (IRBs) 
• intrauterine device (IUD) 
• vasectomy of a female patient’s male partner  
• contraceptive rod implanted into the skin 
Combination method (requires use of 2 of the following): 
• diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• cervical cap with spermicide (nulliparous women only)   
• contraceptive sponge (nulliparous women only)  
• male condom or female condom (cannot be used together) 
• hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
 
3.2.2.8 
Ability to understand and the willingness to sign a written informed consent 
document, unless patient is of impaired decision making capacity in which case 
patient may be eligible if they have a Legal Authorized representative or caretaker 
available. 
 
3.3 
Exclusion Criteria 
 
3.3.1 Patients who have received any monoclonal antibody therapy within 4 weeks prior to 
entering the study.  
 

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3.3.2 Patients who have not recovered from adverse events due to prior anti-cancer therapy 
(i.e., have residual toxicities > Grade 1).   
 
Note:  Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this 
criterion and may qualify for the study. 
 
Note:  If patients received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy. 
 
3.3.3 Patients who are receiving any other investigational agents. 
 
3.3.4 Patients with known brain metastases with progressive neurologic dysfunction, 
requirement of steroids and lack of improvement on head imaging obtained prior to 
consent to this clinical trial should be excluded because of their poor prognosis and 
because they would confound the evaluation of neurologic and other adverse events.  
 
Note: Patients with previously treated brain metastases may participate provided they are 
stable (without evidence of progression by imaging using the identical imaging modality 
for each assessment, either magnetic resonance imaging [MRI] or computed tomography 
[CT] scan, for at least 4 weeks prior to the first dose of trial treatment and any neurologic 
symptoms have returned to baseline), have no evidence of new or enlarging brain 
metastases, and are not using steroids for at least 7 days prior to trial treatment.  
 
Note: Patients with carcinomatosis meningitis should also be excluded.  
 
3.3.5 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to anetumab ravtansine or pembrolizumab. 
 
3.3.6 Patients receiving any medications or substances that are strong inhibitors or inducers of 
CYP3A4, including herbal preparation containing CYP3A4 inducers (e.g., St. John’s 
Wort), grapefruit and grapefruit juice (CYP3A4 inhibitor), within 2 weeks before the start 
of study treatment.   
 
3.3.7 Patients are prohibited from receiving the following therapies during the screening and 
treatment phases (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy.  
• Immunotherapy not specified in this protocol. 
• Chemotherapy not specified in this protocol. 
• Investigational agents other than anetumab ravtansine and pembrolizumab. 
• Radiation therapy (Note:  Radiation therapy to a symptomatic solitary lesion or to 
the brain may be considered on an exceptional case by case basis after 
consultation with CTEP.  The patient must have clear measurable disease outside 
the radiated field.  Administration of palliative radiation therapy will be 
considered clinical progression for the purposes of determining PFS.) 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, 
the following:  measles, mumps, rubella, chicken pox, yellow fever, rabies, 

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Bacillus Chalmette–Guérin (BCG), and typhoid (oral) vaccine.  Seasonal 
influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
• Systemic glucocorticoids for any purpose other than to modulate symptoms from 
an event of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the study PI and CTEP.  
 
3.3.8 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.3.9 Women who are pregnant or breastfeeding. 
 
Note: Pregnant women are excluded from this study because anetumab ravtansine and 
pembrolizumab are agents with the potential for teratogenic or abortifacient effects.  
Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with anetumab ravtansine and pembrolizumab, 
breastfeeding should be discontinued if the mother is treated with anetumab ravtansine or 
pembrolizumab.  
 
3.3.10 HIV-positive patients who do not meet all of the following and/or are on HIV 
medications considered to be strong inhibitors or inducers of CYP3A4: 
• Undetectable HIV viral load by standard clinical assay within 6 months of 
registration 
• Willing to adhere to antiretroviral therapy that has minimal overlapping toxicity 
or pharmacokinetic interactions with protocol therapy 
• No AIDS-defining events other within the past 12 months 
• Near normal life expectancy if not for the presence of the cancer 
 
3.3.11 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 [qualitative] is 
detected) infection.  
 
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority. 
 
3.3.12 Patients who are known to have a history of or a finding of corneal epitheliopathy at pre-
study are excluded because anetumab ravtansine may worsen this condition and reduce 
vision.  
 
3.3.13 Known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin 
that has undergone potentially curative therapy, or in situ cervical cancer. 
 

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3.3.14 Receipt of transfusion of blood products (including platelets or red blood cells) or 
administration of colony stimulating factors (including granulocyte colony-stimulating 
factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF], or 
recombinant erythropoietin) within 4 weeks prior to study treatment. 
 
3.3.15 Patient with active interstitial lung disease (ILD)/pneumonitis or a prior history of 
ILD/pneumonitis requiring treatment with steroids 
 
3.3.16 Patient has received prior treatment with PD-1, PD-L1 or PD-L2 inhibitor. 
 
 
 
 

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3.4 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their 
subpopulations be included in all NIH-supported biomedical and behavioral research 
projects involving NIH-defined clinical research unless a clear and compelling rationale 
and justification establishes to the satisfaction of the funding Institute & Center (IC) 
Director that inclusion is inappropriate with respect to the health of the subjects or the 
purpose of the research.  Exclusion under other circumstances must be designated by the 
Director, NIH, upon the recommendation of an IC Director based on a compelling 
rationale and justification.  Cost is not an acceptable reason for exclusion except when 
the study would duplicate data from other sources.  Women of childbearing potential 
should not be routinely excluded from participation in clinical research.  Please see 
http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
This study will be available to all eligible patients regardless of race or ethnic group. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam.  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to Oncology Patient Enrollment Network (OPEN), Rave, or acting as a 
primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.    
 
RCR utilizes five person registration types. 
• IVR:  MD, DO, or international equivalent, 
• NPIVR:  advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD), 
• AP:  clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
(e.g., Roster Update Management System [RUMS], OPEN, Rave,), 
• Associate (A):  other clinical site staff involved in the conduct of NCI-sponsored trials, 
and 
• Associate Basic (AB):  individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
 
Documentation Required 
IV
R 
NPIVR AP A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 

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Documentation Required 
IV
R 
NPIVR AP A 
AB 
NCI Biosketch (education, training, employment, license, and 
certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
 
• Addition to a site roster, 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN, 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval, and 
• Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug shipment, or as 
the CI on the DTL must be rostered at the enrolling site with a participating organization (i.e., 
Alliance).  
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the 
RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval   
 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet for Local Context (SSW) to the CIRB using IRBManager to indicate 
their intent to open the study locally.  The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network.  Site preferences can be set at the network 
or protocol level.  Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by emailing the email address above or calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following five criteria to complete processing of the IRB/REB approval record: 
• Holds an Active CTEP status, 
• Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) 
and on at least one participating roster, 

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• If using NCI CIRB, rostered on the NCI CIRB Signatory record, 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile, and 
• Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
 
Additional requirements to obtain an approved site registration status include: 
• An active Federalwide Assurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization, and 
• Compliance with all protocol-specific requirements (PSRs). 
 
4.2.1 Downloading Regulatory Documents 
 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website.  Permission to view and download this protocol and its supporting documents 
is restricted based on person and site roster assignment.  To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a Participating 
Organization on the protocol.  
 
• Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password, 
• Click on Protocols in the upper left of your screen 
• Enter the protocol number in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand, then select LAO-MA036, and 
protocol number 10107, 
• Click on Documents, select Site Registration, and download and complete the forms 
provided.  (Note:  For sites under the CIRB initiative, IRB data will load automatically to 
the CTSU as described above.) 
 
4.2.2 Protocol Specific Requirements For 10107 Site Registration 
 
Upon site registration approval in RSS, the enrolling site may access OPEN to complete 
enrollments.  The enrolling site will select their credentialed provider treating the subject in the 
OPEN credentialing screen, and may need to answer additional questions related to treatment in 
the eligibility checklist.   
 
• A site initiation teleconference (SIV TC) with the lead site 
 
4.2.3 Requirements For Protocol # 10107 Site Registration for Sites Participating in the 
Medidata Patient Cloud ePRO to collect PRO-CTCAE Items 
 
• 
After the patient is registered to the trial via OPEN, and if the patient reads or 
understands English, and is willing to participate in electronic data collection 
using their personal smart phone or tablet (or clinic owned tablets if available), 
the site staff will then need to complete a separate registration for the patient to 

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27 
 
the Patient Cloud ePRO through iMedidata.  
 
• 
For sites participating in the ePRO pilot, site CRAs must complete training prior 
to registering to ePRO.  This training includes an eLearning module that will be 
made available in each CRA’s iMedidata screen (Tasks panel) titled “Patient 
Cloud: Registering Your Subjects”, as well as review of ePRO resource materials 
available on the CTSU website.  Training information is in Appendix D. 
 
• 
For patients who agree to participate, the pre-study visit questionnaires will not be 
available in paper form.  Therefore, site CRAs must take the ePRO training when 
a patient is identified for the study, if they have not already taken the training so 
they can perform the ePRO registration. 
 
• 
The registration to the Patient Cloud ePRO will create a unique patient 
registration code that the site staff will provide to the patient.  The patient (with 
assistance from the site staff) should be instructed to download the Patient Cloud 
ePRO app onto his/her own device (IOS, Android, phone or tablet) and use the 
unique patient registration code to create an account.  Once the patient's account 
is set up, the patient will be able to complete the submission of patient reported 
outcomes electronically for the trial.  
 
• 
For sites providing a shared institutional device for use by multiple patients on 
site, the site staff should assist the patient with access and registration to the 
Patient Cloud ePRO app and the patient can then complete the electronic data 
submission independently.  Site staff may need to assist patients with logging 
onto the device at each visit. 
 
4.2.4 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website.  
 
To access the Regulatory Submission Portal, log on to the CTSU members’ website → 
Regulatory → Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
 
4.2.5 Checking Site Registration Status 
 
You can verify your site’s registration status on the members’ side of the CTSU website.  
 
• Log on to the CTSU members’ website 
• Click on Regulatory at the top of your screen 

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28 
 
• Click on Site Registration  
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note:  The status shown only reflects institutional compliance with site registration requirements 
as outlined above.  It does not reflect compliance with protocol requirements for individuals 
participating on the protocol or the enrolling investigator’s status with the NCI or their affiliated 
networks. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and with the Lead 
Protocol Organization (LPOs) registration/randomization systems or Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment.  OPEN 
will populate the patient enrollment data in NCI’s clinical data management system, Medidata 
Rave. 
 
Requirements for OPEN access:   
 
• A valid CTEP-IAM account. 
• To perform enrollments or request slot reservations:  Be on an LPO roster, ETCTN 
Corresponding roster, or Participating Organization roster with the role of Registrar.  
Registrars must hold a minimum of an AP registration type. 
• If a DTL is required for the study, the registrar(s) must hold the OPEN Registrar task on 
the DTL for the site. 
• Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in 
OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR.  If a DTL is required for the study, the IVR or NPIVR must be 
assigned the appropriate OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
• Patient has met all eligibility criteria within the protocol stated timeframes, and  
• All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website.  
Further instructional information is in the OPEN section of the CTSU website at 

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29 
 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with the registration system in OPEN.  Prior to discussing protocol entry with the 
patient, all site staff must use the CTSU OPEN Slot Reservation System to ensure that a slot on 
the protocol is available to the patient.  Once a slot reservation confirmation is obtained, site staff 
may then proceed to enroll the patient to this study.  
 
4.3.1 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU website at 
https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which is 
available on the Theradex website: http://www.theradex.com/clinicalTechnologies/?National-
Cancer-Institute-NCI-11. This link to the Theradex website is also on the CTSU website OPEN 
tab.  For questions about the use of IWRS for slot reservations, contact the Theradex Helpdesk at 
609-619-7862 or Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 14 days.  Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  If a patient 
does not receive protocol therapy following registration, the patient’s registration on the study 
may be canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.   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 patient's malignancy. 
 
Phase 2, Group 1: Pembrolizumab Alone 
MK-3475 (Pembrolizumab) will be administered as a dose of 200 mg using a 30-minute IV 
infusion.  Infusion timing should be as close to 30 minutes as possible; however, a window of 
minus 5 minutes and plus 10 minutes is permitted (i.e., infusion time is 30 minutes: minus 5 
minutes to plus 10 minutes).  Treatment with pembrolizumab may continue for up to 24 months 
total. Refer to Section 5.1.2. 
 
Phase 1 and Phase 2, Group 2: Anetumab ravtansine and Pembrolizumab 
Pembrolizumab will be administered as described for Group 1; anetumab ravtansine will be 
administered at 6.5 mg/kg as determined by the phase 1 safety lead-in portion of the study using 

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a 60-minute IV infusion.  Infusion timing should be as close to 60 minutes as possible; however, 
a window of minus 5 minutes and plus 10 minutes is permitted (i.e., infusion time is 60 minutes: 
minus 5 minutes to plus 10 minutes). The study drugs are administered in the following order 
when give together: anetumab ravtansine first followed by pembrolizumab.  Treatment with 
anetumab ravtansine may continue for up to 12 months total. Treatment with pembrolizumab 
may continue for up to 24 months total. For patients receiving both drugs, the intravenous 
catheter must be flushed with either D5W or 0.9% sodium chloride between the two infusions.  
Pre-medication is not needed unless a patient develops an infusion reaction.  Refer to sections 
5.1.1 and 5.1.2. 
 

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Phase 1 Dose Safety Run-In Schedule 
Dose De-Escalation Schedule for Phase 1 Study 1, 2 
Dose Level 
Dose 
Anetumab ravtansine  
(mg/kg) 
 Pembrolizumab  
(mg) 
 1* 
6.5 
200 
-1 
5.5 
200 
-2 
4.5 
200 
1.    Both agents will be given every 21 days. Anetumab ravtansine will be administered prior 
to pembrolizumab. 
2.    In obese patients, anetumab ravtansine dose should be calculated considering a maximum 
weight of 100 kg 
* Starting dose level 
 
Randomized Phase 2 Dose Schedule 
Dose Schedule for Randomized Phase 2 Study 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Anetumab 
ravtansine 
None 
 
6.5 mg/kg1, 2 
IV over 1 
hour 
Days 1 
21 days 
(3 weeks) 
 
 
 
Pembrolizumab3 
None 
200 mg1 
IV over 30 
minutes after 
anetumab 
ravtansine in 
patients 
assigned to 
the 
combination 
Day 1 
1.   Doses may be modified or held as per Section 6 Dosing Delays/Dose Modifications 
2.   In obese patients, anetumab ravtansine dose should be calculated considering a maximum 
weight of 100 kg 
3.   In subjects randomized to receive the combination, anetumab ravtansine will be 
administered prior to pembrolizumab when given together. 
 
 
 

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32 
 
 
5.1.1 Anetumab Ravtansine 
 
Administer anetumab ravtansine as an IV infusion over 1 hour. Please refer to section 
8.1.1 for compatible infusion set materials including the in-line filter. 
 
No specific prophylactic medications are recommended for anetumab ravtansine.  Full 
supportive care is recommended as per community standards of medical care as 
determined by the treating physician; however, patients should not take any medications 
or substances that are strong inhibitors or inducers of CYP3A4 including herbal 
preparation containing CYP3A4 inducers (e.g. St. John’s Wort), grapefruit and grapefruit 
juice (CYP3A4 inhibitor) within 2 weeks before the start of study treatment or while on 
treatment because DM4 is a substrate of CYP3A4.  Because the lists of these agents are 
constantly changing, it is important to regularly consult a frequently-updated medical 
reference for a list of drugs to avoid or minimize use of.   
 
If a patient experiences a CTCAE Grade ≥ 2 anetumab ravtansine infusion reaction or 
other CTCAE Grade ≥ 2 hypersensitivity event deemed at least possibly related to 
anetumab ravtansine, the infusion of anetumab ravtansine will be interrupted.  If 
treatment interruption is caused by a CTCAE Grade ≥ 2 anetumab ravtansine infusion 
reaction or other CTCAE Grade ≥ 2 hypersensitivity event deemed at least possibly 
related to anetumab ravtansine, treatment may be re-started at the time determined at the 
investigator’s discretion.  Re-treatment should be at the infusion rate reduced by 50%, 
along with anti-allergic prophylaxis (e.g. anti-histamines, acetaminophen, and/or 
corticosteroids) chosen at the investigator’s discretion or according to the institutional 
guidelines.  
 
5.1.2 Pembrolizumab (MK-3475)  
 
Pembrolizumab will be administered on Day 1 of each 3-week treatment cycle after all 
procedures/assessments have been completed.  Pembrolizumab may be administered up 
to 3 days before or after the scheduled Day 1 of each cycle due to administrative reasons 
(up to 5 days after randomization is permitted). 
 
Note:  Dosing interruptions are permitted in the case of medical/surgical events or 
logistical reasons (i.e., elective surgery, unrelated medical events, patient vacation and 
holidays) not related to study therapy.  Patients should be placed back on study therapy 
within 3 weeks of the scheduled interruption.  The reason for interruption should be 
documented in the patient’s study record. 
 
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion.  
Infusion timing should be as close to 30 minutes as possible; however, a window of 
minus 5 minutes and plus 10 minutes is permitted (i.e., infusion time is 25 to 40 minutes.  
Please refer to section 8.1.2 for compatible infusion set materials including the in-line 
filter.   
 
Anetumab ravtansine will be given prior to pembrolizumab for the combination therapy 

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33 
 
when given together. 
 
No specific prophylactic medications are recommended for pembrolizumab.  Full 
supportive care is recommended as per community standards of medical care as 
determined by the treating physician. 
 
Infusion-related reactions have been reported with pembrolizumab. Infusion-related 
reactions may present as allergic reaction (hypersensitivity), serum sickness, infusion and 
infusion-like reactions, cytokine release syndrome, or anaphylaxis. Mild infusion 
reactions can generally be treated with interruption of the infusion and medical 
intervention including IV fluids, antihistamines, nonsteroidal anti-inflammatory drugs, 
acetaminophen, and narcotics as needed. More severe or life-threatening reactions may 
require vasopressors, corticosteroids, and epinephrine. If symptoms resolve within one 
hour 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 subject should be premedicated for the next scheduled dose. In 
the case of severe or life-threatening reactions, subsequent doses of pembrolizumab 
should not be administered. 
 
5.2 
Phase 1 Study 
 
Since this combination has not been studied to date, the first 6 patients treated at dose 
level 1 will be used as an early safety lead-in per Section 13.2.  If 2 or more patients 
experience a dose-limiting toxicity (DLT) as defined below, then the starting dose level 
will be adjusted and additional cohorts may be evaluated at dose levels -1 and -2 in the 
safety lead-in stage as described in section 13.1.2.  The acceptable DLT rate is 0.20. 
 
5.2.1 Definition of Dose Limiting Toxicity (DLT) 
 
The NCI-CTCAE version 5.0 will be used to assess toxicities. Dose limiting toxicities 
(DLT) will be defined as any of the following events possibly related to the study drugs 
that occur during the first 2 cycles of therapy (6 weeks): 
• Non-resolving (within 6 weeks) grade ≥ 2 corneal ulcer 
• Any grade ≥ 3 uveitis or non-resolving (within 6 weeks) grade 2 uveitis 
• Any grade ≥ 3 pneumonitis or non-resolving (within 6 weeks) grade 2 
pneumonitis 
• Any treatment-related grade 4 adverse event or non-resolving (within 6 weeks) 
treatment-related grade 3 adverse event 
• Infusion reaction or hypersensitivity to anetumab ravtansine not controlled by 
infusion rate reduction and anti-allergic prophylaxis. 
• Grade 5 toxicity 
 
The DLT period is during the first two cycles. Patients who (a) have been on treatment 
for at least 28 days and received at least 85% of the total prescribed dose of each drug 
(combined over the 2 cycles) or (b) have experienced a DLT, will be “DLT evaluable” 
and included in the dose de-escalation decisions. Non-evaluable patients will be replaced 
for DLT assessment. 

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Management and dose modifications associated with the above adverse events are 
outlined in Section 6. 
 
Note: PRO-CTCAE data should not be used for determining attribution, dose 
modifications or reporting of serious adverse events. 
 
5.3 
Phase 2 Study 
 
Patients will be randomized 1:1 to receive the safe dosing combination of anetumab 
ravtansine with pembrolizumab identified during phase 1 or pembrolizumab alone.  
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Supportive care is otherwise recommended per community standards and may include 
oral and parenteral anti-coagulation if deemed necessary by the treating physician’s 
discretion; prophylactic anti-emetics such as 5-HT3 blocks (granisetron, ondansetron); 
bisphosphonates or denosumab; analgesics; beta-blockers or digoxin. 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing trial. If there is a clinical indication for any medication or 
vaccination specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The investigator should discuss any questions regarding this 
with CTEP. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the patient's primary physician; however, the decision to continue the 
patient on trial therapy or vaccination schedule requires the mutual agreement of the 
Investigator, CTEP, and the patient. 
 
Acceptable Concomitant Medications: All treatments that the investigator considers 
necessary for a patient’s welfare may be administered at the discretion of the investigator 
in keeping with the community standards of medical care.  All concomitant medication 
will be recorded on the case report form (CRF) including all prescription, over-the-
counter (OTC), herbal supplements, and IV medications and fluids.  If changes occur 
during the trial period, documentation of drug dosage, frequency, route, and date may 
also be included on the CRF. 
 
All concomitant medications received within 30 days before the first dose of study 
treatment and 30 days after the last dose of study treatment should be recorded.  
Concomitant medications administered after 30 days after the last dose of trial treatment 
should be recorded for serious adverse events (SAEs). 
 
Prohibited concomitant medications are listed in the exclusion criteria, sections 3.31, 3.36 
and 3.37.  Patients who, in the assessment by the investigator, require the use of any of 
the aforementioned treatments for clinical management should be removed from the trial.  
Patients may receive other medications that the investigator deems to be medically 
necessary.  The study team should check a frequently- updated medical reference for a 
list of drugs to avoid or minimize use of.  Appendix B Patient Drug Information Handout 
and Wallet Card should be provided to patients.   

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There are no prohibited therapies during the post-treatment follow-up portion of the 
study. 
 
5.5 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment with anetumab 
ravtansine may continue for up to a maximum of 12 months and treatment with 
pembrolizumab (all groups) may continue for up to 24 months or until one of the 
following criteria applies: 
• Disease progression; see sections 5.7 and 5.9. 
• Intercurrent illness that prevents further administration of treatment 
• Adverse event(s) which require(s) treatment discontinuation: 
o Any dosing interruption lasting >12 weeks with the following exceptions:  
Dosing interruptions >12 weeks that occur for non-drug-related reasons 
may be allowed if approved by the Principal Investigator.  Prior to re-
initiating treatment in a patient with a dosing interruption lasting >12 
weeks, the Principal Investigator must be consulted. 
o Tumor assessments should continue as per protocol even if dosing is 
interrupted. 
• Patient decides to withdraw from the study 
• General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
• Clinical progression is defined as occurring when a patient’s condition has 
deteriorated and the patient cannot continue with study treatment per the 
investigator’s judgment regardless of imaging findings 
• Patient non-compliance 
• Pregnancy 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., 
missed or late menstrual period) at any time during study participation. 
o The investigator must immediately notify CTEP in the event of a 
confirmed pregnancy in a patient participating in the study. 
• Termination of the study by sponsor 
• The drug manufacturer can no longer provide the study agent 
• If a patient has had a confirmed complete response (CR) that have been treated for at 
least 24 weeks with pembrolizumab and has continued at least two cycles beyond 
complete response, discussion between the treating physician and investigator 
regarding discontinuation of study treatment may be considered. 
 
The reason(s) for protocol therapy discontinuation must be documented in the Case 
Report Form (CRF). 
 
5.6 
Duration of Follow Up 
 

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36 
 
Patients will be followed for 12 months after removal from study treatment or until death, 
whichever occurs first.  Patients will be followed every three months by a telephone call 
or letter to assess vital status.  Patients removed from study for unacceptable adverse 
event(s) will be followed longer if needed until resolution or stabilization of the adverse 
event. 
 
5.7 
Criteria for Removal from Study 
 
Patients will be removed from study treatment when any of the applicable criteria, 
including confirmed progressive disease as the overall objective status (Section 11.1.5.3), 
adverse events, patient withdrawal or inability to follow study protocol as listed in 
Section 5.5.  The reason for study removal and the date the patient was removed must be 
documented in the Case Report Form. 
 
If radiologic imaging shows progressive disease (PD), tumor assessment should be 
repeated by the site ≥ 4 weeks later in order to confirm PD with the option of continuing 
treatment while awaiting radiologic confirmation of progression as per section 5.9. 
 
As per section 5.6 patients will be followed for 12 months after removal from study 
treatment or until death, whichever occurs first.  Patients will be followed every three 
months by a telephone call or letter to assess vital status.  Patients removed from study 
for unacceptable adverse event(s) will be followed longer if needed until resolution or 
stabilization of the adverse event. 
 
5.8 
Criteria to Resume Treatment Following a Drug-Related Adverse Event 
 
For non-autoimmune or inflammatory events, patients may resume treatment with study 
drug when the drug-related AE(s) resolve to ≤ Grade 1 or baseline value, with the 
following exceptions: 
• Patients may resume treatment in the presence of Grade 2 fatigue.  
• Patients with baseline Grade 1 AST/ALT or total bilirubin who require dose 
delays for reasons other than a 2-grade shift in AST/ALT or total bilirubin may 
resume treatment in the presence of Grade 2 AST/ALT OR total bilirubin. 
• Patients with combined Grade 2 AST/ALT AND total bilirubin values meeting 
study parameters outlined in Section 6.1 should have treatment permanently 
discontinued. 
• Non-drug-related toxicity including hepatic, pulmonary toxicity, diarrhea, or 
colitis, must have resolved to baseline before treatment is resumed. 
• Drug-related endocrinopathies (not including drug-related adrenal insufficiency or 
hypophysitis) adequately controlled with only physiologic hormone replacement 
may resume treatment after replacement correction and clinically stable regimen. 
 
If the criteria to resume treatment are met, the patient should restart treatment no sooner 
than the next scheduled time point per protocol.  However, if the treatment is delayed 
past the next scheduled time point per protocol, the treatment should resume at the 
earliest convenient point that is within the 12 week delay period.  
 

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If treatment is delayed >12 weeks, the patient must be permanently discontinued from 
study therapy, except as specified in Section 5.5 (Duration of Therapy). 
 
Note: PRO-CTCAE data should not be used for determining treatment resumption 
following a drug-related symptomatic adverse event. 
 
5.9 
Treatment Beyond 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 
cytotoxic agents and can manifest as a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions.    The date of initial progression will be 
used for the determination of the primary endpoint of overall response rate. 
 
If radiologic imaging shows progressive disease (PD) and the patient is clinically stable, 
tumor assessment may be repeated by the site ≥ 4 weeks later in order to confirm PD with 
the option of continuing treatment per below while awaiting radiologic confirmation of 
progression.  If repeat imaging shows a reduction in the tumor burden compared to the 
initial scan demonstrating PD (i.e., PD is not confirmed), treatment may be continued as 
per treatment calendar.  If repeat imaging confirms PD, patients will be discontinued 
from study therapy.  In determining whether or not the tumor burden has increased or 
decreased, investigators should consider all target lesions as well as non-target lesions as 
defined in Section 11.1.5.1 and Section 11.1.5.2.  The decision to continue study 
treatment after the first evidence of disease progression determined by radiologic imaging 
is based on the clinical status of the patient as described in the table below.  
 
Patients may receive study treatment while waiting for confirmation of PD if they are 
clinically stable as defined by the following criteria: 
• Absence of signs and symptoms (including worsening of laboratory values) 
indicating disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention. 
 

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Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
evidence of PD 
Repeat imaging 
at ≥ 4 weeks 
to confirm PD 
Continue study 
treatment while 
awaiting 
confirmatory scan  
Repeat imaging 
at ≥ 4 weeks to 
confirm PD per 
physician 
discretion only 
Discontinue 
treatment  
Repeat scan 
confirms PD 
No additional 
imaging required 
Discontinue 
treatment  
No additional 
imaging 
required 
Discontinue 
treatment  
Repeat scan 
shows SD, PR, 
or CR 
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue study 
treatment  
No additional 
imaging 
required  
Discontinue 
treatment  
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
PRO-CTCAE Data 
PRO-CTCAE data should not be used for determining dose delays or dose modifications 
or any other protocol directed action.  
 
6.2 
Dose Modifications for Anetumab Ravtansine 
 
Dose Level 
Anetumab Ravtansine Dose 
1 
6.5 mg/kg 
-1 
5.5 mg/kg 
-2 
4.5 mg/kg 
 
 
Neutrophil count 
decreased1, 2 
Management/Next Dose  
≤ Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3 
Hold2 until < Grade 2.  Resume at one dose level lower. 
Grade 4 
Hold2 until < Grade 2.  Resume at one dose level lower. 
1.     Patients with febrile neutropenia should hold** until < grade 2 and resume at one dose level 
lower. 
2.   G-CSF and other hematopoietic growth factors may be used during the study in the 
management of acute toxicity such as febrile neutropenia when clinically indicated per 
ASCO Recommendations for Therapeutic Use of CSF (63) or at the discretion of the 
investigator; however they may not be substituted for a required dose reduction. 
3.   Patients requiring a delay of > 12 weeks should go off protocol therapy. 
 

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39 
 
 
Platelet count 
decreased1 
Management/Next Dose  
≤ Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3 
Hold2 until < Grade 2.  Resume at one dose level lower. 
Grade 4 
Hold2 until < Grade 2.  Resume at one dose level lower. 
1.   Patients with active bleeding related to drug-induced thrombocytopenia should reduce by 
one dose level. 
2.  Patients requiring a delay of > 12 weeks should go off protocol therapy. 
 
 
Non-hematologic 
toxicities 
Management/Next Dose  
≤ Grade 1 
No change in dose. 
Grade 2 
No change in dose. 
Grade 3 
Hold1 until ≤ Grade 2.  Resume at same level or at one dose level lower, 
per investigator’s discretion.2 
Grade 4 
Off protocol therapy 
1.   Patients requiring a delay of > 12 weeks should go off protocol therapy. 
2.   Patients requiring > two dose reductions should go off protocol therapy. 
 
 
Corneal 
Epitheliopathy 
Definition 
Management/Next Dose1, 2  
Grade 0 
No pathologic changes 
No change in anetumab ravtansine; 
ocular lubricants at discretion of 
investigator or ophthalmologist 
Grade 1 
Any stage of superficial punctate 
keratitis (SPK; as per the Oxford 
Schema for grading SPK from 
stage 0 to IV) 
No change in anetumab ravtansine; 
ocular lubricants; add topical 
steroids if SPK shows treatment 
emergent progression by ≥ 2 SPK 
grades 
Grade 2 
Epithelial opacities; micro-cysts, 
micro-deposits; corneal erosion; 
non-central stromal opacity 
Keep treatment dose level and 
schedule if the ophthalmological 
exam can be performed as needed; 
otherwise consider dose reduction 
by -1 dose level without dose 
schedule change at the discretion 
of investigator and 
ophthalmologist; intensive 
treatment with ocular lubricants 
enhanced with ointments; topical 
steroids; therapeutic contact lens 
may be considered at the discretion 
of investigator and ophthalmologist 

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Corneal 
Epitheliopathy 
Definition 
Management/Next Dose1, 2  
Grade 3 
Corneal ulcer without risk of acute 
rupture; Central stromal opacity 
1) Decrease dose to -1 dose level 
(or -2 dose level if event does not 
resolve to Grade ≤ 2 at the -1 dose 
level within 3 weeks)  
2) Re-start at the original dose 
level if the first Grade 3 event 
resolves to Grade ≤ 2 within 
3 weeks and does not recur 
3) If not resolved within 3 weeks 
continue at reduced -1 dose level 
(or -2 dose level); 
Intensive therapy with ointments; 
topical steroids; therapeutic contact 
lens or occlusion recommended at 
the discretion of investigator and 
ophthalmologist 
Grade 4 
Corneal ulcer more severe than 
grade 3 
Discontinue anetumab ravtansine;  
Intensive therapy with lubricants, 
ointments, topical steroids and 
antibiotics as needed; occlusion or 
therapeutic contact lens 
recommended; amniotic membrane 
transplant and other locally 
approved therapies to be 
considered at the discretion of 
investigator and ophthalmologist 
1.   Other remedial therapies for corneal epitheliopathy may be added or substituted at 
investigator's discretion or according to the institutional standards. 
2.   Treatment decisions are based on corneal morphology changes only, not on visual acuity 
changes. 
Recommended Measures in case of Eye Dryness and Ocular Hypertension 
Changes in tear production as evaluated by the Schirmer test and in intraocular pressure (IOP) 
are not expected to occur as a direct consequence of anetumab ravtansine therapy.  However, 
IOP may increase in some patients as a consequence of the therapy with topical steroid eye 
drops.  Since these drugs may be required to manage the corneal epitheliopathy syndrome, IOP 
will be monitored during this study for patients receiving topical steroid eye drops. 
 
Changes in IOP should be managed by an ophthalmologist.  The remedial therapy should be 
chosen at investigator’s discretion or according to the institutional standards; therapeutic 
measures can include modification of the type or posology of topical steroid eye drop, initiation 
of topical IOP lowering drugs and any other therapeutic options according to the local standard 
of care.  Ophthalmological monitoring should be maintained until the IOP has returned to 
normal values.  
 

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41 
 
Corneal 
Epitheliopathy 
Definition 
Management/Next Dose1, 2  
Reductions in tear production evaluated by the Schirmer test, while not being a part of the 
corneal epitheliopathy syndrome, are a risk factor for developing ocular surface disease 
including corneal epithelial defects.  Therefore, the tear production will be evaluated in this 
study to determine if changes in this parameter may be helpful to identify patients at higher risk 
of developing the corneal epitheliopathy syndrome.  Abnormal values in the Schirmer test 
should be evaluated and managed by an ophthalmologist to provide adequate protection to the 
corneal epithelium.  The remedial therapy for the treatment-emergent changes in the Schirmer’s 
test (dry eye) should be chosen at investigator’s discretion or according to the institutional 
standards.  These measures may include topical lubricants such as eye drops and ointments, 
punctual occlusion, use of therapeutic contact lenses and any other treatment approaches 
according to the local standard of care. 
 
Note: PRO-CTCAE data should not be used for determining dose delays or dose modifications. 
 
6.3 
Dose Modifications for Pembrolizumab (MK-3475) 
 
Both serious and non-serious adverse events associated with pembrolizumab may represent an 
immunologic etiology and may occur shortly after the first dose or several months after the last 
dose.  Pembrolizumab must be withheld for drug-related toxicities and severe or life-threatening 
AEs. 
Dose interruptions are permitted in the case of medical/surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation and/or 
holidays).  Patients should be placed back on study therapy within 3 weeks of the scheduled 
interruption.  The reason for interruption should be documented in the patient's study record. 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology guidelines include the use of oral or IV treatment with 
corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids.  Note that several courses of steroid tapering may be necessary 
as symptoms may worsen when the steroid dose is decreased.  For each disorder, attempts should 
be made to rule out other causes such as metastatic disease or bacterial or viral infection, which 
might require additional supportive care.  The treatment guidelines are intended to be applied 
when the investigator determines the events to be related to pembrolizumab. 
  
Note:  If after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance as outlined below. 
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of the evaluation of the event. 
 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other 
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids.  

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2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not 
≤10 mg/day within 12 weeks of the last pembrolizumab treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after 
corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
Corticosteroid and/or 
other therapies  
Monitoring and follow-up  
Pneumonitis  
Grade 2 
Withhold  
•  Administer 
corticosteroids (initial 
dose of 1 - 2 mg/kg 
prednisone or 
equivalent) followed 
by taper 
•  Add prophylactic 
antibiotics for 
opportunistic 
infections 
•  Monitor participants for 
signs and symptoms of 
pneumonitis 
•  Evaluate participants with 
suspected pneumonitis 
with radiographic imaging 
and initiate corticosteroid 
treatment 
Recurrent Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
•  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 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 
AST or ALT 
elevation or 
Increased Bilirubin 
Grade 2 a 
Withhold 
•  Administer 
corticosteroids (initial 
dose of 0.5 - 1 mg/kg 
prednisone or 
equivalent) followed 
by taper 
•  Monitor with liver 
function tests (consider 
weekly or more frequently 
until liver enzyme value 
returned to baseline or is 
stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
•  Administer 
corticosteroids (initial 
dose of 1 - 2 mg/kg 
prednisone or 

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equivalent) followed 
by taper 
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
New onset T1DM 
or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold d 
•  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 
Hypophysitis 
Grade 2 
Withhold 
•  Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated 
•  Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism 
and adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyperthyroidism  
Grade 2 
Continue 
•  Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate 
•  Monitor for signs and 
symptoms of thyroid 
disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3, 4 
Continue 
•  Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per 
standard of care 
•  Monitor for signs and 
symptoms of thyroid 
disorders 
Nephritis: 
grading according 
to increased 
creatinine or acute 
kidney injury 
Grade 2 
Withhold 
•  Administer 
corticosteroids 
(prednisone 
1 – 2 mg/kg or 
equivalent) followed 
by taper 
•  Monitor changes of renal 
function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
•  Based on severity of 
AE administer 
corticosteroids 
•  Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All Other immune-
related AEs 
Persistent Grade 2 
Withhold 
•  Based on severity of 
AE administer 
corticosteroids 
•  Ensure adequate 
evaluation to confirm 
etiology or exclude other 
causes 
Grade 3 
Withhold or 
discontinue based 
on the event e  
Recurrent Grade 3 
or Grade 4  
Permanently 
discontinue 

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a AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 - 3.0 x ULN if baseline normal; >1.5 - 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 - 10.0 x 
ULN if baseline normal; >3.0 - 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, Stevens-
Johnson Syndrome and toxic epidermal necrolysis. 
 
 
 
 
Note: PRO-CTCAE data should not be used for determining dose delays or dose modifications 
 
 
6.4 
Continuation of Therapy When One Agent is Held or Discontinued  
 
Patients who participate in the Phase 1 portion of this trial or are assigned to Treatment 
Group 2 (the combination of anetumab ravtansine and pembrolizumab) may continue to 
receive one agent if the other is held or discontinued for toxicity, and the toxicity is 
clearly attributable to the held or discontinued agent.  If the toxicity in question is 
possibly related to either agent, then both agents should be held.  These decisions may be 
discussed with the Principal Investigator. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Sections 7.2 
and 7.3) will determine whether the event requires expedited reporting via the CTEP 
Adverse Event Reporting System (CTEP-AERS) in addition to routine reporting. 
 
Clinician graded CTCAE is the AE (adverse event) safety standard.  PRO-CTCAE items are to 
complement CTCAE reporting.  Patients will respond to PRO-CTCAE items but no protocol 
directed action will be taken. The specific PRO-CTCAE items for this protocol can be found in 
Appendices C and D.   
 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPRs) 
 
7.1.1 Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Anetumab ravtansine (BAY 94-9343, NSC 791065) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 

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45 
 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  
for further clarification. Frequency is provided based on 652 patients. Below is the CAEPR for Anetumab 
ravtansine (BAY 94-9343). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
Version 2.4, November 14, 20191 
 
 Adverse Events with Possible  
 Relationship to Anetumab ravtansine (BAY 94-9343) 
 (CTCAE 5.0 Term) 
[n= 652] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
  
EYE DISORDERS 
  
 
Blurred vision 
 
 Blurred vision (Gr 2) 
 
Dry eye 
 
 Dry eye (Gr 2) 
Eye disorders - Other 
(corneal disorder)2 
 
 
 Eye disorders - Other (corneal 
disorder)2 (Gr 2) 
 
Keratitis 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Constipation 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Gastroesophageal reflux 
disease 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 2) 
 
Alkaline phosphatase increased  
  
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 2) 
 
Blood bilirubin increased 
 
  
 
Lipase increased 
 
  
 
Lymphocyte count decreased 
 
  
 
 
Neutrophil count decreased 
  
 
Platelet count decreased 
 
 Platelet count decreased (Gr 2) 
 
Weight loss 
 
  
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Muscle cramp 
 
  
 
Myalgia 
 
  

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 Adverse Events with Possible  
 Relationship to Anetumab ravtansine (BAY 94-9343) 
 (CTCAE 5.0 Term) 
[n= 652] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
  
 
Nervous system disorders - 
Other (neuropathy peripheral) 
 
 Nervous system disorders - 
Other (neuropathy peripheral) 
(Gr 2) 
 
Paresthesia 
 
  
 
Peripheral sensory neuropathy  
 Peripheral sensory neuropathy 
(Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Dyspnea 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Rash maculo-papular 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Corneal disorder includes corneal cyst, corneal deposits, corneal epithelial microcycysts, corneal 
epitheliopathy, corneal epithelium defect, corneal erosion, corneal intraepithelial microcycysts, corneal 
neovascularization, corneal opacity, and corneal verticillata. 
 
 
Adverse events reported on anetumab ravtansine (BAY 94-9343) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that anetumab ravtansine 
(BAY 94-9343) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated intravascular coagulation; Febrile 
neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Chest pain - cardiac; Palpitations; Pericardial effusion; 
Pericarditis; Sinus tachycardia; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus; Vertigo 
ENDOCRINE DISORDERS - Hypothyroidism 
EYE DISORDERS - Cataract; Eye disorders - Other (blepharitis); Eye disorders - Other (eye irritation); 
Eye disorders - Other (eye pruritus); Eye disorders - Other (keratopathy); Eye disorders - Other (macular 
degeneration); Eye disorders - Other (ocular hyperemia); Eye disorders - Other (Schirmer's test 
abnormal); Eye pain; Floaters; Photophobia; Retinal vascular disorder; Vision decreased 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Dry mouth; Dyspepsia; 
Esophagitis; Flatulence; Gastritis; Mucositis oral; Periodontal disease 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Flu like 
symptoms; Gait disturbance; General disorders and administration site conditions - Other (general 
physical health deterioration); Infusion site extravasation; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (hepatocellular injury) 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis 
INFECTIONS AND INFESTATIONS - Bronchial infection; Conjunctivitis; Sepsis; Skin infection; Thrush; 
Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Fall 
INVESTIGATIONS - Cholesterol high; Creatinine increased; Ejection fraction decreased; 
Electrocardiogram QT corrected interval prolonged; Electrocardiogram T wave abnormal; GGT increased; 
Serum amylase increased 

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47 
 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; 
Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypokalemia; Hypomagnesemia; Hyponatremia; 
Hypophosphatemia; Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Flank pain; Generalized 
muscle weakness; Joint range of motion decreased; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysesthesia; Headache; Lethargy; Movements 
involuntary; Nervous system disorders - Other (neurotoxicity); Nervous system disorders - Other 
(polyneuropathy); Neuralgia; Peripheral motor neuropathy; Tremor 
PSYCHIATRIC DISORDERS - Anxiety; Insomnia 
RENAL AND URINARY DISORDERS - Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Epistaxis; Hiccups; Hypoxia; 
Nasal congestion; Oropharyngeal pain; Pleural effusion; Pleuritic pain; Sinus disorder; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Nail changes; 
Pruritus; Rash acneiform; Urticaria 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Thromboembolic event 
 
 
Note: Anetumab ravtansine (BAY 94-9343) in combination with other agents could cause an exacerbation 
of any adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
 
 
7.1.2 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
MK-3475 (pembrolizumab, NSC 776864) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. 
Frequency is provided based on 3793 patients. Below is the CAEPR for MK-3475 (pembrolizumab). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the 
SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required. 
       Version 2.6, July 15, 20211 
 
 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
 
Anemia2 
 
 
 
 
 
Blood and lymphatic system 
disorders - Other (immune 
thrombocytopenic purpura)2 
 
 
 
Lymph node pain2 
 
 
 
CARDIAC DISORDERS 
 
 
 
 
Myocarditis2 
 
 
 
 
Pericarditis2 
 
 

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency2 
 
  
 
Endocrine disorders - Other 
(thyroiditis)2 
 
  
 
Hyperthyroidism2 
 
  
 
Hypophysitis2 
 
  
 
Hypopituitarism2 
 
  
 
Hypothyroidism2 
 
  
EYE DISORDERS 
  
 
 
Uveitis2 
  
 
 
Eye disorders - Other (Vogt-
Koyanagi-Harada syndrome) 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Colitis2 
 
  
 
Diarrhea2 
 
 Diarrhea2 (Gr 2) 
 
Mucositis oral2 
 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis2 
 
  
 
Small intestinal mucositis2 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills2 
 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever2 
 
  
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary disorders - Other 
(autoimmune hepatitis)2 
 
  
 
 
Hepatobiliary disorders - Other 
(sclerosing cholangitis) 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis2 
  
 
 
Cytokine release syndrome2 
  
 
 
Immune system disorders - Other 
(acute graft-versus-host-disease)2,3 
  
 
 
Immune system disorders - Other 
(hemophagocytic 
lymphohistiocytosis)2 
  
 
Immune system disorders - Other 
(pseudoprogression/tumor 
inflammation)2 
 
  
 
Immune system disorders - Other 
(sarcoidosis)2 
 
  
 
 
Serum sickness2 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
 Infusion related reaction 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase increased2 
 
  
 
Alkaline phosphatase increased 
 
  

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Aspartate aminotransferase increased2  
  
 
Blood bilirubin increased 
 
  
 
CPK increased 
 
  
 
 
GGT increased 
  
 
 
Serum amylase increased 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Hyponatremia 
 
  
 
 
Metabolism and nutrition 
disorders - Other (diabetic 
ketoacidosis)2 
  
 
 
Metabolism and nutrition 
disorders - Other (type 1 diabetes 
mellitus)2 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia2 
 
 Arthralgia2 (Gr 2) 
 
Arthritis2 
 
  
 
Avascular necrosis2 
 
  
 
Back pain 
 
  
 
Joint effusion2 
 
  
 
Joint range of motion decreased 
 
  
 
Musculoskeletal and connective tissue 
disorder - Other (tenosynovitis)2 
 
  
 
Myalgia2 
 
  
 
Myositis2 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Guillain-Barre syndrome2 
  
 
 
Nervous system disorders - Other 
(myasthenic syndrome)2 
  
 
 
Nervous system disorders - Other 
(neuromyopathy)2 
  
 
 
Nervous system disorders - Other 
(non-infectious encephalitis)2 
  
 
 
Nervous system disorders - Other 
(non-infectious meningitis)2 
  
 
 
Nervous system disorders - Other 
(non-infectious myelitis) 
  
 
 
Nervous system disorders - Other 
(polyneuropathy)2 
  
 
 
Paresthesia 
  
 
 
Peripheral motor neuropathy2 
  
RENAL AND URINARY DISORDERS 
  
 
 
Renal and urinary disorders - 
Other (autoimmune nephritis)2 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 Cough 
 
  
 
 Pleuritic pain2 
 
  
 
 Pneumonitis2 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Bullous dermatitis2 
 
  

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
 
 Erythema multiforme2 
  
 
Erythroderma 
 
  
 
 
Palmar-plantar erythrodysesthesia 
syndrome 
  
 
Pruritus2 
 
 Pruritus2 (Gr 2) 
 
Rash acneiform2 
 
  
 
Rash maculo-papular2 
 
 Rash maculo-papular2 (Gr 2) 
 
Skin and subcutaneous tissue disorders 
- Other (dermatitis)2 
 
  
 
Skin hypopigmentation2 
 
  
 
 
Stevens-Johnson syndrome2 
  
 
 
Toxic epidermal necrolysis 
  
 
Urticaria2 
 
  
VASCULAR DISORDERS 
  
 
 
Vasculitis2 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Immune-mediated adverse reactions have been reported in patients receiving MK-3475 (pembrolizumab).  Adverse 
events potentially related to MK-3475 (pembrolizumab) may be manifestations of immune-mediated adverse events. 
In clinical trials, most immune-mediated adverse reactions were reversible and managed with interruptions of MK-
3475 (pembrolizumab), administration of corticosteroids and supportive care. 
 
3Acute graft-versus-host disease has been observed in patients treated with MK-3475 (pembrolizumab) who 
received hematopoeitic stem cell transplants. 
 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Adverse events reported on MK-3475 (pembrolizumab) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that MK-3475 (pembrolizumab) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Disseminated intravascular coagulation; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Heart failure; Myocardial 
infarction; Pericardial effusion; Pericardial tamponade; Ventricular arrhythmia 
EYE DISORDERS - Eye pain 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Constipation; Duodenal hemorrhage; 
Dysphagia; Gastritis; Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal disorders - Other (intestinal 
obstruction); Gastrointestinal disorders - Other (intussusception); Oral pain; Rectal hemorrhage; Small intestinal 
perforation; Upper gastrointestinal hemorrhage; Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Edema limbs; Facial 
pain; Gait disturbance; General disorders and administration site conditions - Other (general physical health 
deterioration); Generalized edema; Malaise; Non-cardiac chest pain; Pain 
INVESTIGATIONS - Cholesterol high; Creatinine increased; Fibrinogen decreased; Lymphocyte count decreased; 
Neutrophil count decreased; Platelet count decreased; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; 

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Hyperkalemia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypokalemia; Hypophosphatemia; 
Metabolism and nutrition disorders - Other (failure to thrive); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Generalized muscle 
weakness; Musculoskeletal and connective tissue disorder - Other (groin pain); Pain in extremity 
NERVOUS SYSTEM DISORDERS - Aphonia; Depressed level of consciousness; Dysarthria; Edema cerebral; 
Encephalopathy; Headache; Hydrocephalus; Lethargy; Meningismus; Nervous system disorders - Other (brainstem 
herniation); Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Nephrotic syndrome; Proteinuria; Renal and 
urinary disorders - Other (hydronephrosis); Urinary incontinence; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; Hypoxia; Laryngeal 
inflammation; Pleural effusion; Pneumothorax; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Skin and subcutaneous tissue 
disorders - Other (drug eruption) 
VASCULAR DISORDERS - Hypertension; Peripheral ischemia; Thromboembolic event 
 
 
Note: MK-3475 (pembrolizumab) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
     
 
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 that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 
• 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. 
 
• PRO-CTCAE is not intended for expedited reporting, real time review or safety 
reporting. 
 
7.3 
Expedited Adverse Event Reporting 
 

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7.3.1 Rave-CTEP-AERS Integration 
 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS) 
integration enables evaluation of post-baseline AEs entered in Rave to determine whether they 
require expedited reporting, and facilitates entry in CTEP-AERS for those AEs requiring 
expedited reporting.    
 
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event form, 
which is available for entry at each treatment or reporting period, and used to collect AEs that 
start during the period or persist from the previous reporting period.  CRA will enter AEs that 
occur prior to the start of treatment on a baseline form that is not included in the Rave-CTEP-
AERS integration.  AEs that occur prior to enrollment must begin and end on the baseline 
Adverse Event form and should not be included on the standard Adverse Events form that is 
available at treatment unless there has been an increase in grade. 
 
Prior to sending AEs through the rules evaluation process, site staff should verify the following 
on the Adverse Event form in Rave: 
 
• The reporting period (course/cycle) is correct, and 
• AEs are recorded and complete (no missing fields) and the form is query-free.  
 
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules evaluation 
by completing the Expedited Reporting Evaluation form.  Both NCI and protocol-specific 
reporting rules evaluate the AEs submitted for expedited reporting.  A report is initiated in 
CTEP-AERS using information entered in Medidata Rave for AEs that meet reporting 
requirements.  The CRA completes the report by accessing CTEP-AERS via a direct link on the 
Medidata Rave Expedited Reporting Evaluation form. 
 
In the rare occurrence that Internet connectivity is lost, a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497.  Once internet connectivity is restored, the 24-hour 
notification that was phoned in must be entered immediately into CTEP-AERS using the direct 
link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the CTSU website: 
 
• Study specific documents:  Protocols > Documents > Education and Promotion, and   
• Expedited Safety Reporting Rules Evaluation user guide:  Resources > CTSU Operations 
Information > User Guides & Help Topics. 
 
NCI requirements for SAE reporting are available on the CTEP website:  
 
• NCI Guidelines for Investigators:  Adverse Event Reporting Requirements is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf. 
 

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7.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the Reporter 
and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, malignant 
and unspecified (incl cysts and polyps) - Other (Progressive Disease)” under the system 
organ class (SOC) of the same name.  Evidence that the death was a manifestation of underlying 
disease (e.g., radiological changes suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted.  
 
Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last 
Administration of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 

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NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 
7.3.4 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting 
via CTEP-AERS.  However, they still must be reported through the routine reporting 
mechanism (Section 7.4): 
 
CTCAE SOC 
Adverse Event 
CTCAE Grade at 
which the event will 
not require 
expedited reporting1 
Investigations 
Neutrophil count decreased 
≤ Grade 4 
Platelet count decreased 
≤ Grade 4 
White blood count  
≤ Grade 4 
Lymphocyte count decreased 
≤ Grade 4 
Blood and lymphatic system 
disorders 
Anemia 
≤ Grade 4 
Endocrine disorders 
Hyperthyroidism 
≤ Grade 2 
Hypothyroidism 
≤ Grade 2 
 Musculoskeletal and 
connective tissue disorders 
Chest wall pain   
≤ Grade 3 
Respiratory, thoracic and 
mediastinal disorders 
Dyspnea 
≤ Grade 3 
 
1 These exceptions only apply if the adverse event does not result in hospitalization. If the 
adverse event results in hospitalization, then the standard expedited adverse events reporting 
requirements must be followed.  

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Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(i.e., there is no untoward medical occurrence) associated with the hospitalization: 
• Hospitalizations for respite care 
• Planned hospitalizations required by the protocol 
• Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
• Hospitalization for elective procedures unrelated to the current disease and/or treatment on 
this trial 
• Hospitalization for administration of study drug or insertion of access for administration of 
study drug 
• Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in 
place before study entry 
• Hospitalization, or other serious outcomes, for signs and symptoms of progression of the 
cancer. 
 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents.  AEs are reported in a routine manner at 
scheduled times during the trial using Medidata Rave.  For this trial the Adverse Event 
CRF is used for routine AE reporting in Rave. 
 
Symptomatic Adverse Events reported by patients through PRO-CTCAE are not safety 
reporting and may be presented with other routine AE data. 
 
 
7.5 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are 
available to describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia   
(AML)  

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• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  The 
pathology report documenting the diagnosis of the secondary malignancy is required to 
be submitted for review. 
 
7.6 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy).  Second malignancies require ONLY 
routine AE reporting unless otherwise specified. 
 
7.7 
Pregnancy 
If a patient inadvertently becomes pregnant while on treatment with pembrolizumab, the 
patient will immediately be removed from the study.  The site will contact the patient at 
least monthly and document the patient’s status until the pregnancy has been completed 
or terminated.  The outcome of the pregnancy will be reported without delay and within 
24 hours if the outcome is a serious adverse experience (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn).  
The study investigator will make every effort to obtain permission to follow the outcome 
of the pregnancy and report the condition of the fetus or newborn.  If a male patient 
impregnates his female partner, the study personnel at the site must be informed 
immediately and the pregnancy reported and followed.  
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 7.1. 
 
 
8.1 
CTEP IND Agent(s) 
 
8.1.1 Anetumab ravtansine (NSC 791065) 
 
Chemical Name or Amino Acid Sequence: Immunoglobulin G1, anti-(human 
mesothelin) human monoclonal MF-T-IgG1 heavy chain, disulfide with human 
monoclonal MF-T-IgG1 gamma--chain, dimer, triamide with N2´-[4-[(3-carboxypropyl) 
dithio]-4-methyl-1-oxopentyl]-N2´-deacetylmaytasine 
 
Other Names: BAY 94-9343 
 
Classification: antibody-drug conjugate (ADC) targeting mesothelin 
 
Molecular Weight: ~150 kDa 

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CAS Registry Number: 1375258-01-7 
 
Approximate Solubility: At least 5 g/L in 10 mM histidine/130 mM glycine buffer at pH 5.5 
 
Mode of Action: Anetumab ravtansine is an ADC consisting of a fully human IgG1 
antibody directed at the mesothelin antigen and conjugated to a maytansine derivative, 
which acts as a tubulin polymerization inhibitor.  Mesothelin is a tumor differentiation 
antigen frequently overexpressed in certain tumors while showing limited expression in 
nonmalignant tissues.    
 
Description: White to off-white lyophilized cake or powder.  Clear to slightly opalescent 
solution pH 5.5 following reconstitution. 
 
How Supplied: Bayer HealthCare AG supplies and CTEP, DCTC, NCI distributes 
anetumab ravtansine as 60 mg lyophilized powder for injection.  It is packaged in 30 mL 
single use, clear glass  vials  with coated bromobutyl rubber stoppers and flip-off caps.  The 
excipients used to manufacture anetumab ravtansine include histidine, glycine, sucrose, 
polysorbate 80, hydrochloric acid, and water for injection. 
 
Preparation: Using appropriate aseptic technique, reconstitute each 60 mg vial of anetumab 
ravtansine with 11.9 mL sterile water for injection (SWFI) to yield a 5 mg/mL solution.  The 
SWFI should be directed to the glass wall of the vial and not directly to the lyophilized cake. 
Do not let the syringe needle come into contact with the lyophilized cake.  Avoid shaking. 
The reconstituted solution should be clear to slightly opalescent and free from visible 
particles.  Do not use if the reconstituted solution contains visible particles.  Anetumab 
ravtansine must be further diluted with 0.9% sodium chloride or dextrose 5% to a final 
concentration between 0.1 and 3 mg/mL prior to administration in IV infusion bags 
composed of PVC, polyethylene or polypropylene.  A slight turbidity may occur during 
dilution but does not affect the quality of the drug product.  Mix gently.  Do not shake.  
 
Storage: Store intact vials refrigerated between 2° to 8°C in the original box until use.  
Protect from sunlight. 
 
If a storage temperature excursion is identified, promptly return anetumab ravtansine to 
2°to 8°C and quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Stability studies of the intact vials are ongoing. Avoid exposure to bright light.  
Standard room illumination does not necessitate any precautions.  Administer prepared 
infusions immediately following preparation within 2 hours if stored at room 
temperature.  If the diluted solution is not used immediately, store it between 2° to 8°C 
and use within 6 hours. 
 
CAUTION: The single-use lyophilized dosage form contains no antibacterial 
preservatives.  Reconstituted vials are to be used immediately.  If not used immediately, 

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store between 2º to 8º C and discard 6 hours after reconstitution. 
 
Route of Administration: IV infusion.  
 
Method of Administration: Administer anetumab ravtansine as an IV infusion over 1 hour 
using PVC, polyurethane, polybutadiene, or polyethylene infusion sets with 0.2 to 1.2 
micron polyethersulfone in-line filter.  If the diluted solution is refrigerated, it takes 
approximately one hour for 100 mL of solution to reach room temperature.  
 
Potential Drug Interactions: The maytansinoid-derivative toxophore or DM4 (BAY 100-
6640) and its active S-methyl metabolite DM4-Me (BAY 100-6641) are mainly metabolized 
by CYP3A4 in vitro with minor contribution from CYP3A5 and 2D6.  Therefore, 
concomitant administration of strong inhibitors and inducers of CYP3A4 are prohibited 
within 2 weeks before the start of and during treatment with anetumab ravtansine. DM4 and 
DM4-Me are substrates of P-gp but not substrates for BCRP, OATP1B1, or OATP1B3 in 
vitro.  Use caution when given with potent inhibitors or inducers of P-gp. 
 
In vitro DM4 and DM4-Me do not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 
2E1. Both showed little inhibitory effect on CYP3A4 and no clinically relevant inhibition 
toward P-gp, BCRP.  
 
Both DM4 and DM4-Me are not inducers of CYP1A2 and 3A4. 
 
Both DM4 and DM4-Me are highly protein bound in vitro. 
 
Patient Care Implications: Anetumab ravtansine is expected to adversely affect male and 
female reproduction in vitro.  Women of childbearing potential and men must use adequate 
contraception during the study and for at least 6 months after the last dose of anetumab 
ravtansine.  Breast-feeding should be discontinued before start of treatment, during 
treatment, and for 8 weeks after end of treatment.   
 
 
8.1.2 Pembrolizumab (MK-3475) (NSC 776864) 
 
Other Names: SCH 900475, pembrolizumab (MK-3475) 
 
Classification: Anti-PD-1 MAb 
 
Molecular Weight: 148.9-149.5 KDa 
 
CAS Number: 1374853-91-4 
 
Mode of Action: The programmed cell death 1 (PD-1) receptor is an inhibitory receptor 
expressed by T cells.  When bound to either of its ligands, PD-L1 or PD-L2, activated 
PD-1 negatively regulates T-cell activation and effector function.  The pathway may be 
engaged by tumor cells to suppress immune control.  Pembrolizumab blocks the negative 
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between PD-1 and its ligands. 
 
Description: Pembrolizumab is a humanized MAb of the IgG4/kappa isotype. 
 
 
 How Supplied: Pembrolizumab (MK-3475) is supplied by Merck & Co., Inc. and 
distributed by the Pharmaceutical Management Branch, CTEP/DCTD/NCI. Pembrolizumab 
(MK-3475) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to 
slightly yellow solution for intravenous use. Each vial contains 100 mg of pembrolizumab 
(MK-3475) in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab 
(MK-3475) and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 
mg), and Water for Injection, USP.  
 
Preparation: Pembrolizumab solution for infusion must be diluted prior to administration.    
Do not shake the vials.  Do not use if opaque or extraneous particulate matter other than 
translucent to white proteinaceous particles is observed.  Do not use if discolored.  To 
prepare the infusion solution add the dose volume of pembrolizumab to an infusion bag 
containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.  Gently 
invert the bag 10-15 times to mix the solution.  The final concentration must be between 
1 mg/mL to 10 mg/mL. 
 
Compatible IV bag materials: PVC plasticized with DEHP, non-PVC (polyolefin), EVA, 
or PE lined polyolefin 
 
Storage: Store intact vials between 2°C - 8°C (36°F - 46°F).  Do not freeze.  Protect from 
light by storing in the original box.   If a storage temperature excursion is identified, 
promptly return pembrolizumab to between 2-8°C and quarantine the supplies. Provide a 
detailed report of the excursion (including documentation of temperature monitoring and 
duration of the excursion) to PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Refer to the package label for expiration.  
Administer prepared solutions immediately after preparation. If not administered immediately, 
prepared solutions may be stored refrigerated for up to 24 hours. Pembrolizumab (MK-3475) 
solutions may be stored at room temperature for a cumulative time of up to 6 hours. This includes 
room temperature storage of liquid drug product solution in vials, room temperature storage of 
infusion solution in the IV bag, and the duration of infusion.  
Route of Administration: IV infusion only.  Do not administer as an IV push or bolus 
injection. 
 
Method of Administration:  Infuse over approximately 30 minutes (range: 25 - 40 
minutes) using an infusion set containing a low-protein binding 0.2 to 5 µm in-line filter 
made of polyethersulfone or polysulfone.  Infusion rate should not exceed 6.7 mL/min.  A 
central line is not required; however if a patient has a central venous catheter in place, it is 
recommended that it be used for the infusion.  Do not co-administer other drugs through the 
same infusion line.  Following the infusion, flush the IV line with normal saline. 
 
Compatible infusion set materials: PVC plasticized with DEHP or DEHT, PVC and tri-
(2-ethylhexyl) trimellitate, polyethylene lined PVC, polyurethane, or polybutadiene 

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Patient Care Implications: Refer to the protocol for information on evaluation and 
management of potential immune-related adverse events. 
 
Availability: Pembrolizumab is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
Pembrolizumab is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.1.3 Agent Ordering and Agent Accountability 
 
8.1.3.1 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.    The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents.  The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form 
(FDF).  If there are several participating investigators at one institution, CTEP-
supplied investigational agents for the study should be ordered under the name of one 
lead participating investigator at that institution.  
 
Subjects must be enrolled and randomized prior to submitting the clinical drug request to PMB. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status, a “current” password, and active person registration status.  For questions 
about drug orders, transfers, returns, or accountability, call or email PMB any time.  
Refer to the PMB’s website for specific policies and guidelines related to agent 
management.   
 
8.1.3.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
 
8.1.3.3 
Investigator Brochures - The current versions of the IBs for PMB-supplied agents will 
be accessible to site investigators and research staff through the PMB Online Agent 
Order Processing (OAOP) application.  Access to OAOP requires the establishment 
of a CTEP Identity and Access Management (IAM) account and the maintenance of 
an “active” account status, a “current” password, and active person registration status.  
Questions about IB access may be directed to the PMB IB coordinator via email. 
 
 

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8.1.3.4 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP  
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/ 
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
• IB Coordinator: ibcoordinator@mail.nih.gov 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Specimen Requirements for Correlative Studies 
 
In this study, we propose several correlative studies, as detailed below.   These assays are 
specifically chosen to provide information on immunologic markers that may be 
predictive of treatment responses as well as specific information related to the mechanism 
of action of the study drugs.  Six integrated biomarker studies have been included; all 
other correlative studies will be exploratory in nature.  They are intended to be 
hypothesis-generating and will help us advance our understanding of the systemic 
immunologic environment. 
 
Submission of archived tumor tissue is mandatory if archived tissue is available from a 
prior biopsy or surgery; do not perform a biopsy solely to provide tissue for this 
correlative study.  All tumor biopsy tissue will be submitted in either slides or formalin-
fixed paraffin-embedded (FFPE) tissue blocks and will be used to produce specimens for 
an exploratory biomarker study of tissue expression of PD-L1. 
 
Serial collection of peripheral blood is also mandatory for patients participating in this 
study.  Peripheral blood will be collected at pre-study, day 1 of each cycle, cycle 1 day 8 
and cycle 3 day 8.  Peripheral blood will be used to assay the 1) pharmacokinetics of 
anetumab ravtansine; 2) presence of anti-anetumab ravtansine antibodies; 3) 
megakaryocyte potentiating factor; 4) mononuclear Phagocyte System (MPS) - Fc-
gamma-receptors (FcɣR); 5) chemokine mediators of mononuclear phagocyte system; 6) 
Bim in tumor reactive T cells TTR and 7) soluble PD-L1. 
  
Any surplus of blood, plasma, serum, DNA, cells and tissue will be banked at Mayo 
Clinic for additional studies for the patients who provide additional consent for specimen 
banking.  If consent for specimen banking was not provided by the patient, the remaining 
blocks or slides will be returned to the original institution and the remaining blood, 
plasma, serum, DNA and cells will be discarded if the patient did not provide consent for 

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banking of specimens. 
 
Summary Table for Specimen Collection 
All correlative specimens in the table below are required unless noted otherwise. 
Study and Time Point(s) 
Specimen and Quantity 
Send Specimens to: 
Baseline 
Mesothelin expression 
 
Ph 1: Pre-study (only if available); 
Ph 2: Pre-registration 
FFPE block 
OR 
5-10 X  4-5µ unstained, positively 
charged slides from archival tissue 
OR 
Fresh tissue (Ph 2 only) 
Hematogenix Laboratory 
Services (HLS) 
Tissue expression of PD-L11 (only if 
available) 
 
FFPE block 
OR 
3-5 X 4-5µ unstained, positively 
charged slides from archival tissue 
Mayo Clinic 
MPF 
4 mL whole blood in red tube top Liang Cao, NCI 
Bim in TTR 
10 mL whole blood in EDTA 
(purple top) tube 
Mayo Clinic 
sPD-L1 
Cycle 1 Day 1 
PKs3: 
• 
Pre-treatment; 
• 
end of anetumab ravtansine 
infusion2; 
• 
7 hrs post-anetumab 
ravtansine infusion2. 
Whole blood in 1 X 3 mL lavender 
top EDTA tube per time point 
AND 
Whole blood in 1 X 2.7 mL 
lavender top EDTA monovette per 
time point 
Covance 
ADA3 
Whole blood in 1 X 4 mL gold top 
SST 
Covance 
MPS-chemokine mediators 
Whole blood in 1 X 5 mL gold top 
SST processed to serum 
Bill Zamboni, UNC 
MPS-FcɣRs 
20 mL whole blood in K2 EDTA 
(purple top) tubes processed to 
PBMCs 
Bill Zamboni, UNC 
Cycle 1 Day 8 
PKs3: 
• 
Any time 
Whole blood in 1 X 3 mL lavender 
top EDTA tube per time point 
AND 
Whole blood in 1 X 2.7 mL 
lavender top EDTA monovette per 
Covance 

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Study and Time Point(s) 
Specimen and Quantity 
Send Specimens to: 
time point 
MPS-chemokine mediators 
Whole blood in 1 X 5 mL gold top 
SST processed to serum 
Bill Zamboni, UNC 
MPS- FcɣRs 
20 mL whole blood in K2 EDTA 
(purple top) tubes processed to 
PBMCs 
Bill Zamboni, UNC 
Cycle 2 Day 1 
MPF 
4 mL whole blood in red top tube Liang Cao, NCI 
Bim in TTR 
10 mL whole blood in EDTA 
(purple top) tube 
Mayo Clinic 
sPD-L1 
Cycle 3 Day 1 
MPS-chemokine mediators 
Whole blood in 1 X 5 mL gold top 
SST processed to serum 
Bill Zamboni, UNC 
MPS-FcɣRs 
20 mL whole blood in K2 EDTA 
(purple top) tubes processed to 
PBMCs 
Bill Zamboni, UNC 
ADA3 
Whole blood in 1 X 4 mL gold top 
SST 
Covance 
Cycle 3 Day 8 
MPS-chemokine mediators 
Whole blood in 1 X 5 mL gold top 
SST processed to serum 
Bill Zamboni, UNC 
MPS-FcɣRs 
20 mL whole blood in K2 EDTA 
(purple top) tubes processed to 
PBMCs 
Bill Zamboni, UNC 
Cycle 4 Day 1 
MPF 
4 mL blood in red top tube 
Liang Cao, NCI 
Bim in TTR 
10 mL whole blood in EDTA 
(purple top) tube 
Mayo Clinic 
sPD-L1 
Cycle 6 Day 1 
ADA3 
Whole blood in 1 X 4 mL gold top 
SST 
Covance 
Cycle 9 Day 1 then every 3 months through 1 year from registration then every 6 months through 
2 years from registration 
ADA3 
Whole blood in 1 X 4 mL gold top 
SST 
Covance 
1Testing for mesothelin expression should take priority over testing for PD-L1 expression. 

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2 Samples should be drawn within +/- 15 minutes of the stated time point. 
3 These may be discontinued for patients who discontinue treatment with anetumab ravtansine. 
 
9.2 
Integral Laboratory Studies 
 
9.2.1 
Mesothelin Expression 
Anetumab ravtansine is an IgG1 antibody-drug conjugate that recognizes mesothelin 
and is bound to a potent microtubule inhibitor, DM4.  Patients in Phase 2 of the study 
will be selected for participation in this clinical trial based on mesothelin expression 
by immunohistochemistry (clone SP74). 
Please refer to Hematogenix lab manual for additional instructions. 
 
9.2.1.1 
Collection of Specimen(s) 
Archival formalin fixed tumor tissue can be submitted in blocks or in freshly cut 
sections, depending on availability.  Fresh core biopsies may also be submitted if 
archival tissue is not available or sufficient for testing.  
If tissue is provided in sections, unstained slides should be provided: minimum of 5 
slides of 4-5 microns thickness.  Sections must be mounted on positively charged 
glass slides of the correct type – Super frost® Plus Micro Slides (positively charged 
microscope slides).  
Fine needle aspiration (FNA) material is not acceptable.   
 
9.2.1.2 
Handling of Specimens(s) 
For the archival specimens, storage temperatures ranges between 15°C and 25°C are 
preferred. Mesothelin stability on cut slides is not expected to exceed 7 months.  
For fresh core biopsies, if the size of the material is larger than 3 mm, please cut the 
tumor into 2 pieces to allow for formalin penetration and fixation.  Transfer the tumor 
biopsy to the container of 10% neutral-buffered formalin (NBF) as soon as possible 
(within 15 minutes) of tumor removal.  The formalin solution should be at least 10 
times the volume of the tumor specimen.  Allow the tumor biopsy to stay in formalin 
for 24 hours +/- 1 hour at 4°C.  Transfer the tumor biopsy to the vial containing 70% 
histology alcohol.  Dispose of the 10% NBF in an appropriate hazardous waste 
container at your facility.  Store the biopsy in the vial with 70% histology alcohol at 
4°C until shipping.  Please ship immediately to the analytical laboratory below for 
further processing into FFPE tumor blocks.  Do not ship specimens in formalin. 
Tumor tissue needs to be embedded within 1 week of biopsy. 
 
9.2.1.3 
Shipping of Specimen(s) 
Supplies for preparing and shipping of tissue samples should be provided by the sites.  
The central lab will provide labels for specimens, a requisition form to submit along 
with the tissue sample for mesothelin testing, and airway bills for shipping. Samples 
should be shipped as soon as they are available.   

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9.2.1.4 
Site Performing Correlative Study 
Mesothelin testing will be performed by Hematogenix. Results will be available on 
the central lab’s HematoPass portal. Results should be available within 3-5 days of 
sample receipt. 
 
9.3 
Integrated Correlative Studies 
 
9.3.1 
Anetumab Ravtansine Pharmacokinetics (PKs) 
Anetumab Ravtansine PK studies consist of three analyses: 
1. BAY 94-9343 ADC 
2. BAY 94-9343 TAB (Total Antibody) 
3. DM4 (BAY 1006640) and DM4-Me (BYA1006441) 
Refer to Covance lab manual for additional instructions. 
 
9.3.1.1 
Collection of Specimen(s) 
a. BAY 94-9343 ADC and BAY 94-9343 TAB 
Collect minimum 2.7 mL whole blood in 3 mL lavender top EDTA tubes at the 
collection time points listed in Section 9.1.  
b. DM4 (BAY 1006640) and DM4-Me (BYA1006441) 
Collect minimum 2.7 mL whole blood in 2.7 mL lavender top EDTA monovette at 
the collection time points listed in Section 9.1. 
 
9.3.1.2 
Handling of Specimens 
a. BAY 94-9343 ADC and BAY 94-9343 TAB 
Store collected blood in refrigerator until centrifugation. Centrifuge at 2000g at 
~4ºC for 10 min. Transfer plasma equally into labeled polypropylene tubes; each 
tube must contain at least 0.2 mL of plasma. Total duration time between sample 
collection at room temperature and final storage MUST NOT exceed 60 min. Store 
frozen at < -15ºC until shipping. 
b. DM4 (BAY 1006640) and DM4-Me (BYA1006441) 
Immediately centrifuge at 2000g at ~4ºC for 10 min. Transfer exactly 0.8 mL of 
plasma into labeled plasma collection tube prefilled with 0.08 mL 10% aqueous 
formic acid); thoroughly vortex. Total duration time between sample collection at 
room temperature and final storage MUST NOT exceed 30 min. Store frozen at <  
-15ºC until shipping. 
 

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9.3.1.3 
Shipping of Specimen(s) 
All samples to be stored in freezer as outlined in handling instruction and then 
batched and shipped to Covance using air bills and requisitions provided every 3 
months on dry ice according to instructions.  
 
9.3.1.4 
Site(s) Performing Correlative Study   
a. BAY 94-9343 ADC: Syrinx Bioanalytics 
b. BAY 94-9343 TAB (Total Antibody): Syrinx Bioanalytics 
c. DM4 (BAY 1006640) and DM4-Me (BYA1006441): Swiss BioQuant (SBQ), 
Switzerland  
 
9.3.2 
Anti-Anetumab Ravtansine Antibodies (ADA) 
Anetumab ADA consists of 2 studies: 
a. BAY 94-9343 ADA 
b. BAY 94-9343 nAB (neutralizing antibodies) 
Refer to Covance lab manual for additional instructions. 
 
9.3.2.1 
Collection of Specimen(s) 
 
a. BAY 94-9343 ADA 
Collect minimum 2 mL whole blood in 4 mL gold top serum separation tube at the 
collection time points listed in Section 9.1. Collection may be combined with nAB 
collection. 
b. BAY 94-9343 nAB (neutralizing antibodies) 
Collect minimum 2 mL whole blood in 4 mL gold top serum separation tube at the 
collection time points listed in Section 9.1. Collection may be combined with BAY 
94-9343 ADA collection. 
 
9.3.2.2 
Handling of Specimens(s) 
 
a. BAY 94-9343 ADA and BAY 94-9343 nAB (neutralizing antibodies) 
Total duration between blood sample collection and final storage of the serum sample 
must not exceed 120 min. Store blood samples at ambient temperature (<25°C) for 30 
minutes. Centrifuge blood samples at approx. 2000g for approx. 10 minutes at 
approx. 4°C. After centrifugation, transfer serum equally into the labeled 
polypropylene tubes. Each tube must contain at least 0.5 mL of serum. Store samples 
in an upright position until shipment at <–15°C in a temperature controlled freezer. 
 
9.3.2.3 
Shipping of Specimen(s) 
 
All samples to be stored in freezer as outlined in handling instruction and then 
batched and shipped to Covance using air bills and requisitions provided every 3 
months on dry ice according to instructions.  

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9.3.2.4 
Site(s) Performing Correlative Study 
Bayer, Germany 
 
9.3.3 
Megakaryocyte Potentiating Factor (MPF) 
 
MPF is cleaved from the amino terminus of a precursor protein that leaves mesothelin 
linked to the cell surface by glycophosphatidylinositol (65, 66).  Thus, serum MPF is 
correlated with mesothelin expression and provides a blood-based marker of 
mesothelin-positive tumor burden.  In a recently published clinical trial that tested the 
anti-mesothelin immunotoxin SS1P in patients with MPM (67), serum MPF levels 
correlated with radiographic responses.  Accordingly, it is hypothesized that serum 
MPF may correlate with radiographic responses to treatment with anetumab 
ravtansine in this clinical trial. 
In the current trial, MPF is not intended to provide clinical guidance.  Results will be 
provided at an interim point and at the end of the study when all of the samples have 
been collected to explore the associations of MPF with treatment response. 
Testing for MPF has demonstrated a sensitivity of < 10 pg/mL with an analytic range 
of 0.02-100 ng/mL.  With adjustments for 5-fold sample dilution, the test has a 
quantification range of 0.10-500 ng/mL.  The current upper reference value is 1.2 
mg/mL, with values above the reference level considered to be elevated. 
The test of MPF test was effective in mesothelioma patients with elevated MPF.   In 
mesothelioma patients, MPF was elevated in a high percentage of these patients 
(70%). Thus, statistically significant data can be obtained with as few as 20 treatment 
naïve mesothelioma patients in our study.  
Blood will be collected from patients concurrently with clinical blood draws, when 
possible, in order to minimize any discomfort. 
 
9.3.3.1 
Collection of Specimens 
A venous blood collection tube will be used to collect 4 mL of blood at pre-study, 
C2D1 and C4D1. 
 
9.3.3.2 
Handling of Specimens 
Gently invert the tube 5 times and allow a clotting time of a minimum of 30 minutes 
at room temperature.  The blood samples should be processed the same day of blood 
draw.  If the samples must be stored overnight before processing, after 30 minutes of 
coagulation at room temperature, the blood collection tube can then be stored at 4°C 
for up to 24 hrs. 
Centrifuge the tubes at 1200 RCF for 10 min in a swing-head centrifuge, or 15 min in 
a fixed angle centrifuge (balance the tube in the centrifuge).  Carefully aspirate the 
supernatant (serum) into a new centrifuge tube.  Inspect serum for turbidity.   Turbid 
samples should be centrifuged and aspirated again to remove insoluble matter. 
Aliquot each sample into two cryovials with printed labels with a sample identifier 

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and store them at -80oC. 
 
9.3.3.3 
Shipping of Specimens 
The samples should be shipped to Dr. Liang Cao at the National Cancer Institute in 
batches on dry ice.  A separate sample sheet with at least a patient identifier and a 
sample identifier for each sample should be provided via secured electronic mail.  A 
separate email with tracking information should be sent to the recipient at the time of 
shipping to ensure the receiving of the samples package on time. 
 
Shipping information is as follows: 
Liang Cao, Ph.D. 
Center for Cancer Research  
National Cancer Institute 
37 Convent Dr. MSC 4265 
Bldg 37, Rm 6040 
Bethesda, MD 20892-1906 
Phone: (301) 435-9039  
E-mail: caoli@mail.nih.gov 
 
9.3.3.4 
Site Performing Correlative Study 
Testing for MPF will be performed in Professor Cao’s laboratory at the National 
Cancer Institute. Professor Cao has developed the MPF assay and his laboratory has 
extensive expertise with it. 
 
9.3.4 
Mononuclear Phagocyte System (MPS) - Fc-gamma-receptors (FcɣR) 
MPS-FcɣRs is an integrated biomarker assay comparing the three primary FcɣRs 
(CD64, CD32, CD16) on the surface of monocytes (CD14+) from a peripheral blood 
mononuclear cell (PBMC) fraction obtained from blood.  Compared to small 
molecule drugs, nanoparticles (NPs), monoclonal antibodies (mAb) and antibody-
drug conjugates (ADC) are cleared via the cells of MPS, also called antigen 
presenting cells.  Variability in MPS function and chemokines mediators (CCL2 and 
CCL5) have been shown to predict variability in the pharmacokinetics (PK) and 
pharmacodynamics (PD) of NPs such as PEGylated liposomal doxorubicin (Doxil; 
PLD) in patients and preclinical tumor models (36).  While NPs are cleared via 
phagocytosis by MPS cells, the MPS also serves as a natural mechanism of clearance 
for antibodies and immune complexes via their FcɣR on MPS cells. Myeloid cells 
express various forms of FcɣRs (CD64, cD32, CD16) that will interact with 
monomeric or aggregated IgGs and therapeutic mAbs and ADCs. Due to the 
differences in types and affinity in FcɣRs, variations in receptor expression can lead 
to significant differences in the ability of MPS cells to clear immune complexes from 
the blood.  Preliminary data from our group shows that the expression of CD64, 
CD32 and CD16 FcɣRs on MPS cells is highly variable in healthy volunteers and 
patients with cancer.  Thus, variability in MPS FcɣRs and mediators in blood may be 
responsible for the high and clinically relevant variability in the PK and PD of mAb 
and ADC.   

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The high PK variability is clinically important for mAbs, and especially for ADCs, as 
these agents have a narrow therapeutic index.  Moreover, the combination of ADCs, 
such as anetumab ravtansine, with other mAbs and immune modulators has the high 
likelihood of causing drug-drug interactions which results in altered PK and PD of the 
ADC and mAb as both undergo clearance by the MPS.  Thus, the evaluation of 
biomarkers of the MPS, such as FcɣRs, is critically important to optimizing the 
treatment of anetumab ravtansine and other ADCs alone and in combination with 
other agents.   
The MPS-FcɣRs assay has been validated as a relative quantitative flow cytometry-
based assay using standard methods.  Data will be obtained on the flow cytometry 
instrument as mean fluorescence intensity (MFI).  Data will be converted to mean 
equivalent soluble fluorophore (MESF) and antibody bound to cell (ABC) units using 
appropriate bead-based standards.  Appropriate background and controls will be 
collected for analytical determination/compensation.  This assay has demonstrated a 
coefficient of variation of sensitivity of 0.3-1.1% using frozen PBMCs. 
It is hypothesized that mAbs and ADCs (anetumab ravtansine) are cleared via the 
FcɣRs on MPS cells and that biomarkers of MPS-FcɣRs can be used to evaluate 
patient-specific differences in PK and PD of these agents and drug-drug interactions, 
especially for regimens combining these agents with other mAbs and immune 
modulators.  We anticipate that patients with lower expression of FcɣRs will have 
slower clearance of anetumab ravtansine and increased risk of significant drug-drug 
interactions when combined with other mAbs and immune modulators. 
The MPS-FcɣRs biomarker will be used retrospectively to evaluate the mechanisms 
associated with the variability in the pharmacokinetics and pharmacodynamics of 
anetumab ravtansine and mechanisms of drug-drug interactions of anetumab.  Blood 
should be collected from patients concurrently with clinical blood draws, when 
possible, in order to minimize any discomfort. 
 
9.3.4.1 
Collection of Specimen(s) 
EDTA vacutainers will be used to collect 20 mL of whole blood at C1D1, C1D8, 
C3D1 and C3D8. 
 
9.3.4.2 
Handling of Specimens(s) 
Whole blood will be processed into PBMCs and cryo-preserved at each clinical study 
site per institutional SOP. Clinical study sites may choose to follow the SOP detailed 
in Appendix E. Whole blood should be processed to PBMCs by staff/technicians 
within 3 hours of venipuncture. Frozen PBMCs will be stored in liquid nitrogen 
(preferred) or at -80ºC.  
At the time of analysis, frozen PBMCs will be brought to 37ºC rapidly via water bath 
and culture rested overnight (~18 hours) using standard methods before undergoing 
additional sample processing for analysis by flow cytometry.  Cultured PBMCs will 
be stained with fluorescent antibodies before fixation and analysis using a flow 
cytometer.   
Note: On a case-by-case basis, it may be possible for sites unable to perform PBMC 

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isolation to make advanced arrangements to ship whole blood samples to the 
Zamboni Lab at UNC for processing. Ahead of collection, sites should contact Drs. 
Zamboni and Lucas using the information listed below for confirmation this would be 
acceptable and to ensure the lab is able to receive and process the samples. 
 
9.3.4.3 
Shipping of Specimen(s) 
Cryo-preserved PBMC samples for FcɣRs analyses should be shipped over night on 
enough dry ice to guarantee temperature for at least 36 hours to Dr. Zamboni’s 
laboratory at the University of North Carolina. Samples should only be batch 
shipped approximately every 3 months on Monday, Tuesday or Wednesday. 
Samples should NOT be shipped on Thursday, Friday, Saturday or Sunday. 
If prior arrangement has been made to ship samples to UNC for processing, whole 
blood samples (EDTA/purple-top tubes) should be shipped ambient overnight the day 
of collection to the address noted below. Samples should be shipped Monday, 
Tuesday, or Wednesday. If shipment outside of that time frame is deemed necessary, 
contact the lab ahead of time to determine if alternate arrangements can be made. 
Shipping information is as follows: 
Attn: Andrew Lucas 
Zamboni Lab at UNC 
120 Mason Farm Road 
1022A Genetic Medicine Building, CB#7361 
Chapel Hill, NC  27599 
Lab Phone: (919) 966-1622 
Please email Drs. Lucas (andrew_lucas@unc.edu) and Zamboni (zamboni@unc.edu) 
at UNC prior to shipping samples. 
 
9.3.4.4 
Site(s) Performing Correlative Study   
The MPS- FcɣRs assay will only be performed at UNC in the facility listed above. 
We plan to perform all analyses on the same cytometer.   In addition, day-to-day 
operation and potential instrument-to-instrument variability will be monitored and 
normalized using MESF calibration beads.  
 
9.3.5 
Chemokine Mediators of the MPS 
Differences in exposures of CCL2 and CCL5 chemokines can lead to significant 
variability in MPS function and the ability of MPS cells to take up mAbs and ADCs.  
The change in MPS function could then affect the PK and PD of anetumab 
ravtansine. Accordingly, the evaluation of chemokine biomarkers such as CCL2 and 
CCL5 is critically important to optimizing the treatment of anetumab ravtansine and 
other ADCs alone and in combination with other agents.   
The assay for chemokine biomarkers CCL2 and CCL5 has been validated as an 
absolute quantitative bead-based Luminex assay against a known standard curve.  
Data will be obtained on instrumentation as mean fluorescence intensity (MFI).  

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Known standard concentrations will be plotted against their determined MFI on a log-
log plot to generate the standard curve.  Patient samples will be analyzed and their 
corresponding MFI compared to the standard curve to determine unknown 
concentrations of chemokines.  
It is hypothesized that mAbs and ADCs (anetumab ravtansine) are cleared via MPS 
cells and that chemokine mediators can be used as biomarkers of the MPS and to 
evaluate patient-specific differences in PK and PD of these agents and drug-drug 
interactions, especially for regimens combining anetumab ravtansine with other mAbs 
and immune modulators.   Specifically, it is anticipated that patients with lower 
exposures of CCL2 and CCL5 chemokines will have lower MPS function, slower 
clearance of anetumab ravtansine and increased risk of significant drug-drug 
interactions when combined with other mAbs and immune modulators. 
The chemokine biomarkers will be used retrospectively to evaluate the mechanisms 
associated with the variability in the pharmacokinetics and pharmacodynamics of 
anetumab ravtansine and mechanisms of drug-drug interactions of anetumab 
ravtansine.  
 
9.3.5.1 
Collection of Specimen(s) 
Blood will be obtained by venipuncture in a 5 mL serum-separator tube (SST; gold-
top). Collected blood samples should be stored at ambient room temperature and 
upright when possible until processed. 
 
9.3.5.2 
Handling of Specimens(s) 
Whole blood will be allowed to clot, with the tube standing up-right, for at least 30 
minutes at room temperature. It will then be processed into serum via centrifugation 
at 1,500 x g for 15 minutes at 4ºC. Whole blood should be processed to serum by 
each clinical site within 3 hours after obtaining the sample from the patient. Based on 
published literature, chemokines will have begun to significantly degrade if left at 
ambient temperatures for longer than 3 hours. Sera will be aliquoted into separate 
tubes (2 mL cryo-vials) and stored at -80ºC. 
At the time of analysis, frozen plasma samples will be brought to the UNC Cytokine 
and Biomarker Core Facility in dry ice for processing.  Samples will be stored and 
processed per Core Facility methods.  Plasma samples will be diluted and analyzed 
per the manufacturer’s protocol provided with the analytical kits.  Assay results will 
be returned to Dr. Zamboni’s laboratory for analysis.  
 
9.3.5.3 
Shipping of Specimen(s) 
Frozen serum samples will batched and shipped in enough dry ice to guarantee 
temperature for at least 36 hours overnight to Dr. Zamboni’s laboratory at the 
University of North Carolina. Samples should only be batch shipped every 3 months 
on Monday, Tuesday or Wednesday.  Samples should NOT be shipped on Thursday, 
Friday, Saturday or Sunday. 
Shipping information is as follows: 
Attn: Andrew Lucas 

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Zamboni Lab at UNC 
120 Mason Farm Road 
1022A Genetic Medicine Building, CB#7361 
Chapel Hill, NC  27599 
Lab Phone: (919) 966-1622 
Please email Drs. Lucas (andrew_lucas@unc.edu) and Zamboni (zamboni@unc.edu) 
at UNC prior to shipping samples. 
 
9.3.5.4 
Site(s) Performing Correlative Study   
The CCL2 and CCL5 chemokine assay will only be performed at UNC Cytokine and 
Biomarker Core Facility.  Plasma samples will be analyzed in batches in order to 
reduce variability due to sample processing issues.  Appropriate controls and 
instrument quality control sample will also be used to address for day-to-day 
variability. 
 
9.4 
Exploratory Correlative Studies 
 
9.4.1 Bim in tumor-reactive T cells (TTR) 
In order to improve upon the use of tumor cell PD-L1 expression as a predictive 
biomarker, work has been done to identify the signaling cascade in T cells that follows 
PD-1 engagement with PD-L1 and to determine if these events are predictive of 
responses to immunotherapy.  The identification of tumor-reactive T cells (TTR) based on 
the expression of CD8, CD11a and PD-1 (61), and the use of knock-out models and 
blocking antibodies, led to the identification of Bim as a downstream signaling molecule 
of the PD-1 pathway (62).  High levels of Bim in circulating TTR cells were prognostic of 
poor survival in patients with metastatic melanoma who did not receive anti–PD-1 
therapy, and were also predictive of clinical benefit (i.e. response) in patients with 
metastatic melanoma who were treated with the PD-1 inhibitor pembrolizumab. 
Moreover, this circulating TTR cell population significantly decreased after successful 
anti–PD-1 therapy (62).  Accordingly, we hypothesize that Bim expression in TTR will 
provide a non-invasive means of predicting responses to PD-1 inhibition in 
mesothelioma. 
 
9.4.1.1 Collection of Specimen(s) 
Please draw 10 mL of peripheral blood into an EDTA tube at pre-study, C2D1 and C4D1.  
Gently invert the tube 8-10 times to mix immediately after collection. 
 
9.4.1.2 Shipping of Specimen(s) 
Blood may be shipped overnight at ambient temperature.   
Please ship specimens to the address listed below as close to collection date as possible.  
Please ship samples only Monday through Thursday, please do not ship samples Friday, 
Saturday or Sunday.   Please call or email Xin (Cindy) Liu to notify her of an impending 
shipment: 
Xin Liu 

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Mayo Clinic 
Guggenheim 406 
200 First Street SW 
Rochester, MN 55905  
Telephone: (507) 266-5004 
Email: Liu.Xin2@mayo.edu 
 
9.4.1.3 Site(s) Performing Correlative Study 
The assay for Bim in TTR will be completed in Dr. Haidong Dong’s laboratory, at the 
address above, where the assay was developed. 
 
9.4.2 Soluble PD-L1 (sPD-L1) 
Given the heterogeneity and dynamics of PD-L1 expression by tumor cells, sPD-L1 is a 
potential blood-based biomarker that can detect PD-L1 expression when a biopsy does 
not. sPD-L1 can be detected in the supernatants of many PD-L1-positive cell lines, and 
that sPD-L1 retains pro-apoptotic signaling properties to T cells (59).  sPD-L1 has been 
detected in patients with renal cell carcinoma, is associated with a more aggressive 
phenotype (59).  A preliminary study also suggests that sPD-L1 is predictive of worse 
survival in patients with metastatic melanoma. In this clinical trial, we hypothesize that 
detection of sPD-L1 will correlate with responses to treatment. 
The first assay for sPD-L1 was developed in Dr. Dong’s laboratory.  This assay detects 
sPD-L1 with a dynamic range of 0.1-10 ng/mL, is specific for PD-L1, and is reproducible 
with interplate correlation of r2=0.99. 
9.4.2.1 Collection, Handling and Shipment of Specimen(s) 
The blood drawn for Bim in TTR will suffice for measurement of sPD-L1.  No extra blood 
needs to be drawn.   
9.4.2.2 Site(s) Performing Correlative Study   
The assay for sPD-L1 will be completed in Dr. Dong’s laboratory, at the address above, 
where the assay was developed. 
9.4.3 Tissue expression of PD-L1  
PD-L1 is commonly expressed in MPM and is associated with poor survival (23). 
Although PD-L1 is thought to provide some degree of prediction for response to 
inhibition of the PD-1/PD-L1 axis, one of the early phase clinical trials for MPM has 
identified responders despite lack of detectable PD-L1 (29).  This may be due to the 
heterogeneity and dynamics of PD-L1 expression seen in other malignancies (57, 58), 
and in preliminary data also occurs in MPM.  Due to the uncertainty of the predictive 
significance of PD-L1 expression in MPM, we would like to measure PD-L1 expression 
in available archival tissue.  Our null hypothesis is that 5% or greater PD-L1 expression 
is not predictive of response to treatment.   Mayo Clinic developed the first 
immunohistochemical assay for PD-L1 (21, 24), and has since validated the use of the 
newer PD-L1 clones on archival tissue, including the companion diagnostic for 
pembrolizumab 22C3. 

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9.4.3.1 Collection of Specimen(s) 
Submission of tissue is mandatory if archived tissue is available from a prior biopsy or 
surgery; do not perform a biopsy solely to provide tissue for this correlative.  Archival 
formalin fixed material can be submitted in tumor blocks or in freshly cut sections, 
depending on availability.  Fine needle aspiration (FNA) material is not acceptable.  If 
tissue is provided in sections, unstained slides should be provided: minimum of 3 slides 
of 4-5 microns thickness.  Sections must be mounted on positively charged glass slides 
(positively charged microscope slides).  
Fresh core biopsies may also be provided if a biopsy was performed because archival 
tissue is not available or sufficient. Do not perform a biopsy solely for this correlative 
study. 
 
9.4.3.2 Handling of Specimens(s) 
For the archival specimens, storage temperatures ranges between 15°C and 25°C are 
preferred. Samples are expected to be shipped as soon as they are available. 
 
9.4.3.3 Shipping of Specimen(s) 
 
Please ship specimens to the address listed below as close to collection date as possible.  
Please ship samples only Monday through Thursday, please do not ship samples Friday, 
Saturday or Sunday.   Please call or email Xin (Cindy) Liu to notify her of an impending 
shipment. 
Xin Liu 
Mayo Clinic 
Guggenheim 406 
200 First Street SW 
Rochester, MN 55905  
Telephone: (507) 266-5004 
Email: Liu.Xin2@mayo.edu 
 
9.4.3.4 Site(s) Performing Correlative Study   
 
PD-L1 expression by tumor cells will be assessed at Mayo Clinic’s Pathology Research 
Core with the 22C3 companion diagnostic. 
 
 
9.5 
Patient-Reported Outcomes Versions of the Common Terminology Criteria for 
Adverse Events (PRO-CTCAE) Assessment 
 
9.5.1 Site Study Team Medidata Patient Cloud ePRO Training 
 
For sites participating in the ePRO pilot, at least one member of the site study team must 
successfully complete the training to use the Medidata Patient Cloud ePRO, see 
Appendix D for information about this training.  
 
 

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10. 
STUDY CALENDAR 
Tumor tissue for the mesothelin expression assay is mandatory at pre-registration to establish eligibility for Phase 2 subjects. Pre-
study evaluations are to be conducted within 14 days of registration unless stated otherwise.  An ophthalmological exam is to be 
conducted within 28 days prior to the start of protocol therapy.  Scans and x-rays must be done < 4 weeks prior to the start of therapy.  
Windows of ± 1 to 2 days are permissible for cycles 1, 2 and 3; windows of ± 3 days are permissible for cycles 4 and beyond.  In the 
event that the patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the 
next cycle of therapy. 
 
Pre-
registration  
(Phase 2 
only) 
Pre- 
study 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and 
higher 
Off  
Study k 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Anetumab ravtansine 
 
 
A 
 
 
A 
 
 
A 
 
 
A 
 
 
 
Pembrolizumab 
 
 
B 
 
 
B 
 
 
B 
 
 
B 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
 
X 
X--------------------------------------------------------------------------X 
 
Physical exam a 
 
X  
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Ophthalmologic exam b 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Performance status 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
CBC w/diff, plts 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Serum chemistry c 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
TSH, T3, T4 d 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
PT/INR, aPTT 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy e 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 

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Pre-
registration  
(Phase 2 
only) 
Pre- 
study 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and 
higher 
Off  
Study k 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Echo or MUGA f 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
 
X-------------------------------------------------------------------------X 
X 
Radiologic evaluation/ 
Tumor  
measurements 
 
X 
Radiologic evaluation and tumor measurements are performed at the end 
of cycle 3/before cycle 4 begins and every 3 cycles thereafter.  
Documentation (radiologic) must be provided for patients removed from 
study for progressive disease. 
X 
Tissue for mesothelin 
assay g 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue for PD-L1 assay h 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for PKs and 
correlative studies i 
 
X 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
 
 
PRO-CTCAE j 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
A: Anetumab Ravtansine:  For all phase 1 and phase 2 group 2 patients: Dose as determined by the phase 1 study by IV infusion 
over 60 minutes on day 1 of each cycle for up to 12 months total.  Anetumab ravtansine is to be administered prior to 
pembrolizumab. 
B: Pembrolizumab: 200 mg by IV infusion over 30 minutes on day 1 of each cycle for up to 24 months total for all groups.   
a: Physical exam at pre-study includes height/weight, vital signs, demographics and medical history.  Physical exam at all other visits 
includes weight and vital signs.  Vital signs include pulse, blood pressure and temperature. 
b:   For all patients at screening then only those randomized to receive anetumab ravtansine: Perform ophthalmologic exam within 28 
days prior to Cycle 1 Day 1. The exam will include visual acuity [BCVA according to ETDRS, or Snellen, or Landolt C or other 
charts], intra-ocular pressure, dry eye test [Schirmer test] and slit lamp.  For all subsequent cycles after Cycle 1, visual acuity and a 
slit lamp examination will be repeated before infusion in every cycle and at safety follow-up visit, or more frequently at 
investigator’s and ophthalmologist’s discretion.  The IOP measurement is to be repeated during anetumab ravtansine therapy if the 

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patient receives steroid eye drops for more than 10 days as treatment for corneal epitheliopathy.  This measurement is performed at 
2 weeks and 6 weeks after the initiation of steroid treatment.  If IOP increases by < 7 mmHg, the frequency of IOP evaluation can 
be reduced to every 4 months.  If IOP increases by ≥ 7 mmHg, a medical management plan with follow-up IOP evaluations will be 
initiated after consultation with an ophthalmologist and investigator.  The Schirmer test is performed at baseline and then at C3D1 
and C5D1.  All these tests may be repeated during treatment at the investigator’s discretion. 
 
Note: Ophthalmologic exams do not need to be continued for patients assigned to combination therapy who later discontinue 
anetumab ravtansine due to non-ocular toxicities. 
c:   Labs include albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
d:   Patients receiving pembrolizumab should be monitored for changes in thyroid function at the timepoints listed in the calendar and 
as clinically indicated for clinical signs and symptoms of thyroid disorders.  
e: Serum pregnancy test for females of childbearing potential. 
f. Echocardiogram or Multigated Acquisition Scan (MUGA; radionucleotide angiography) is performed at pre-study and then only 
as clinically indicated.  
g:   For Phase 2, submission of a tissue sample at pre-registration is required to perform the mesothelin expression assay to establish 
eligibility.  Archived tumor tissue may be submitted; if archived tumor tissue is not available to establish eligibility, a fresh tumor 
tissue sample must be obtained by biopsy. If a biopsy is required, it may be performed ≤ 28 days prior to start of therapy. For 
Phase 1 subjects, submission of archived tumor tissue, if available, is required for mesothelin expression testing. Please refer to 
Section 9. 
h: For subjects in both Phases 1 and 2, submission of a stored tissue sample is mandatory, if available, for the tissue expression of 
PD-L1: do not perform a biopsy solely to provide tissue for this correlative.  Tumor tissue may be submitted as blocks or slides; 
please refer to section 9. 

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i: Blood samples for correlatives are collected as follows (see also Section 9): 
1) Phase 1 and Phase 2 Group 2 patients only: Pharmacokinetics of anetumab ravtansine (including anetumab ravtansine 
ADC, anetumab ravtansine total antibody, and DM4/DM4-Me) on C1D1: pre-treatment, end of anetumab ravtansine 
infusion (+/- 15 minutes), and 7 hours after the end of anetumab ravtansine infusion (+/- 15 minutes); C1D8: any time. 
Note: These may be discontinued for patients who discontinue anetumab ravtansine. 
2) Phase 1 and Phase 2 Group 2 patients only: Anti-anetumab ravtansine antibodies (including anetumab ravtansine ADA 
and neutralizing antibodies) pre-dose on Day 1 of Cycles 1, 3, 6 and 9 and pre-dose every 3 months after cycle 9 in the 
first year and every 6 months in the second year of treatment. Note: These may be discontinued for patients who 
discontinue anetumab ravtansine. 
3)  Megakaryocyte Potentiating Factor: pre-study, C2D1, and C4D1.  
4)  Mononuclear Phagocyte System-FcɣR: C1D1, C1D8, C3D1 and C3D8. 
5)  Chemokine Mediators of Mononuclear Phagocyte System: C1D1, C1D8, C3D1 and C3D8. 
6) Bim in Tumor Reactive T cells and soluble PD-L1: pre-study, C2D1, and C4D1.  
 
j:   For sites and patients that agree to participate, PRO-CTCAE is completed by ePRO application on patients’ personal devices or on 
a tablet kept at the study site weekly during the first 3 cycles and at off-study. Questionnaires should be administered prior to 
treatment on days study treatment is administered. See Appendices C and D. 
k:  Off-study evaluation to be performed at 30 ± 3 days after the last dose of study drug. 

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11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
Response and progression will be evaluated in this study using modified pleural RECIST for 
pleural disease (27) and the international criteria proposed by the revised Response Evaluation 
Criteria in Solid Tumors (RECIST) guideline (version 1.1) for non-pleural disease (68).  
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
 
11.1.1 Schedule of Evaluations 
 
For the purposes of this study, patients should be re-evaluated for response every 9 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained 4-6 weeks following 
initial documentation of objective response. 
 
11.1.2 Definitions 
 
11.1.2.1 
Evaluable for Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with anetumab 
ravtansine and pembrolizumab or pembrolizumab. 
 
11.1.2.2 
Evaluable for Objective Response 
 
All patients meeting the eligibility criteria who have signed a consent form, have been 
randomized and have begun treatment will be evaluable for response.  These patients will have 
their response classified according to the definitions stated below  
 
11.1.3 Disease Parameters 
 
11.1.3.1 
Pleural Measurable Disease 
 
At baseline, the pleural disease to be measured should have a short-axis diameter of at least 1 cm 
for at minimum one of the 6 measurements, as lesions < 1 cm are considered non-measurable. 
Unidimensional measurements of tumor thickness perpendicular to the chest wall or 
mediastinum should be performed, measured in 2 sites (or positions) at 3 separate levels on 
transverse cuts of contrast-enhanced CT scan (or MRI).  The sum of the measurements which 
meet the definition of measurable disease defines a pleural unidimensional measure: sum of up to 
6 pleural thickness measurements = 1 univariate diameter.  Transverse cuts used for 
measurements must be at least 1 cm apart and related to anatomical landmarks in the thorax as 
determined by the reviewer during baseline assessment by means of appropriate markers these 
cuts are chosen to allow reproducible assessment at later time points.  If measureable tumor is 
present, transverse cuts in the upper thorax, above the level of division of the main bronchi are 

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preferred.  At reassessment, pleural thickness must be measured at the same position at the same 
level and by the same observer, whenever possible.  This is not necessarily the greatest tumor 
thickness at that level. 
 
Tumor lesions that are situated in a previously irradiated area might or might not be considered 
measurable.  If there is demonstrable progression following radiation, then a previously 
irradiated lesion may be included as measurable.  
 
 
11.1.3.2 
Extra-Pleural Measurable Disease 
 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) by chest x-ray or as ≥10 mm 
(≥1 cm) with CT scan, MRI, or calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
11.1.3.3 
Malignant Lymph Nodes 
  
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm (≥ 1.5 
cm) in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm [0.5 cm]).  At baseline and in follow-up, only the short axis will be measured 
and followed. 
 
11.1.3.4 
Non-Measurable Disease 
 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm [< 1 
cm] or pathological lymph nodes with ≥ 10 to < 15 mm [≥ 1 to < 1.5 cm] short axis), are 
considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
11.1.3.5 
Target Lesions 
 
All measurable lesions including the sum of the pleural thickness measurements and up to a 
maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, 
should be identified as target lesions and recorded and measured at baseline.  Target lesions 
should be selected on the basis of their size (lesions with the longest diameter), be representative 

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of all involved organs, but in addition should be those that lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short axis is 
added into the sum.  The baseline sum diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the disease. 
 
11.1.3.6 
Non-Target Lesions 
 
Any other lesions (or sites of disease) beyond the target lesions should be identified as non-
target lesions and should also be recorded at baseline.  Measurements of these lesions are not 
required, but the presence, absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
 
11.1.4 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  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. 
 
11.1.4.1 
Clinical Lesions   
 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes) and ≥10 mm (≥1 cm) 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.  
 
11.1.4.2 
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.  
 
11.1.4.3 
Conventional CT and MRI   
 
This guideline has defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is 5 mm (0.5 cm) or less.  If CT scans have slice thickness greater than 5 mm (0.5 
cm), the minimum size for a measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (e.g. for body scans).   

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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. 
 
11.1.4.4 
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.   
 
11.1.4.5 
Ultrasound   
 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement.  Ultrasound examinations cannot be reproduced in their entirety for independent 
review at a later date and, because they are operator dependent, it cannot be guaranteed that the 
same technique and measurements will be taken from one assessment to the next.  If new lesions 
are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised.  If 
there is concern about radiation exposure at CT, MRI may be used instead of CT in selected 
instances. 
 
11.1.4.6 
Endoscopy, Laparoscopy   
 
The utilization of these techniques for objective tumor evaluation is not advised.  However, such 
techniques may be useful to confirm complete pathological response when biopsies are obtained 
or to determine relapse in trials where recurrence following complete response (CR) or surgical 
resection is an endpoint. 
 
11.1.4.7 
Tumor Markers   
 
Tumor markers alone cannot be used to assess response.   
 

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11.1.4.8 
Cytology, Histology   
 
These techniques can be used to differentiate between partial responses (PR) and complete 
responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
11.1.4.9 
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. 
 
11.1.4.10 Measurement at Follow-up Evaluation 
 
A subsequent scan must be obtained at least 4 weeks (within 8 weeks but not less than 4 weeks 
apart) following initial documentation of an objective status of either complete response (CR), 
partial response (PR), or preliminary progression (PD) for confirmation. 
 
11.1.5 Response Criteria 
 

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11.1.5.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm (<1 cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm (0.5 cm).  (Note:  the appearance of one or more new lesions is 
also considered progressions). 
 
Due to the natural evolution of MPM, an isolated new pleural or pericardial effusion should be 
only considered as a new lesion and thus calling for PD in case it is substantial, cytological 
malignancy is confirmed and the patient had not had any pleural or pericardial effusion history 
before treatment. However, any isolated new or significant increases in existing pleural or 
pericardial effusions in a stable or responding patient, without any other evidence of progression, 
is insufficient evidence to call progression. 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
11.1.5.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 

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11.1.5.3 
Evaluation of  Overall Objective Status 
 
The overall objective status for an evaluation is determined by combining the patient’s status on 
target lesions, non-target lesions, new lesions, and previous objective status as defined in the 
following tables: 
 
For Patients with Measurable Disease  
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Previous Overall 
Objective Status 
–Preliminary PD  
Overall Objective Status 
CR 
CR 
No 
N/A 
CR 
CR 
Non-CR/ 
Non-PD 
Not Evaluated 
No 
N/A  
PR 
PR 
Non-CR/ 
Non-PD/ 
Not evaluated 
No 
N/A  
PR 
SD 
Non-CR/ 
Non-PD/ 
Not evaluated 
No 
N/A  
SD  
 
PD 
Any 
Yes or No 
No 
Preliminary PD 
PD 
Any 
Yes or No 
Yes 
PD (Confirmed) 
Any 
Unequivocal 
PD  
Yes or No 
No 
Preliminary PD 
Any 
Unequivocal 
PD 
Yes or No 
Yes 
PD (Confirmed) 
Any 
Any 
Yes 
No 
Preliminary PD 
Any 
Any 
Yes 
Yes 
PD (Confirmed) 
Not All 
Evaluated 
CR 
Non-CR/ 
Non-PD 
Not evaluated 
No 
N/A 
Not Evaluated (NE) 
 
For Patients with Non-Measurable Disease  
 
Non-Target Lesions 
New Lesions 
Previous Overall 
Objective Status – 
Overall Objective 
Status 

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Preliminary PD 
CR 
No 
N/A 
CR 
Non-CR/Non-PD 
No 
N/A 
Non-CR/ 
Non-PD 
Not all evaluated 
No 
N/A 
Not evaluated 
Unequivocal PD 
Yes or No 
No 
Preliminary PD 
Unequivocal PD 
Yes or No 
Yes 
PD (Confirmed) 
Any 
Yes 
No 
Preliminary PD 
Any 
Yes 
Yes 
PD (Confirmed) 
 
Preliminary Progressive Disease (PD) 
All of the following must be true: 
a. Progressive Disease defined in Section 11.5.1 and 11.5.2 in the target lesions and non-
target lesions, or appearance of new lesions. 
b. No substantial clinical decline. 
 
Confirmed Progressive Disease (PD)  
Patients without substantial clinical decline who meet all the following would have confirmed 
PD as their overall object status:  
a. Previously considered Preliminary PD.  
b. Repeating imaging at least 4 weeks apart after initial imaging shows progressive disease.  
 
Confirmed complete response (CR) or partial response (PR) 
A subsequent scan must be obtained at least 4 weeks (within 8 weeks but not less than 4 weeks 
apart) following initial documentation of an objective status of either complete response (CR), 
partial response (PR), or preliminary progression (PD) for confirmation. 
 
Symptomatic Deterioration: Patients with global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that time, and 
not either related to study treatment or other medical conditions, should be reported as PD 
(confirmed) due to “symptomatic deterioration.” Every effort should be made to document the 
objective progression even after discontinuation of treatment due to symptomatic deterioration. 
A patient is classified as having PD (confirmed) due to “symptomatic deterioration” if any of the 
following occur that are not either related to study treatment or other medical conditions:  
• Weight loss >10% of body weight.  
• Worsening of tumor-related symptoms.  
• Decline in performance status of >1 level on ECOG scale 
 

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11.1.6 Duration of Response 
 
Duration of Overall Response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
progressive disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
 
Duration of Stable Disease:  Stable disease is measured from the start of the treatment until the 
first date that progressive disease is objectively documented taking as reference the smallest 
measurements recorded since the treatment started, including the baseline measurements.  
 
11.1.7 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment until the first date that progressive 
disease is objectively documented or death from any cause, whichever occurs first. 
 
11.1.8 Response Review 
 
For trials where the response rate is the primary endpoint, it is strongly recommended that all 
responses be reviewed by an expert(s) independent of the study at the study’s completion.  
Simultaneous review of the patients’ files and radiological images is the best approach. For this 
trial, review by the local investigator will be sufficient. 
 
 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
For the phase 1 portion of this study, the Protocol Principal Investigator will have at least 
monthly, or more frequently, conference calls with the Study Investigators and the CTEP 
Medical Officer(s) to review accrual, progress, and adverse events and unanticipated problems.   

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During the randomized phase 2 portion of the study, the Protocol Principal Investigator will 
have, at a minimum, quarterly conference calls with the Study Investigators and the CTEP 
Medical Officer(s) to review accrual, progress, and pharmacovigilance.   
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
12.2 
Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  To access Rave via iMedidata: 
 
• 
Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM 
account, and  
• 
Assigned one of the following Rave roles on the relevant Lead Protocol Organization 
(LPO) or Participating Organization roster at the enrolling site:  Rave CRA, Rave Read 
Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
o To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must hold a 
minimum of an AP registration type, 
o To hold Rave Investigator role, the individual must be registered as an NPIVR or 
IVR, and 
o To hold Rave Read Only role, site staff must hold an Associates (A) registration 
type. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata.  To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, and 
click on the accept link in the upper right-corner of the iMedidata page.  Site staff will not be 
able to access the study in Rave until all required Medidata and study specific trainings are 
completed.  Trainings will be in the form of electronic learnings (eLearnings), and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen.  If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under the study name 
in iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name.  

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Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account.  Account activation instructions are located on the CTSU 
website in the Rave section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance).  Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.  
 
12.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted three times annually (one annual site visit and two data audits).  For 
CTMS monitored studies, after users have activated their accounts, please contact the Theradex 
Help Desk at (609) 619-7862 or by email at CTMSSupport@theradex.com for additional support 
with Rave and completion of CRFs. 
 
For ePRO-CTCAE data, once a patient electronically submits the responses, the data is 
transmitted from the device into the Rave database.  There are no documents to audit.  The 
electronic responses are the source documentation. 
 
PRO-CTCAE is not intended for expedited reporting, real time review or safety reporting. PRO-
CTCAE data are exploratory and not currently intended for use in data safety monitoring or 
adverse event stopping rules.  
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks.  The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS.  Metrics for timeliness will be followed and assessed on a quarterly basis.  
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received.  Queries will be issued by CTMS directly within Rave.  The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  Monthly web-
based reports are posted for review by the Drug Monitors in the IDB, CTEP.  Onsite audits will 

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be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm)  and 
CTSU websites. 
 
An End of Study CRF is to be completed by the PI and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the recommended 
phase 2 dose (RP2D), and a description of any dose-limiting toxicities (DLTs).  CTMS will 
utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository (caDSR) 
compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and-
semantics/metadata-and-models).  Customized eCRFs will be included when appropriate to meet 
unique study requirements.  The PI is encouraged to review the eCRFs, working closely with 
CTMS to ensure prospectively that all required items are appropriately captured in the eCRFs 
prior to study activation.  CTMS will prepare the eCRFs with built-in edit checks to the extent 
possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex on a monthly 
basis.  The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
 
12.3 
Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data Management.  The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries.  DQP Queries, DQP Delinquent Forms, and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, and 
timeliness reports.  Review the DQP modules on a regular basis to manage specified 
queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website.  Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 

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Home, DQP Queries, and DQP Delinquent Forms modules. 
 
Note:  Some Rave protocols may not have delinquent form details or reports specified on the 
DQP.  A protocol must have the Calendar functionality implemented in Rave by the Lead 
Protocol Organization (LPO) for delinquent form details and reports to be available on the 
DQP.  Site staff should contact the LPO Data Manager for their protocol regarding questions 
about Rave Calendaring functionality. 
12.4 
CTEP Multicenter Guidelines 
 
Not applicable 
 
12.5 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators.  The protocol documents for studies 
utilizing Agents contain confidential information and should not be shared or distributed 
without the permission of the NCI.  If a copy of this protocol is requested by a patient or 
patient’s family member participating on the study, the individual should sign a 
confidentiality agreement.  A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to 
and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NCI, 
the design of the proposed combination protocol, and the existence of any 
obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 

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other Collaborator to develop, obtain regulatory approval or commercialize its 
own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as described 
in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  Additionally, 
all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable 
Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is 
a DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by 
the Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication.  Collaborator(s) will have 30 days from 
the date of receipt for review.  Collaborator shall have the right to request that publication 
be delayed for up to an additional 30 days in order to ensure that Collaborator’s 
confidential and proprietary data, in addition to Collaborator(s)’s intellectual property 
rights, are protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) 
days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings.  Press releases and other media presentations must also be 
forwarded to CTEP prior to release.  Copies of any manuscript, abstract and/or press 
release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 

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12.6 
Genomic Data Sharing Plan 
 
Not applicable 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
13.1.1 Overview       
This is a phase 1 safety run-in and randomized phase 2 study designed to evaluate the 
safety and efficacy of the addition of anetumab ravtansine to pembrolizumab for patients 
with mesothelin positive malignant pleural mesothelioma.  The study will utilize a 
randomized phase 2 study design to determine the anti-tumor activity of combination 
therapy with anetumab ravtansine and pembrolizumab (Group 2; experimental group) as 
compared to pembrolizumab alone (Group 1; control group), where response will be 
evaluated based on the modified pleural RECIST for pleural disease. 
 
13.1.2 Primary Endpoint  
 
The primary endpoint of the phase 1 safety run-in is the randomized phase 2 dose of 
anetumab ravtansine with combination of pembrolizumab.  
 
The primary endpoint of the randomized phase 2 is the confirmed tumor response rate, 
which will be compared between the two groups.  A confirmed tumor response rate 
defined as 100% times the number of eligible patients who have started the treatment and 
whose objective tumor status was a CR or PR on 2 consecutive evaluations at least 
4 weeks apart (using RECIST v1.1 criteria) divided by the number of eligible patients 
who have started the treatment.  All patients meeting the eligibility criteria who have 
signed a consent form, have been randomized and have begun treatment will be evaluable 
for overall response.  
 
13.1.3 Statistical Design 
 
13.1.3.1 
Phase 1 Safety Run-In 
A phase 1 safety run-in will be performed after the first 6 patients have been accrued 
to the safety lead-in portion of the study at dose level 1 and observed for one cycle.  If 
2 or more of the first 6 patients experience a DLT as defined in Section 5.2.1, then the 
starting dose level will be adjusted and additional cohorts may be evaluated at dose 
levels -1 and -2 as described below.  Accrual will be halted while evaluating each 
cohort in the safety lead-in analysis.  
 

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• Dose level 1: Six evaluable patients will be accrued onto dose level 1 and 
observed until they complete two cycles of treatment.  If  0 or 1 out of 6 patients 
experience a DLT, accrual will continue in the phase 2 portion at dose level 1 
after the expansion cohort per Section 13.2.2.  If 2 or more patients experience a 
DLT on dose level 1, the toxicity level for dose level 1 will be considered 
unacceptable and six additional patients will be treated on dose level -1.  
 
• Dose de-escalation to dose level -1: If dose level 1 has an unacceptable level of 
toxicity, six evaluable patients will be accrued onto dose level -1.  If 0 or 1 out of 
6 patients experience a DLT on dose level -1, accrual will continue in the phase 2 
portion at dose level -1 after the expansion cohort per Section 13.2.2.  If 2 or more 
patients experience a DLT, the toxicity level for dose level -1 will be considered 
unacceptable and six additional patients will be treated on dose level -2.  
 
• Dose escalation to dose level -2: If dose level -1 has an unacceptable level of 
toxicity, six evaluable patients will be accrued onto dose level -2.  If 0 or 1 out of 
6 patients experience a DLT on dose level -2, accrual will continue in the phase 2 
portion at dose level -2 after the expansion cohort per Section 13.2.2.  If 2 or more 
patients experience a DLT, the toxicity level for dose level -2 will be considered 
unacceptable and accrual to the study will be temporarily closed, evaluated and 
potentially amended. 
 
The simulations below demonstrate the chance of the design to select a dose with an acceptable 
probability of DLT of 0.2.  
 
 
Dose Level 
 
 
 
1 (6.5 mg/kg) 
-1 (5.5 mg/kg) 
-2 (4.5 mg/kg) 
No selection % 
Ave # of pts 
True DLT rate 
0.2 
0.1 
0.05 
 
 
Select % 
68 
30 
2 
0 
8.04 
# pts treated 
6 
1.92 
0.12 
 
 
True DLT rate 
0.4 
0.2 
0.1 
 
 
Select % 
31 
49 
18 
2 
11.34 
# pts treated 
6 
4.14 
1.20 
 
 
True DLT rate 
0.5 
0.4 
0.2 
 
 
Select % 
14 
19 
43 
24 
15.18 
# pts treated 
6 
5.16 
4.02 
 
 
 
 
13.1.3.2 
Expansion Cohort 
Once the final dose level is determined, an additional 6 patients will be enrolled to the 
final dose level to ensure safety.  If 2 or less out of the 12 patients experience a DLT, 
this dose level will be determined as the safe dose for the randomized phase 2 study. 
If 3 or more than 3 patients experience a DLT, this dose level will considered 
unacceptable and accrual to the study will be temporarily closed, evaluated and 
potentially amended. With a maximum of 12 patients at the randomized phase 2 dose, 
the probability of observing at least one grade 3 or higher AE is 86% when the true 

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rate of such AE is 15% for the combination arm.  
 
13.1.3.3 
Randomized Phase 2 Study 
Decision Rule: A randomized phase 2 trial comparing combination therapy with 
anetumab ravtansine and pembrolizumab as compared to pembrolizumab alone will 
be conducted, once a safe combination of doses is identified.  We will enter 49 
evaluable patients on each arm (98 total) of the study using a 1:1 randomization 
scheme utilizing the permutated block procedure, where patients are stratified based 
on ECOG performance score (0 vs. 1).  A sample size of 49 patients per arm provides 
80% power to detect an improvement in response rate from 20% to 40%, using a one-
sided test at a significance level of 0.10.  The baseline response rate of 20% is based 
on a prior study73. In addition, this trial implements a group sequential design with a 
single interim analysis, adopting the Rho family (Rho=2) beta spending function for 
controlling the overall type II error rates. The interim and final analysis boundaries 
and characteristics were generated using the East 6 clinical trial software program 
(version 6.4, Cytel Inc.). 
 
The Z-score will be calculated for testing the null hypothesis that the difference of 
response rates between two arms is equal to zero, based on the normal approximation 
with pooled variance of standardized test statistics.  The study design will be 
implemented as follows: 
 
Interim Analysis Decision Rule: An interim analysis will be performed for futility.  
After the first 25 patients randomized into each arm (the first 50 patients in both arm) 
become evaluable for the primary endpoint, if the z-score is less than -0.072, we will 
terminate accrual and consider this early evidence that the experimental arm does not 
have a higher overall response rate and accrual will be terminated.   Otherwise, we 
will continue accrual.  
 
Final Decision Rule: If the interim analysis criteria are met for full accrual, a total of 
49 evaluable patients per arm will be enrolled into this study.  At the final analysis, it 
will be concluded that the experimental arm (combination therapy) is superior to the 
control arm (pembrolizumab alone), if the z-score is greater than 1.282.  This will be 
considered sufficient evidence that the experimental arm may be recommended for 
further testing in subsequent studies.  Otherwise, we will conclude that there is no 
statistical evidence of superiority of the experimental regimen (combination therapy). 
 
Over Accrual: If more than the target number of patients are accrued, the additional 
patients will not be used to evaluate the stopping rule or used in any decision making 
process however, they will be included in final point estimates and confidence 
intervals.   
 

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NOTE:  The trial will not be halted while the first 25 patients in each group are 
evaluated for the interim analysis.  However, if the accrual is especially rapid, we 
may temporarily suspend accrual to prevent missing important acute toxicity 
patterns. 
 
Other Considerations: Toxicity, quality/duration of response, and patterns of 
treatment failure observed in this study, as well as scientific discoveries or changes in 
standard care will be taken into account in any decision to terminate the study. 
 
Power and Significance Level: Assuming that the response rate is binomially 
distributed in each group, the operating characteristics of the current design can be 
tabulated according to various true difference of the proportions, including the 
probabilities of the experimental arm (combination therapy) is superior to control arm 
(pembrolizumab alone), i.e. power which warrants further studies on experimental 
regimen, and probabilities of stopping the trial early due to futility of the 
experimental regimen. 
 
If the true difference of 
proportion is  
-0.1 
0 
0.1 
0.2 
0.3 
Then the probability of declaring 
that the experimental regimen 
warrants further studies is…  
0.004 
0.009 
0.424 
0.805 
0.970 
*Probability of stopping at the 
interim analysis due to futility 
is…  
0.805 
0.458 
0.183 
0.051 
0.009 
*Probabilities are based on simulation study with 50,000 replicates 
 
 
13.2 
Analysis Plan  
The analysis for this trial will commence at planned time points and at the time the 
patients have become evaluable for the primary endpoint.  Such a decision will be made 
by the Statistician and Study Chair, in accord with ETCTN Standard Operating 
Procedures, availability of data for secondary endpoints (e.g. laboratory correlates), and 
the level of data maturity.   
 
 
13.2.1 
Phase1 Safety Run-in Primary Analysis 
All patients that have received any amount of the combination anetumab ravtansine and 
pembrolizumab will be evaluable for toxicity. Please note this is different from the 
definition of evaluable for dose-limiting toxicity (DLT) where patients who cannot 
complete the planned dose due to reasons other than toxicity will be replaced. 
 
13.2.2 
Randomized Phase 2 Primary Endpoint Estimation  
The proportion of successes will be estimated in each group by the number of successes 

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divided by the total number of evaluable patients.   Confidence intervals for the true 
success proportion will be calculated in each arm.   Comparison of confirmed response 
rates between the two treatment groups will be performed using a one-sided z-test with 
pooled variance at significance level 0.10.   
 
13.3 
Sample Size/Accrual Rate 
 
13.3.1 Sample Size 
The phase 1 safety lead-in is expected to require a minimum of 12 patients and a 
maximum of 24 patients. The randomized phase 2 portion of this study is expected to 
require a minimum of 50 and a maximum of 98 evaluable patients. We anticipate 
accruing an additional 12 patients during the phase II portion of the trial to account for 
ineligibility, cancellation, major treatment violation, or other reasons. Therefore, the 
phase II portion is expected to accrue a maximum of 110 patients and overall sample size 
will be a maximum of 134 patients.  
 
13.3.2 Accrual Rate and Study Duration 
The anticipated accrual rate is approximately 4-5 patients per month.  Therefore, the 
accrual period for phase 2 portion is expected to be about 34 months.  The final analysis 
can begin approximately 39.5 months after the phase 2 portion begins, i.e. as soon as the 
final patient randomized to this trial has been followed for at least 18 weeks.  
 
13.3.3 Inclusion of Women and Minorities 
This study will be available to all eligible patients, regardless of race, gender or ethnic 
origin. 
 
There is no information currently available regarding differential effects of this regimen 
in subsets defined by race or gender, and there is no reason to expect such differences to 
exist.  Therefore, although the planned analysis will, as always, look for differences in 
treatment effect based on racial and gender groupings, the sample size is not increased in 
order to provide additional power for subset analyses. 
 
Based on prior studies involving similar disease sites, we expect about 20-25% of 
patients will be classified as minorities by race and about 40% of patients will be women. 
The expected sizes of racial by gender subsets are shown in the following table: 
 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ 
Alaska Native 
1 
2 
0 
0 
3 

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Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
Asian 
1 
1 
0 
0 
2 
Native Hawaiian or 
Other Pacific Islander 
0 
1 
0 
0 
1 
Black or African 
American 
1 
3 
0 
0 
4 
White 
36 
51 
7 
10 
104 
More Than One Race 
3 
6 
4 
7 
20 
Total 
42 
64 
11 
17 
134 
 
 
13.4 
Stratification Factors 
 
13.4.1 For the randomized phase 2: ECOG performance score: 0 vs. 1  
 
13.5 
Analysis of Secondary Endpoints 
 
13.5.1 Duration of Response 
Duration of response is defined for all evaluable patients who have achieved a response 
as the date at which the patient’s objective status is first noted to be a PR or CR to the 
earliest date progression is objectively documented.  If a patient has not had disease 
progression, they will be censored on the date of their last disease assessment.  The 
distribution of duration of response will be estimated using the method of Kaplan-Meier.  
The comparison of duration of response between two treatment arms will be based on the 
log-rank test. This calculation will start with the date of start of treatment. 
 
13.5.2 Overall Survival 
Overall survival is defined as the time from the start of treatment to death due to any 
cause. The distribution of survival time will be estimated using the method of Kaplan-
Meier. The comparison of overall survival between two treatment arms will be based on 
the log-rank test.   
 
13.5.3 Progression Free Survival 
Progression free survival is defined as the start of treatment to the earliest date that 

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disease progression is objectively documented or death due to any cause.  The 
distribution of progression-free survival will be estimated using the method of Kaplan-
Meier.  The comparison of progression-free survival between two treatment arms will be 
based on the log-rank test.   
 
   
13.5.4 Adverse Events 
All eligible patients that have initiated treatment will be considered evaluable for 
assessing adverse event rate(s).  The maximum grade for each type of adverse event will 
be recorded for each patient, and frequency tables will be reviewed for each arm to 
determine patterns.  Additionally, the relationship of the adverse event(s) to the study 
treatment will be taken into consideration.  The overall adverse event rates for Grade 3 or 
higher hematologic and non-hematologic adverse events at least possibly related to 
treatment will be compared between the two treatment groups using the Chi-square test 
(or Fisher’s exact test if the data in the contingency table is sparse). 
 
13.5.5 The Pharmacokinetics of Anetumab ravtansine 
The analysis of the pharmacokinetics of anetumab ravtansine (including anti-drug 
conjugate (ADC) anetumab ravtansine, total antibody, DM4 (BAY 1006640) and DM4-
Me (BAY 1006641)) will be largely descriptive.  Changes over time will be plotted and 
assessed for each patient. 
 
13.5.6 Megakaryocyte Potentiating Factor (MPF) 
 
The test for MPF is quantitative and continuously distributed.  A reference value will 
be provided and samples with tumor antigen MPF levels above the reference value 
will be considered positive.  The relative changes in biomarker levels will be 
compared by best overall response groups using the non-parametric Wilcoxon rank-
sum test.  Also, the associations between changes in MPF levels and ordered response 
categories (i.e. CR-PR-SD-PD) will be assessed with the Jonckheere-Terpstra test for 
trend. 
 
13.5.7 MPS-FcɣRs and chemokine mediators of MPS 
 
The mean equivalent soluble fluorophore (MESF) and antibody bound to cell (ABC) 
will be determined for each specimen.  Linear regression will be used to explore the 
linear relationship between the continuous values of these MPS-FcɣRs probes and 
anetumab ravtansine levels. 
 
The concentrations of CCL2 and CCL5 will be determined for each specimen.  Linear 
regression will be used to explore the linear relationship between the continuous 
values of these chemokines and anetumab ravtansine levels. 
 
 

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13.6 
Analysis of Exploratory Endpoints 
 
13.6.1 Measurements of Bim in TTR as a predictor of responses to treatment. 
 
Based on previous experiences with the distribution of Bim in TTR, it is anticipated that a 
non-parametric test such as the Mann-Whitney test should be used to compare Bim in 
TTR between subjects that do and do not respond to therapy. 
 
13.6.2 Measurements of soluble PD-L1 as a predictor of responses to treatment. 
 
Based on previous experiences with the distribution of sPD-L1, it is anticipated that a 
non-parametric test such as the Mann-Whitney test should be used to compare sPD-L1 
between subjects that do and do not respond to therapy. 
 
 
13.6.3 PD-L1 expression in archival tissue as a predictive marker of response to 
pembrolizumab-based therapy. 
 
We will compare whether there is a difference in the number of responders with 50% or 
greater PD-L1 tumor cell expression and those without with the Chi-square test (or 
Fisher’s exact test if the data in the contingency table is sparse). 
 
13.6.4 PRO-CTCAE 
Protocol investigators should provide appropriate analysis of the data and account for 
missing data. 
 
 
13.7 
Data and Safety Monitoring 
 
13.7.1 
DSMB Review 
 
The principal investigator and the study statistician will review the study at least every 
quarter to identify accrual, adverse event, and any endpoint problems that might be 
developing.  The accrual and safety data provided by Theradex for this trial will be 
reviewed and monitored by the Mayo Clinic Cancer Center (MCCC) Data Safety 
Monitoring Board (DSMB) at least twice a year, or more frequently as warranted. 
 
13.7.2 
PRO-CTCAE 
PRO-CTCAE data should not be used in adverse event stopping rules. 
 
 
13.7.3 Phase 2 Adverse Event Stopping Rule 
 
The stopping rule applies to each group independently. 
 

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The stopping rule specified below is based on the knowledge available at study 
development.  We note that the rule may be adjusted in the event of either (1) the study 
re-opening to accrual or (2) at any time during the conduct of the trial and in 
consideration of newly acquired information regarding the adverse event profile of the 
treatments under investigation.  The study team may choose to suspend accrual because 
of unexpected adverse event profiles that have not crossed the specified rule below. 
 
Accrual will be temporarily suspended to both groups if at any time we observe events 
considered at least possibly related to study treatment (i.e., an adverse event with 
attribute specified as “possible,” “probable,” or “definite”) that satisfy either of the 
following: 
 
• if 4 or more patients in the first 20 treated patients in either group experience a 
grade 4 or higher non-hematologic adverse event at least possibly related to 
treatment. 
 
• if after the first 20 patients have been treated, 25% of all patients in either 
group experience a grade 4 or higher non-hematologic adverse event at least 
possibly related to treatment. 
 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence of a 
previously unrecognized treatment-related adverse event. 
 
After consideration by the Principal Investigator and the statisticians and consultation 
with CTEP and CIRB, a decision will be made as to whether and how the study will 
proceed. 
 
 
13.8 
Reporting and Exclusions 
 
13.8.1 PRO-CTCAE 
Refer to Appendices C and D for PRO-CTCAE references. 
 
13.8.2 Evaluation of Response 
 
All patients 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 patient will 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).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those 

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who received no study medication) should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific.  
 
All conclusions should be based on all eligible patients.  Sub analyses may then be 
performed on the basis of a subset of patients, 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 sub 
analyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.  The 95% confidence intervals should also be provided.  
 
 
 
 

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MD:  Article: e1356146 | Received 03 May 2017, Accepted 07 Jul 2017, Accepted author 
version posted online: 27 Jul 2017, Published online: 27 Jul 2017 
 
73. http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30169-9/fulltext as a   
reference by Alley et al in Lancet Oncology  
 

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

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APPENDIX B: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, anetumab ravtansine and pembrolizumab. This clinical trial is 
sponsored by the National Cancer Institute.  This form is addressed to the patient, but includes 
important information for others who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
  
Anetumab ravtansine interacts with specific enzymes in the liver and certain transport proteins 
that help move drugs in and out of cells. 
 
• The enzymes in question are CYP3A4/5 and 2D6.  Anetumab ravtansine is broken down 
by these enzymes and may be affected by other drugs that inhibit or induce these 
enzymes.  Strong inhibitors and inducers of CYP3A4 are prohibited within 2 weeks of 
the start of and during treatment with anetumab ravtansine. 
• The protein in question is P-gp.  Anetumab ravtansine is moved in and out of cells/organs 
by this transport protein. 
• Anetumab ravtansine is highly protein bound.  Patients receiving other medications that 
are also highly protein bound may need to be monitored more frequently. 
 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
Anetumab ravtansine and pembrolizumab may interact with other drugs which can cause side 
effects.  For this reason, it is very important to tell your study doctors of any medicines you are 
taking before you enroll onto this clinical trial.  It is also very important to tell your doctors if 
you stop taking any regular medicines, or if you start taking a new medicine while you take part 
in this study.  When you talk about your current medications with your doctors, include medicine 
you buy without a prescription (over-the-counter remedy), or any herbal supplements such as St. 
John’s Wort.  It is helpful to bring your medication bottles or an updated medication list with 
you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  
 
These are the things that you and they need to know:  
 
Anetumab ravtansine must be used very carefully with other medicines that use certain liver 
enzymes or transport proteins to be effective or to be cleared from your system.  Before you 

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enroll onto the clinical trial, your study doctor will work with your regular health care providers 
to review any medicines and herbal supplements that are considered strong inducers/inhibitors 
of CYP3A4/5, 2D6 or P-gp. 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  
• You may need to be monitored more frequently if you are receiving other medications that 
are also highly protein bound. 
• Do not eat or drink grapefruit juice, grapefruit, or Seville oranges while taking anetumab 
ravtansine. 
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  Your study doctor’s name is  
 
_____________________________________ and he or she can be contacted at  
 
_____________________________________. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study  
drug anetumab ravtansine.  This clinical trial is sponsored by the NCI.  
Anetumab ravtansine may interact with drugs that are processed by 
your liver or use certain transport proteins in your body.  Because of 
this, it is very important to: 
➢ Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
➢ Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
➢ You may need to be monitored more frequently if you are 
receiving other medications that are also highly protein bound. 
 
 
 
 
➢ Do not eat or drink grapefruit juice, grapefruit, or Seville oranges 
while taking anetumab ravtansine. 
Anetumab ravtansine interacts with specific liver enzyme called 
CYP3A4/5,2D6 and transport protein P-gp and must be used very 
carefully with other medicines that interact with these enzymes or 
transporter.  
➢ Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines  and herbal supplements that are considered strong 
inducers/inhibitors of CYP3A4/5, 2D6 or transporter P-gp.  
➢ Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for 
a list of drugs to avoid, or contact your study doctor.   
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  

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APPENDIX C: PRO-CTCAE QUESTIONNAIRE 
 
PRO-CTCAE is intended to enhance the quality of adverse event data reporting in clinical trials, 
provide data that complements and extends the information provided by clinician reporting using 
CTCAE, represent the patient perspective of the experience of symptomatic adverse events, and 
improve detection of potentially serious adverse events.   
 
The selection of PRO-CTCAE should be complementary to the clinician identified AEs for 
ongoing monitoring.  
 
Adverse Events Specific to Protocol 10107 / MC1721: 
System/ 
 Organ/ 
Class 
Anetumab 
ravtansine 
Adverse Event 
term from IB 
Pembrolizumab 
(MK-3475)  
Adverse Event 
term from 
CAEPR 
Possible 
Related 
PRO-
CTCAE 
Items 
Attributes 
Eye Disorders 
Corneal 
toxicity 
syndrome 
 
Blurred 
vision 
Severity, 
Interference 
Gastrointestinal 
Disorders  
Diarrhea 
Diarrhea 
Diarrhea 
Frequency 
Nausea 
Nausea 
Nausea 
Frequency, 
Severity 
Vomiting 
 
Vomiting 
Frequency,  
Severity 
General Disorders 
Fatigue 
Fatigue 
Fatigue 
Severity, 
Interference 
Metabolism and 
Nutrition Disorders 
Decreased 
appetite 
 
Decreased 
appetite 
Severity, 
Interference 
Musculoskeletal 
Disorders 
 
Arthralgia 
Joint pain 
Frequency, 
Severity, 
Interference 
Nervous System 
Disorders 
Neuropathy 
peripheral 
 
Numbness 
and tingling 
Severity, 
Interference 
Skin and 
Subcutaneous 
Tissue Disorders 
 
Pruritus 
Itching 
Severity 
 
Rash  
maculopapular 
Rash 
Present/Absent 
 
Please refer to the PRO-CTCAE Terms of Use website at 
https://healthcaredelivery.cancer.gov/pro-ctcae/terms_of_use.html for more information.  
 
References  
• PRO-CTCAE Website: https://healthcaredelivery.cancer.gov/pro-ctcae/  
• PRO-CTCAE Items Library  

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• PRO-CTCAE NCI Scientific Leadership Team  
• PRO-CTCAE Development Team  
• Publications  
 
Study Specific PRO-CTCAE Questionnaire: All subjects on the study will receive the same 
PRO-CTCAE questions as listed below. For this study, questions will be administered via 
ePRO and thus will be formatted for electronic delivery.  
 
NCI PRO-CTCAE ™ ITEMS 
Item Library Version 1.0 
English 
Form Created on 15 December 2020 
As individuals go through treatment for their cancer they sometimes experience different 
symptoms and side effects. For each question, please select the one response that best 
describes your experiences over the past 7 days… 
1a.  In the last 7 days, what was the SEVERITY of your DECREASED APPETITE at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
1b.  In the last 7 days, how much did DECREASED APPETITE INTERFERE with your usual or 
daily activities? 
Ο Not at all 
ΟA little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
2a.  In the last 7 days, how OFTEN did you have NAUSEA? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
2b.  In the last 7 days, what was the SEVERITY of your NAUSEA at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
 
3a.  In the last 7 days, how OFTEN did you have VOMITING? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
3b.  In the last 7 days, what was the SEVERITY of your VOMITING at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
 
4a.  In the last 7 days, how OFTEN did you have LOOSE OR WATERY STOOLS 
(DIARRHEA/DIARRHOEA)? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
 

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5a.  In the last 7 days, did you have any RASH? 
Ο Yes 
Ο No 
 
6a.  In the last 7 days, what was the SEVERITY of your ITCHY SKIN at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
 
The PRO-CTCAE™ items and information herein were developed by the Division of Cancer Control and 
Population Sciences in the NATIONAL CANCER INSTITUTE at the NATIONAL INSTITUTES OF HEALTH, in 
Bethesda, Maryland, U.S.A. Use of the PRO- CTCAE™ is subject to NCI’s Terms of Use. 
 
7a.  In the last 7 days, what was the SEVERITY of your NUMBNESS OR TINGLING IN YOUR 
HANDS OR FEET at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
7b.  In the last 7 days, how much did NUMBNESS OR TINGLING IN YOUR HANDS OR FEET 
INTERFERE with your usual or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
8a.  In the last 7 days, what was the SEVERITY of your BLURRY VISION at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
8b.  In the last 7 days, how much did BLURRY VISION INTERFERE with your usual or daily 
activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
9a.  In the last 7 days, how OFTEN did you have ACHING JOINTS (SUCH AS ELBOWS, KNEES, 
SHOULDERS)? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
9b.  In the last 7 days, what was the SEVERITY of your ACHING JOINTS (SUCH AS ELBOWS, 
KNEES, SHOULDERS) at their WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
9c.  In the last 7 days, how much did ACHING JOINTS (SUCH AS ELBOWS, KNEES, SHOULDERS) 
INTERFERE with your usual or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
10a.  In the last 7 days, what was the SEVERITY of your FATIGUE, TIREDNESS, OR LACK OF 
ENERGY at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
10b.  In the last 7 days, how much did FATIGUE, TIREDNESS, OR LACK OF ENERGY INTERFERE 
with your usual or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
The PRO-CTCAE™ items and information herein were developed by the Division of Cancer Control and 

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Population Sciences in the NATIONAL CANCER INSTITUTE at the NATIONAL INSTITUTES OF HEALTH, in 
Bethesda, Maryland, U.S.A. Use of the PRO- CTCAE™ is subject to NCI’s Terms of Use. 
 
OTHER SYMPTOMS 
Do you have any other symptoms that you wish to report? 
Ο Yes 
Ο No 
Please list any other symptoms: 
1. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
O None 
O Mild 
O 
Moderate 
O Severe 
O Very 
Severe 
2. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
O None 
O Mild 
O 
Moderate 
O Severe 
O Very 
Severe 
3. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
O None 
O Mild 
O 
Moderate 
O Severe 
O Very 
Severe 
4. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
O None 
O Mild 
O 
Moderate 
O Severe 
O Very 
Severe 
5. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
O None 
O Mild 
O 
Moderate 
O Severe 
O Very 
Severe 
 
The PRO-CTCAE™ items and information herein were developed by the Division of Cancer Control and 
Population Sciences in the NATIONAL CANCER INSTITUTE at the NATIONAL INSTITUTES OF HEALTH, in 
Bethesda, Maryland, U.S.A. Use of the PRO- CTCAE™ is subject to NCI’s Terms of Use. 

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APPENDIX D: MEDIDATA RAVE ePRO INFORMATION 
 
Optional Electronic Completion of PRO-CTCAE Assessments  
 
Missing data are a significant problem, particularly for PRO-CTCAE assessments. Unlike data 
for traditional endpoints, such as survival, PRO-CTCAE data cannot be accurately obtained 
retrospectively if it is not provided by the patient at the appropriate time point.  This limits 
researchers’ ability to accurately perform PRO-CTCAE statistical analyses and negatively 
impacts the clinical relevance of this effort.   
 
Typically, PRO-CTCAE forms are filled out in hardcopy (paper). To provide a more convenient 
method of completing PRO-CTCAE assessments, NCI, Theradex and the CTSU are working 
with Medidata Rave’s ePRO Cloud product that offers patients on this study the option of 
completing their PRO-CTCAEs questionnaires electronically using an application (app) 
downloaded to their smart phone or from a tablet that has the ePRO app with Internet access.   
 
ePRO Operational Information for Protocol Appendices (06/27/2017) 
 
1.  
Introduction 
 
Electronic collection of patient-reported outcomes (ePRO) through Medidata Patient Cloud 
ePRO is preferred but not mandatory.  Patients who will be submitting PRO data via Patient 
Cloud ePRO must be registered to Patient Cloud ePRO by an authorized site user after the 
patient has been registered to the study.  Patients may use their own device or a tablet maintained 
at the site.  
 
A site-specific tablet may be used for multiple study participants.  If a site-specific tablet is used, 
CRAs need to setup the tablet for multiple users.  Multi-user mode lets multiple study 
participants log in to Patient Cloud ePRO with their passwords or their PIN codes on the same 
device.  Section 4 provides instruction on setting the Patient Cloud ePRO App to Multi-User 
Mode. 
 
2. 
CRA Site Users 
 
Site users of Patient Cloud ePRO require the same access as Rave.  Access to the trial in the 
Patient Cloud ePRO is granted through the iMedidata.  Site users will receive an invitation to 
Patient Cloud ePRO and the site user must accept the invitation to begin patient registration.  
Users who have not previously activated their iMedidata/Rave account at the time of initial 
approval of site registration will also receive a separate invitation from iMedidata to activate 
their account.  Account activation instructions are located on the CTSU website, Rave tab under 
the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance).  
Please note, site users will not be able to access the study in the Patient Cloud ePRO until all 
required Rave and study specific trainings are completed. 
 
Additional information on iMedidata/Rave is available on the CTSU members’ website under the 

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Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or 
by e-mail at ctsucontact@westat.com.   
 
3.  
CRA Patient Registration Instructions for ePRO 
 
Please visit the Medidata Learning Tool for reference information on Patient Cloud ePRO for 
CRAs. https://learn.mdsol.com/patient-cloud/en/video-library-for-providers-102101952.html  
 
i. 
The subject registration process starts in iMedidata.  Begin by selecting the Patient Cloud 
ePRO Registration link for your study 
ii. 
The patient management app will display, select your STUDY and SITE from the drop 
downs and click Launch. 
iii. 
Now you can register your first patient.  Create a subject ID and select a Country / 
Language from the drop down, (these are the only required data fields).  The subject 
initials are optional, but are helpful in identifying which subject ID maps with which 
activation code.  When finished, click Add. 
iv. 
The subject added and will include the date the patient was added, the subject ID, subject 
initials, (if included) and a unique auto-generated activation code.  The activation code is 
unique for each patient and linked to the subject ID, it is not interchangeable.  In addition, 
there is a status section, which indicates if the patient has registered.  When the patient 
has registered the status will change from "invited" to "registered". 
 
4. 
CRA Instructions for Setting the Patient Cloud ePRO App to Multi-User Mode 
 
Sites conducting studies entirely on premise, where participants travel to the sites to fill out 
questionnaires, can use multi-user mode.  Multi-user mode lets multiple study participants log in 
to Patient Cloud with their passwords or their PIN codes on the same device.  If patients will be 
using devices supplied by the institution, site staff will need to help the patient to access the 
device if the device is locked. 
 
The study provider will download the Patient Cloud ePRO app to the device and set the Patient 
Cloud ePRO App to multi-user mode if applicable. 
 
 To switch from personal mode (default setting) to multi-user mode: 
1.     Tap About at the bottom of the log in screen. 
2.     Scroll to the bottom and tap Advanced User. 
3.     Tap Mode and then select Multi-User. 
4.     Tap Yes to confirm. 
5.     Tap the back arrows to return to the log in screen. 
 
Note: If enabling multi-user mode on a device, it is highly recommended that completion 
reminders are turned off on that device. For a video demonstration, see Show Me How to Switch 
to Multi-User Mode. 
 
 

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5. 
Patient Users 
 
To use the Patient Cloud ePRO, patients will need to use their own device (IOS, Android phone 
or tablet).  Short term data will only appear on the patient’s device until responses are completed 
and submitted.  The patient data will import directly into the database once the patient selects the 
“Submit” button and will no longer be visible on the patient's device.    
 
 
6. 
Patient Instructions for Accessing the Patient Cloud Using Your Personal Device 
 
Downloading the Patient Cloud ePRO App 
 
If you are using your personal device, and you do not have the Patient Cloud ePRO app, use the 
following instructions.  When downloading the app, you must use the Apple ID or Google 
account associated with the device.  If the Patient Cloud ePRO app is already on the device, or if 
you are using a provider's device, you can skip this section. 
 
You will need an email address that you agree to use for this purpose.  The e-mail address is 
needed to identify you on the Patient Cloud Application and for you to receive notifications to let 
you know when forms are due.  Your e-mail address will only be used for this survey study, and 
will not be used for mail or marketing purposes. 
 
If you decide to use the electronic method to complete the questionnaires, and do not have an e-
mail address, you may sign up for one at no charge at many different websites.  A few sites that 
are commonly used and will allow you to create an email address very easily are Yahoo, Gmail, 
and Outlook. 
 
For iOS: 
1. An Apple ID is required for downloading the Patient Cloud ePRO app. 
2. Tap the App Store icon. 
3. Search for Medidata Patient Cloud and follow the installation instructions. 
 
Note: Patient Cloud ePRO is listed as an iPhone App in the App store. When using an iPad, 
please view the search results under iPhone apps. 
   
For Android: 
1.  A Google account is required for downloading the Patient Cloud ePRO app 
2.  Tap the Play Store icon. 
3.  Search for Medidata Patient Cloud and follow the installation instructions. 
 
Registering 
 
You must register in order to complete and submit your study forms.  When you register, you 
will create a username, which is your email address, and a password that allows you to log in to 
the Patient Cloud ePRO app. 
 

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Note: You must have an activation code to begin this process.  If you do not have an activation 
code, please contact your provider.  
 
There are two possible ways to register.  Your provider may have sent you a link to a web 
address where you may register from any web browser, including the one on your device.  The 
other way to register is on the Patient Cloud ePRO app. 
 
1. 
If registering from the Patient Cloud app, tap Register on the bottom of the log in page. If 
registering on the web, open the URL shield.imedidata.com on a web browser. 
2. 
Enter your activation code and tap Activate. 
3. 
On the next page, read the instructions and tap Next. 
4. 
Read the privacy notice and tap I agree. Then tap OK to confirm. 
5. 
Enter and confirm your email address. Tap Next. 
6. 
Enter and confirm your password. Tap Next. 
7. 
Choose a security question by scrolling through the dropdown menu to display the question 
of your choice. 
8. 
Enter your security question response. 
9. 
Tap Create my account to complete your registration.  
 
If you registered on the Patient Cloud ePRO app, it automatically logs you out.  If you registered 
on the web, you are presented with the option to download the Patient Cloud ePRO app.  You 
can then proceed to log in with the credentials you created. 
 
Logging in to the App 
 
1. Enter your Email and Password that you created during the registration process. (If you 
previously set a PIN code, just enter your four-digit PIN.) 
2. Tap Log in. 
 
Note: If you do not remember your password, tap Forgot Password, and follow the 
instructions provided 
 
 
Setting a PIN Code 
 
The first time you log in to the Patient Cloud ePRO app, you are given the option to create a PIN 
code.  A PIN code allows you to bypass the step of entering your email and password every time 
you need to log in to the Patient Cloud ePRO app.  Instead, you can enter a four-digit PIN. 
 
1. If you wish to set a PIN code the first time you log in, tap Yes when prompted. 
2. Note: You can also set your PIN at a later time by tapping the options menu on the top left 
of most pages and selecting Set PIN. 
3. Enter a four-digit PIN. 
4. Re-enter the four-digit PIN to confirm. 
 

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If you forget your PIN code, tap Forgot PIN and you can access the app using your email and 
password.  You may reset your PIN by tapping the options menu on the top left of most pages 
and selecting Set PIN. 
 
 
Resetting Your Password 
You can reset your password by using the options menu at the top left of most pages. 
1. Tap the options menu icon. 
2. Tap Reset Password. 
3. Follow the instructions to reset your password. 
 
 
Completing and Submitting Forms 
 
Once logged in, forms related to your study display on the Tasks page.  If you are enrolled in 
multiple studies, select the appropriate study first, and then select a form.  New forms can appear 
on the Tasks page at any time, depending on how the study is designed. 
 
There are two types of forms displayed on the Task List page: 
• Scheduled Forms (with a 
 icon): These forms have a "Due Date" indicator in them so you 
are aware of the last day by which you will need to complete the form.  If the form is due in 
less than one day, you will see the due time in hours. 
• Anytime Forms (with a 
 icon): These forms have "Last Completed Time" indicator on 
them which tells the most recent date or time when you completed the form.  If you start a 
form, but do not complete it, you will see an 'Incomplete" status beneath the form name, 
along with a half-moon icon.  
 
1. Select the appropriate form.  
2. Follow the on-screen instructions until you reach the end of the form where you are given 
the opportunity to review and change your responses prior to submitting. 
3. Review your responses by scrolling down the list. 
4. If you need to change an answer, tap the question to go back and change the answer. 
5. When you are ready to submit, tap Submit Your Data. 
 
Note: Once a form is submitted, you will be unable to edit any of your responses.  In some cases, 
you may be asked to acknowledge your submission by entering your password.  
 
 
7.  
Patient Compliance 
 
The patient data imports directly from a device into the Rave database.  There are no documents 
to audit.  The patient-submitted electronic responses are the source documentation. 
 
 

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NCI Protocol #: 10107 
Local Protocol #: MC1721 
NCI Version Date: October 25, 2021 
 
123 
 
APPENDIX E: SOP for Cryo-preservation of PBMCs for Quantification of FcγRs & 
PBMC PK Studies 
 
Collection of Specimen(s): Blood samples (20 mL) will be obtained using K2 EDTA (purple- 
top) tubes. These whole blood samples will be processed to PBMCs to measure the number of 
FcɣRs on the surface of MPS cells (CD14+ monocytes and DCs) and pharmacokinetic exposure 
of anetumab ravtansine in PBMC. In brief, whole blood will be processed to PBMCs using 
density- gradient centrifugation, then aliquoted into 4 separate cryo-vials (~5 million cells in 
each cryo-vial) and stored under cryo-preservation. If fewer cells are collected that cannot meet 
the ~5 million cells per tube, tubes should be aliquoted as to create as many 5 million cell vials 
as possible (e.g., three vials with 5 million cells and one with 2 million cells; or two vials with 5 
million cells and one with 3 million cells, etc.) A more thorough description of the PBMC 
processing is detailed below: 
 
1. Prepare LeucoSep tube 
a. Warm-up Ficoll medium to room temperature (RT) protected from light. 
b. Fill the Leucosep tube with Ficoll medium using the syringe and needle: 15 ml 
when using tubes 227 290. 
c. Close the LeucoSep tubes containing the separation medium with the screw-cap 
and centrifuge for 30 seconds at 1000 x g at RT. 
2. Prepare Wash Media (all under aseptic technique) 
a. Warm/thaw 100 mL FBS-HI, and 5 mL of antibiotic concentrate (e.g. Gibco 
Pen/Strep/Glutamine 100x) in a 37ºC water bath. 
b. Transfer all thawed reagents and 500 mL RPMI media (no phenol red) container 
into the hood using ethanol. RPMI media can be cold for the purposes of cryo- 
preservation. 
c. Remove and discard 105 mL of RPMI media from the bottle. 
d. Add 100 mL of FBS-HI and 5mL of antibiotic concentrate to the media bottle. 
Mix thoroughly. 
e. Bring final RPMI/20%FBS/(+)Abx media bottle to 4°C. This can also be 
aliquoted frozen at -20°C for longer term storage, then thawed as needed. 
3. Prepare Freezing Media (all under aseptic technique) 
a. In a 15 mL conical tube, add 9 mL of the cold Wash media (RPMI/FBS/Abx 
media) prepared earlier under aseptic technique. 
b. Slowly add 1 mL of DMSO to the tube and mix thoroughly. 
c. Store RPMI/FBS/Abx/DMSO media on ice or at 4°C until used. 
4. PBMC Specimen Processing 
a. Pour 20 mL of DPBS into the previously prepared LeucoSep tubes. 
b. Pour the anticoagulated blood sample (~20mL K2 EDTA; thus a 2:1 dilution) 
directly from the vacutainer into the LeucoSep tube. The sample volume should 
be 
c. ~40 mL in this example. 
d. Place the screw cap on the LeucoSep tube and invert gently 3-4x to mix the blood 
sample. 
e. Centrifuge for 15 minutes at 800 x g at RT in a swinging bucket rotor. Switch-off 

NCI Protocol #: 10107 
Local Protocol #: MC1721 
NCI Version Date: October 25, 2021 
 
124 
 
brakes of the centrifuge. 
f. Aspirate and discard roughly half of the plasma above the interphase/PBMC 
layer. 
g. Harvest the enriched cell fraction (lymphocytes / PBMCs) by means of a Pasteur 
pipette or by pouring the supernatant above the porous barrier from the Leucosep 
tube into another 50 mL centrifugation tube. 
h. Wash the enriched cell fraction with 10 ml of cold Wash Media, subsequently 
centrifugate for 10 minutes at 250 x g at 4°C. 
i. Aspirate and discard the supernatant. 
j. Repeat the washing step twice with 5 mL of cold Wash Media, subsequently 
centrifugate for 5 minutes at 250 x g at 4°C. 
k. Aspirate and discard the supernatant. 
l. Re-suspend cell pellet using 4 mL of Freezing Media (RPMI/FBS/Abx/DMSO) 
previously prepared and stored on ice. Avoid making bubbles. 
m. Distribute 1 mL (roughly 5 million cells/mL) of cell suspension into each of four 
cryo-vials. 
n. Each cryovial tube [e.g. Corning 2 mL externally-threaded cryo-vial (Corning 
catalog #430659). Alternatively, any brand of cryovial can be used as long as the 
cryovial is externally threaded) should be marked on a temperature-resistant label 
with the following mandatory information: 
i. Study Number 
ii. Subject Sequence Number 
iii. Time point 
iv. Date sample drawn and processed 
v. Sample Type (PBMC) 
vi. Cell number 
vii. Freezing Volume 
 
Handling of Specimen(s): Each vial should be put in a pre-chilled slow freezing container (e.g. 
Mr. Frosty) to guarantee that the temperature drops 1 degree/minute, and put it in -80°C freezer 
for 18-72 hours prior to storing them in a cryogenic storage unit (liquid nitrogen in the vapor phase; 
roughly -140°C) using a properly labelled cryogenic storage box. All vials should be transferred to 
cryogenic storage if possible. Otherwise, cells should be removed from the slow freezing container 
(e.g. Mr. Frosty) and stored at -80°C using a properly labelled cryogenic storage box. 
 
Shipping of Specimen(s): Ship according to instructions in Section 9.3.4.3.