Phase II Trial With Safety Run-in of the Anti-Mesothelin Antibody Drug Conjugate Anetumab Ravtansine for Mesothelin Expressing Lung Adenocarcinoma
Phase: PHASE2
Conditions: Lung Neoplasms
Sponsor: National Cancer Institute (NCI)

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Abbreviated Title: Anetumab ravtansine in lung CA 
Version Date: 01-11-18 
Abbreviated Title: Anetumab ravtansine in lung CA 
CC Protocol #: 16C0145D 
NCT #: NCT02839681 
Version Date: January 11, 2018 
Title: Phase II Trial with Safety Run-in of the Anti-Mesothelin Antibody Drug Conjugate 
Anetumab Ravtansine for Mesothelin Expressing Lung Adenocarcinoma  
Principal Investigator: 
Raffit Hassan, MD 
TGIB, CCR, NCI 
Building 10, Room 4-5342 
9000 Rockville Pike 
Bethesda, MD 20892 
Telephone: 240-760-6232 
E-mail: hassanr@mail.nih.gov 
 
 
Investigational Agents:     
Drug or Device Name: 
Anetumab ravtansine 
Mesothelin Expression Testing 
IND Number: 
130915 
NSR device 
Sponsor: 
Center for Cancer Research 
Center for Cancer Research 
Manufacturer: 
Bayer HealthCare 
Pharmaceuticals, Inc. 
NCI Laboratory of Pathology 

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Abbreviated Title: Anetumab ravtansine in lung CA 
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PRÉCIS  
Background: 
• Lung cancer is the leading cause of cancer-related death worldwide, accounting for more 
than one million deaths every year.  
• Non-small-cell lung cancer (NSCLC) constitutes approximately 85% of lung cancers and 
about 40% of patients with newly diagnosed NSCLC have advanced disease. The median 
year overall survival for advanced NSCLC is ~1 year. 
• In recent years, identification of oncogenic alterations such as mutations in EGFR 
and ALK translocations and therapies targeting tumor immune escape mechanisms have 
led to a substantial improvement in the prognosis of patients with advanced lung cancer; 
however, such alterations have been detected in less than half of all advanced NSCLC 
patients in only a small subset of patients respond to immunotherapeutic interventions 
available today.   
• Anetumab ravtansine (BAY 94-9343) is an antibody-drug conjugate targeting mesothelin, 
a protein normally present on mesothelial cells. A Phase I trial showed the overall 
acceptable and manageable safety profile. It is being developed for patients with 
mesothelin expressing cancers; clinical development is furthest along in mesothelioma, 
where it is in a registration phase II clinical trial.  
• NCI researchers have demonstrated that mesothelin mRNA and protein are present in a 
substantial number of lung adenocarcinoma cell lines; mesothelin expression has been 
observed in over 50% of advanced lung adenocarcinomas by immunohistochemical 
assessment  
Objectives: 
Safety Run-in 
• To evaluate safety and tolerability of anetumab ravtansine in patients with previously 
treated unresectable mesothelin expressing advanced lung adenocarcinoma (stage IIIB or 
IV). 
Phase 2 
• To determine the efficacy (objective response rate) of anetumab ravtansine in patients with 
advanced (Stage IIIb) or metastatic (Stage IV) mesothelin expressing lung 
adenocarcinoma.   
Eligibility: 
• Age >18 years.   
• Histologically or cytologically confirmed previously treated unresectable mesothelin 
expressing advanced lung adenocarcinoma (stage IIIB or IV) 
• Positive mesothelin expression in the archival tumor tissue, defined as the mesothelin 
membrane intensity score of 2+ or 3+ (on the 0-3 scale) expressed on the membrane of 
≥10% of tumor cells. 

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• Should have received at least one prior platinum based chemotherapy and an immune 
checkpoint targeted agent. In addition, subjects with epidermal growth factor receptor 
[EGFR]-mutated and anaplastic lymphoma kinase [ALK]-translocated NSCLC should 
have received FDA-approved targeted therapies as appropriate. 
• Normal organ function 
Design: 
• This is an open label, single center, phase I/II study of anetumab ravtansine in subjects with 
mesothelin positive lung adenocarcinoma. 
• During the safety run-in portion of the study, de-escalating doses will be assessed to 
determine a recommended phase 2 dose (RP2D). 
• During the phase 2 portion of the study, the (RP2D) will be assessed for objective response 
rate. 
• During both portions of the study, anetumab ravtansine will be administered intravenously 
every 3 weeks until disease progression in the absence of clinical benefit, patient 
withdrawal or the occurrence of intolerable toxicities. 
• Response assessments (imaging) will occur every 6 weeks for the first 6 months, then every 
9 weeks until the end of year 2, then every 12 weeks thereafter. 
• Up to 12 evaluable patients will be enrolled in the safety run-in portion of the study. 
Approximately twenty patients, including 6 from the safety run-in portion of the study, will 
be evaluated in the phase 2 portion of the study. The accrual ceiling will be set at 55 to 
accommodate screen failures (a 50% failure rate with regard to mesothelin expression) and 
inevaluable subjects. 

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TABLE OF CONTENTS  
PRÉCIS ............................................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................4 
1 
INTRODUCTION ...................................................................................................................8 
1.1 
Study Objectives .............................................................................................................. 8 
1.1.1 Primary Objectives ......................................................................................................8 
1.1.2 Secondary Objectives ..................................................................................................8 
1.1.3 Exploratory Objectives ...............................................................................................8 
1.2 
Background and Rationale ............................................................................................... 8 
1.2.1 Lung cancer .................................................................................................................8 
1.2.2 Mesothelin...................................................................................................................9 
1.2.3 Anetumab ravtansine ................................................................................................11 
1.2.4 Rationale for the study ..............................................................................................17 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ........................................................17 
2.1 
Eligibility Criteria .......................................................................................................... 17 
2.1.1 Inclusion Criteria ......................................................................................................17 
2.1.2 Exclusion Criteria .....................................................................................................19 
2.2 
Screening Evaluation ..................................................................................................... 21 
2.3 
Registration Procedures ................................................................................................. 22 
2.4 
Treatment Assignment and Randomization/Stratification Procedures .......................... 22 
2.5 
Baseline Evaluation ....................................................................................................... 23 
3 
STUDY IMPLEMENTATION .............................................................................................23 
3.1 
Study Design .................................................................................................................. 23 
3.1.1 Study Schema............................................................................................................23 
3.1.2 Dose Limiting Toxicity .............................................................................................25 
3.1.3 Safety Run-in ............................................................................................................26 
3.2 
Drug Administration ...................................................................................................... 27 
3.3 
Dose Modifications ........................................................................................................ 27 
3.3.1 Hematological toxicities ...........................................................................................27 
3.3.2 Non-hematological toxicities ....................................................................................29 
3.3.3 Miscellaneous toxicities ............................................................................................30 
3.3.4 Continuation of treatment with anetumab ravtansine ...............................................33 

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3.3.5 Permanent discontinuation of anetumab ravtansine due to TEAEs ..........................33 
3.4 
Study Calendar ............................................................................................................... 34 
3.5 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 37 
3.5.1 Criteria for removal from protocol therapy ..............................................................37 
3.5.2 Off-Study Criteria .....................................................................................................37 
3.5.3 Off Protocol Therapy and Off Study Procedure .......................................................37 
4 
CONCOMITANT MEDICATIONS/MEASURES ...............................................................37 
4.1 
Supportive care .............................................................................................................. 38 
4.1.1 Biologic response modifiers, such as filgrastim .......................................................38 
4.1.2 Blood products ..........................................................................................................38 
4.1.3 Other .........................................................................................................................38 
4.2 
Prohibited therapies ....................................................................................................... 38 
5 
BIOSPECIMEN COLLECTION ...........................................................................................38 
5.1 
Correlative Studies for Research ................................................................................... 38 
5.1.1 Induction of anti-mesothelin humoral immune response ..........................................38 
5.1.2 Gene expression-based characterization of the immune landscape before and after 
treatment with anetumab ravtansine .........................................................................39 
5.1.3 Assessment of Mesothelin Expression over Time ....................................................40 
5.1.4 Assessment of Myeloid Derived Suppressor Cells (MDSC) in Subjects with Lung 
Adenocarcinoma .......................................................................................................41 
5.2 
Sample Collection Summary ......................................................................................... 41 
5.3 
Sample Storage, Tracking and Disposition .................................................................... 42 
5.3.1 Clinical Pharmacology Program ...............................................................................42 
5.3.2 Laboratory of Dr. Raffit Hassan ...............................................................................43 
5.3.3 Laboratory of Pathology ...........................................................................................43 
5.3.4 NIH Flow Cytometry Laboratory .............................................................................43 
5.3.5 Protocol Completion/Sample Destruction ................................................................43 
6 
DATA COLLECTION AND EVALUATION ......................................................................44 
6.1 
Data Collection .............................................................................................................. 44 
6.2 
Data Sharing Plans ......................................................................................................... 44 
6.2.1 Human Data Sharing Plan .........................................................................................44 
6.2.2 Genomic Data Sharing Plan ......................................................................................45 
6.3 
Response Criteria ........................................................................................................... 45 

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6.3.1 Definitions.................................................................................................................45 
6.3.2 Disease Parameters ...................................................................................................45 
6.3.3 Methods for Evaluation of Measurable Disease .......................................................46 
6.3.4 Response Criteria ......................................................................................................48 
6.3.5 Duration of Response ................................................................................................50 
6.3.6 Progression-Free Survival .........................................................................................51 
6.4 
Toxicity Criteria ............................................................................................................. 51 
6.4.1 Corneal Epitheliopathy and Best Corrected Visual Acuity ......................................51 
6.4.2 All Other Adverse Events .........................................................................................51 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN .....................................................................................................................................51 
7.1 
Definitions...................................................................................................................... 51 
7.1.1 Adverse Event ...........................................................................................................51 
7.1.2 Suspected adverse reaction .......................................................................................51 
7.1.3 Unexpected adverse reaction ....................................................................................51 
7.1.4 Serious.......................................................................................................................52 
7.1.5 Serious Adverse Event ..............................................................................................52 
7.1.6 Disability ...................................................................................................................52 
7.1.7 Life-threatening adverse drug experience .................................................................52 
7.1.8 Hospitalization ..........................................................................................................52 
7.1.9 Protocol Deviation (NIH Definition) ........................................................................52 
7.1.10 Non-compliance (NIH Definition) ............................................................................52 
7.1.11 Unanticipated Problem..............................................................................................52 
7.2 
NCI-IRB and Clinical Director (CD) Reporting ............................................................ 53 
7.2.1 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and 
Deaths .......................................................................................................................53 
7.2.2 NCI-IRB Requirements for PI Reporting at Continuing Review .............................53 
7.2.3 NCI-IRB Reporting of IND Safety Reports..............................................................53 
7.3 
IND Sponsor Reporting Criteria .................................................................................... 54 
7.3.1 Reporting Pregnancy .................................................................................................54 
7.4 
Safety Reporting Criteria to the Pharmaceutical Collaborators ..................................... 55 
7.5 
Data and Safety Monitoring Plan ................................................................................... 56 
7.5.1 Principal Investigator/Research Team ......................................................................56 

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7.5.2 Sponsor Monitoring Plan ..........................................................................................57 
8 
STATISTICAL CONSIDERATIONS ...................................................................................57 
9 
COLLABORATIVE AGREEMENTS ..................................................................................58 
9.1 
Cooperative Research and Development Agreement (CRADA) ................................... 58 
10 HUMAN SUBJECTS PROTECTIONS ................................................................................58 
10.1 Rationale For Subject Selection ..................................................................................... 58 
10.2 Participation of Children ................................................................................................ 59 
10.3 Participation of Subjects Unable to Provide Consent .................................................... 59 
10.4 Evaluation of Benefits and Risks/Discomforts .............................................................. 59 
10.4.1 Risks ..........................................................................................................................59 
10.4.2 Benefits .....................................................................................................................60 
10.5 Consent and Assent Process and Documentation .......................................................... 60 
10.5.1 Telephone re-consent procedure ...............................................................................60 
10.5.2 Informed consent of non-English speaking/writing subjects ....................................60 
11 PHARMACEUTICAL INFORMATION ..............................................................................61 
11.1 Anetumab Ravtansine (IND #: 130915) ........................................................................ 61 
11.1.1 Source .......................................................................................................................61 
11.1.2 Toxicity .....................................................................................................................61 
11.1.3 Formulation and preparation .....................................................................................63 
11.1.4 Administration procedures ........................................................................................63 
11.1.5 Incompatibilities .......................................................................................................63 
12 REFERENCES ......................................................................................................................65 
13 APPENDICES .......................................................................................................................67 
13.1 Appendix A: Non Significant Risk Request and Determination for Mesothelin 
Expression Testing ......................................................................................................... 67 
13.1.1 NSR Determination Request to FDA ........................................................................67 
13.1.2 NSR Designation from FDA .....................................................................................68 
13.2 Appendix B: Performance Status Criteria ...................................................................... 70 
13.3 Appendix C: CYP3A4 Inhibitors and Inducers ............................................................. 71 
 
 
 

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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objectives 
Safety Run-in 
• To evaluate safety and tolerability of anetumab ravtansine in patients with previously 
treated unresectable mesothelin expressing advanced lung adenocarcinoma (stage IIIB or 
IV). 
Phase 2 
• To determine the efficacy (objective response rate) of anetumab ravtansine in patients with 
previously treated, unresectable, advanced (Stage IIIb) or metastatic (Stage IV) mesothelin 
expressing lung adenocarcinoma.   
1.1.2 Secondary Objectives 
All phases 
• To determine the duration of response, progression free survival, overall survival in the 
study population. 
• To correlate mesothelin expression with clinical activity defined as partial response and 
complete response 
1.1.3 Exploratory Objectives 
All phases 
• To determine if treatment with anetumab ravtansine induces a humoral response to 
mesothelin and to correlate a response (if any) with tumor characteristics 
• To characterize the molecular changes that occur within the tumors following treatment 
with anetumab ravtansine 
• To assess myeloid derived suppressor cells in subjects with lung adenocarcinoma 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 Lung cancer 
Lung cancer is the leading cause of cancer-related death worldwide, accounting for more than one 
million deaths every year1. Non-small-cell lung cancer (NSCLC) constitutes approximately 85% 
of lung cancers and about 40% of patients with newly diagnosed NSCLC have advanced disease. 
Until the late 1990s, treatment of advanced lung cancer followed the straightforward algorithm of 
platinum-based combination therapy, irrespective of histological subtype, without any option for 
further lines of treatment2. With the introduction of so-called third-generation cytotoxic drugs such 
as gemcitabine, vinorelbine, docetaxel, and paclitaxel, treatment of non-small-cell lung cancer 
changed, and overall survival improved to about 8 months in clinical trial settings3. However, the 
median overall survival was less than a year; only 3.5% of patients are alive five years after 
diagnosis3. Chemotherapy was also associated with high morbidity. 

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However, since then, overall survival has improved to a median survival of 12 months and longer 
in clinical studies. This progress was enabled by the introduction of new drugs, and patient 
selection based on the recognition that different histological subtypes and driver mutations 
determine the biology of these malignancies, and predict drug efficacy. The most widely 
recognized genomic alterations include epidermal growth factor receptor (EGFR) mutations, 
which have been recorded more frequently in Asian than in non-Asian patients4, and echinoderm 
microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangements5. 
Targeting of the proteins affected by such genetic changes improved the prognosis of these patients 
dramatically. These genetic modifications are significantly more common in patients who have 
never smoked, which makes non-small-cell lung cancer in this population a different disease entity 
to lung cancers caused by cigarette smoke and other toxicants.  
The predictive power of an EGFR mutation was confirmed in the Iressa Pan Asian Study (IPASS), 
a randomized phase 3 study that compared first-line gefitinib with standard chemotherapy in 1217 
Asian non-smokers or light smokers with pulmonary adenocarcinoma4. A subgroup analysis of 
417 patients with known EGFR mutation status confirmed improvement in progression-free 
survival in patients with EGFR mutations (HR 0·48, 95% CI 0·36–0·64) and a detrimental effect 
in patients with wild-type tumor (2·87, 2·05–3·98) (p<0·001). Multiple additional studies of first 
generation and second generation EGFR tyrosine kinase inhibitors, including gefitinib, erlotinib, 
and afatinib, have confirmed similar improvements in tumor response rate and progression-free 
survival. However, no overall survival benefit was reported in any of these studies because most 
patients in the chemotherapy group also received EGFR tyrosine kinase inhibitors as second-line 
or third-line therapy. In view of the significant clinical benefit and low toxicity, EGFR tyrosine 
kinase inhibitors are the first-line therapy of choice for patients with an activating EGFR mutation. 
Rociletinib is active and is approved for patients with EGFR-mutated NSCLC associated with the 
T790M resistance mutation6. 
ELM4-ALK is a rearrangement on chromosome 2. The 5′ fusion is a potent oncogenic 
rearrangement that activates the downstream ALK function. Crizotinib is a small molecule tyrosine 
kinase inhibitor that is highly specific for inhibition of cMET, ALK, and ROS-1. Treatment 
outcomes were reported in a randomized phase 3 study (PROFILE 1007) in which investigators 
compared crizotinib with standard single-agent second-line chemotherapy of either pemetrexed or 
docetaxel2,5. Shaw and colleagues reported higher tumor response rate and prolongation of 
progression-free survival (7·7 vs 3·0 months, HR 0·49, 95% CI 0·37–0·64). Ceritinib and alectinib 
are now approved for patients with resistance to or are intolerant to crizotinib7,8. 
However, “druggable” alterations have been detected in less than half of all advanced NSCLC 
patients in only a small subset of patients respond to immunotherapeutic interventions available 
today.  Clearly there is an urgent need for novel therapies for this deadly disease. 
1.2.2 Mesothelin 
Mesothelin is a 40-kDa cell surface glycoprotein that is present on normal mesothelial cells lining 
the pleura, peritoneum and pericardium 9. Mesothelin expression in normal human tissues is 
observed only in a single layer of mesothelial cells lining the pleura, peritoneum and pericardium10. 
However, mesothelin is highly expressed in several cancers, including epithelioid mesotheliomas, 
pancreatic, biliary adenocarcinomas, gastric and ovarian cancers. The high expression of 
mesothelin in cancers have led to its successful therapeutic targeting using a variety of strategies 

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including immunotoxins, monoclonal antibodies, antibody drug conjugates, vaccines and adoptive 
T cell therapy11. 
1.2.2.1 Targeting mesothelin in lung cancer 
Several lines of evidence suggest that mesothelin is an attractive target in lung adenocarcinoma.  
We and others have described high expression of mesothelin in lung adenocarcinoma. Mesothelin 
expression 
was 
observed 
in 
over 
50% 
of 
advanced 
lung 
adenocarcinomas 
by 
immunohistochemical assessment in a series of 93 patients (Figure 1)12. High mesothelin 
expression, defined as mesothelin positivity in more than 25% of cells, was observed in nearly 
25% of cases. Patients with high mesothelin-expressing tumors had significantly shorter overall 
survival compared with patients with low or no mesothelin expression (median 18.2 months vs. 
32.9 months; P = 0.014). High mesothelin expression was strongly associated with mutant 
KRAS (P < 0.0001) and wild-type EGFR (P = 0.002) (Figure 2).  Similar results have been 
observed by other investigators in early stage lung cancer13.  NCI researchers have demonstrated 
that mesothelin mRNA and protein are present in a substantial number of lung adenocarcinoma 
cell lines14. 
 
Figure 1: Tumor expression of mesothelin in lung adenocarcinoma was evaluated using 
immunohistochemistry. Representative images are depicted (original magnification x400). Focal cytoplasmic 
immunostaining of 2+ intensity in 15% cells (A), membranous and cytoplasmic immunostaining of 2+ intensity in 
1% cells (B), membranous immunostaining in of 3+ intensity in 30% cells (C), membranous and cytoplasmic 
immunostaining of 3+ intensity in 60% cells (D), membranous and cytoplasmic immunostaining of 3+ intensity in 
80% cells (E), membranous and cytoplasmic immunostaining of 3+ intensity in 100% cells (F). 
 

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Figure 2: Association of mesothelin expression with KRAS and EGFR mutations. Individual boxes are 
present a tumor.  
1.2.2.2 Risk designation for the use of mesothelin expression levels as an eligibility criterion 
In order to be eligible for this study, subjects are required to have positive mesothelin expression 
in the archival tumor tissue, defined as the mesothelin membrane intensity score of 2+ or 3+ (on 
the 0-3 scale) expressed on the membrane of ≥10% of tumor cells. Mesothelin expression testing 
is not FDA approved for this purpose; however, it is being used as a companion diagnostic device.  
It has been assessed by the sponsor as non-significant risk.  There is no significant risk incurred 
by the subjects in obtaining the archival specimens; therefore, it is the opinion of the Sponsor that 
the use of this diagnostic device does not pose a serious risk to the health, safety, or welfare of the 
subject and therefore is considered Non-Significant Risk under 21 CFR 812.3(m).  
A similar assay performed by Bayer on other studies of anetumab ravtansine has received the non-
significant risk designation from the FDA.  (See Appendix A) 
1.2.3 Anetumab ravtansine  
Anetumab ravtansine (BAY 94-9343) is an antibody drug conjugate (ADC) targeting mesothelin. 
The differential overexpression in NSCLC as well as the fact that mesothelin is an internalizing 
antigen suggests mesothelin as an excellent target for antibody-mediated delivery of cytotoxics.  
Anetumab ravtansine is composed of the human anti-mesothelin-monoclonal antibody BAY 86-
1903 and the maytansinoid DM4 (BAY 100-6640), conjugated by a disulfide linker moiety to 
lysine residues of the antibody (Figure 3). DM4 is a spindle poison, and its mechanism of action 
is inhibition of microtubule assembly (similar to that of vinca alkaloids). In vivo, anetumab 
ravtansine showed potent inhibition of the growth of mesothelin expressing cells (Figure 4)15. In 
tumors from NCI- H322 cells which have 2+ mesothelin expression, 72% tumor growth inhibition 
was observed at 15 mg/kg and 56% tumor growth inhibition at 5 mg/kg. Anetumab ravtansine has 
also demonstrated monotherapy anti-tumor efficacy in vivo in mesothelin-positive tumor 
models15; only 3 administrations of anetumab ravtansine at 0.2 mg/kg resulted in at least partial 
tumor regression in all mice using a Meso7212 PDX mesothelioma model (P < 0.001). The anti-
tumor efficacy of anetumab ravtansine was more pronounced than cisplatin (P < 0.05) and 
pemetrexed (P < 0.001). 
 

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Figure 3 
 
 
 
Maytansinoid-derivative DM4 
(tubulin polymerization inhibitor) 
 
SPDB 
(disulfide linker) 
(anti-Mesothelin hIgG1) 
 
 
Figure 
4 
 
 
 
1.2.3.1 Anetumab ravtansine clinical experience  
Seventy seven patients with advanced solid tumors expressing mesothelin were treated with 
anetumab ravtansine in the Phase I study16 with a Q3W schedule (Table 1). 

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Table 1. Patient disposition 
Patients treated (FPFV 7-Sep-11)  
Total (n)  
Active (n)  
Overall Q3W  
77  
--  
Dose escalation (0.15–  7.5 mg/kg Q3W) 
45  
--  
MTD Expansion (6.5 mg/kg Q3W) 
32  
3  
Mesothelioma  
12  
3  
Ovarian  
20  
--  
The dose-escalation part of the trial enrolled 45 patients who were evaluated in 10 cohorts 
spanning the dose range from 0.15 mg/kg to 7.5 mg/kg given by 1-hour IV infusion Q3W. The 
maximum tolerated dose (MTD) was defined as 6.5 mg/kg Q3W. The non-tolerated dose was 
determined to be 7.5 mg/kg Q3W. Subsequently 2 expansion cohorts (n=32) were treated 
at 6.5mg/kg Q3W. 
A total of 32 males and 45 females were treated, with a mean age of 61.4 years. Within the 
escalation cohorts (total 45 patients) the most common cancers were mesothelioma (n=21), 
pancreatic (n=9), breast (n=5), and ovarian cancer (n=4) whilst in the 6.5 mg/kg Q3W expansion 
cohorts (total 32 patients) patients had ovarian cancer (n=20) or mesothelioma (n=12). 
Following IV administration, maximum ADC concentrations were typically observed around the 
end of infusion or within 1 h after the end of infusion. The maximum drug concentration (Cmax) 
and area under the curve (AUC) of the ADC, generally increased in a dose proportional manner in 
the 0.15 mg/kg to 7.5 mg/kg dose range studied. At the MTD, average half-life values of the ADC, 
total antibody and DM4-Me were approximately 5 to 6 days, and approximately 3 days for DM4, 
generally consistent with the range of half-life values reported for biologics and with no 
accumulation expected after Q3W dosing (Figure 5). A total of 38 patients were treated at the 
MTD level of 6.5 mg/kg Q3W during the escalation (cohort 9, n=6) and subsequent expansion 
cohort (n=32). Of these, 16 patients had mesothelioma, 21 patients had ovarian cancer and 1 
patient had triple-negative breast cancer (TNBC). 

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Figure 5 
 
 
 
Response rate in the overall patient population treated at the MTD was 18.4%. Of the 16 
mesothelioma patients who were treated at the MTD (data presented at WCLC, Denver 2015. 
Hassan et al. Table 2), 5 (31%) achieved PRs according to modified Response Evaluation Criteria 
in Solid Tumors (mRECIST) (4 with pleural and 1 with peritoneal epithelial mesothelioma). 10 of 
these 16 patients with mesothelioma had received only 1 previous line of systemic cytotoxic 
chemotherapy before enrolling in the study. 5 of 10 patients in this group (50%) had a confirmed 
PR (4 PRs in pleural mesothelioma patients and 1 PR in peritoneal mesothelioma patients). 
Responses were durable.  
 
Table 2 
 
Data from the phase I trial also indicate an overall acceptable and manageable safety profile. At 
the MTD of 6.5 mg/kg Q3W, the most common treatment-emergent adverse events (TEAEs) that 

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were assessed to be at least possibly related to anetumab ravtansine were corneal epitheliopathy, 
peripheral neuropathy, myalgia, weakness, fatigue, anorexia, nausea, vomiting and diarrhea. The 
incidence of treatment-emergent serious adverse events (SAEs) that were considered to be at least 
possibly related to anetumab ravtansine was low in all patients treated at 6.5 mg/kg Q3W (5 of 
38 patients). There were no drug-related deaths throughout the study. 
The safety finding of particular interest at the 6.5 mg/kg Q3W dose has been the corneal 
epitheliopathy probably related to anetumab ravtansine (blurred vision and keratitis with possible 
vision impairment due to corneal epitheliopathy): 11 of 38 patients (29%) developed corneal 
adverse events. None of these events were considered serious or led to drug discontinuation and 
all events were reversible. 
Furthermore, population, physiologically-based pharmacokinetic (PopPBPK) modeling of 
preliminary data from the first in human study 15051 “An open label Phase 1 dose-escalation study 
to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and MTD of the anti-
mesothelin ADC anetumab ravtansine in subjects with advanced solid tumors” (NCT01439152), 
combined with a probabilistic regression analysis provided evidence that the area under the ADC 
plasma concentration-time curve at steady state, AUC(ADC), is a descriptor for the occurrence of 
corneal epitheliopathy, as shown in Figure 6. Based on the on average linear PK of anetumab 
ravtansine (see above in this section), it can be assumed that dose reduction will lead to a reduced 
total drug exposure, i.e. AUC(ADC), and thus, also to a reduced probability of corneal 
epitheliopathy. 

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Figure 6: Probability of corneal epitheliopathy versus model-predicted drug exposure 
 
ADC = Antibody-drug conjugate; AUC = Area under the curve; N = Number of patients; PopPBPK = Population, 
physiologically- based pharmacokinetic; Q3W = Every 3 weeks 
Drug exposure versus the probability of corneal toxicity relationship with AUC(ADC) equals the PopPBPK 
model-predicted area under the anetumab ravtansine plasma concentration-time curve at steady state. 
The solid line indicates the median estimate and the thin lines represent the 90% confidence interval; data used 
for logistic regression model development are shown as diamonds. 
The box plots represent simulated AUC(ADC) distributions in a virtual population of N=1000 subjects receiving 
4.5 mg/kg (dotted box), 5.5 mg/kg (dashed box) or 6.5 mg/kg (solid box) anetumab ravtansine given Q3W. 
 
The other identified risks so far include peripheral neuropathy, liver function test increases and 
hypersensitivity reaction. In the Q3W MTD dose level, 16 of 38 patients (42%) experienced 
peripheral neuropathy and associated disorders (muscle spasms and cramps, gait disorder etc.) as 
expected for the treatment with a taxanes-like anti-cancer agent; all but 1 case were Common 
Terminology Criteria for Adverse Events (CTCAE) Grade 1 or 2, 1 patient developed a Grade 3 
event. It commonly led to dose interruption and reduction but it did not frequently cause treatment 
discontinuation. A notable incidence of the liver function test increases was observed in patients 
treated at the MTD of 6.5 mg/kg Q3W: aspartate aminotransferase (AST) increase in 7 patients (1 
Grade 3), alanine aminotransferase (ALT) increase in 5 patients (no Grade 3), alkaline 
phosphatase (ALP) increase in 4 patients (1 Grade 3), and total bilirubin increase in 1 patient (no 
Grade 3). 2 patients treated at 6.5 mg/kg had a dose-limiting toxicity (DLT) or TEAE requiring 
dose reduction due to drug-related Grade 3 AST increase.  

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In the dose-escalation part of the Study 15404 in Japanese subjects with advanced solid tumors, 
anetumab ravtansine given IV as single agent was generally well tolerated at the dose of 4.5 mg/kg 
Q3W. The most common TEAEs at least possibly related to anetumab ravtansine in the dose 
escalation part of Study 15404 were hematological toxicities (Grade 2-4 thrombocytopenia and 
Grade 2-4 neutropenia). One of the 2 subjects treated at the dose of 6.5 mg/kg Q3W died due to 
hepatic failure that the investigator has considered to be related to anetumab ravtansine. 
In summary, the high tumor response rate and long-lasting responses in Study 15051 would 
indicate a potential for anetumab ravtansine to impart clinical benefit in an unmet medical need 
when given as single agent at the MTD of 6.5 mg/kg Q3W in the treatment of advanced 
predominantly epithelial mesothelioma and ovarian cancer. However, anetumab ravtansine may 
have a narrow therapeutic index, based on the severe and dose-limiting drug-related AEs observed 
at 7.5 mg/kg Q3W in the Study 15051, and on the fact that approximately half of the Western 
subjects with advanced cancer treated at the MTD of 6.5 mg/kg (BW) Q3W required dose 
reduction and/or treatment interruption (most commonly due to drug-related corneal toxicity, 
peripheral neuropathy, fatigue, asthenia/weight loss, anorexia and diarrhea). On the other hand, 
these events in Western subjects were non-life threatening and fully reversible (or showed a clear 
trend to complete resolution at the time of last follow up), and manageable by treatment 
modification. The Japanese subjects with advanced cancer should be carefully monitored for bone 
marrow toxicity and hepatotoxicity during treatment with anetumab ravtansine. The Study 15404 
is ongoing and the maximum tolerated dose of anetumab ravtansine in Japanese subjects has not 
been determined yet. Given the clinical benefit in mesothelioma and ovarian cancer as the high 
unmet medical need, anetumab ravtansine is expected to have an acceptable benefit-risk ratio when 
given as single agent at doses up to 6.5 mg/kg Q3W in patients with advanced cancer in clinical 
trials. 
1.2.4 Rationale for the study  
There is clearly an unmet need to identify improved therapies for patients with NSCLC. Anetumab 
ravtansine is an ADC targeting mesothelin.  It was well tolerated in phase I clinical studies with 
the predictable toxicity profile and evidence of clinical activity. Clinical and pre-clinical data 
indicate that anetumab ravtansine is active in mesothelin-expressing cancers. We have described 
mesothelin expressing lung adenocarcinoma as a specific subgroup of NSCLC with distinct 
mutational characteristics.  The primary objectives of this trial are to assess the safety and 
tolerability of anetumab ravtansine in patients with previously treated unresectable locally 
advanced or metastatic lung adenocarcinoma (stage IIIB or IV), and to determine a preliminary 
estimate of the response rate of the treatment.   
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA  
2.1.1 Inclusion Criteria 
2.1.1.1 Subjects must have histologically or cytologically confirmed previously treated 
unresectable mesothelin expressing advanced lung adenocarcinoma (stage IIIB or IV) as 
confirmed by the Laboratory of Pathology, NCI 

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2.1.1.2 Subjects must have positive mesothelin expression in the archival tumor tissue, defined 
as the mesothelin membrane intensity score of 2+ or 3+ (on the 0-3 scale) expressed on 
the membrane of ≥10% of tumor cells. 
2.1.1.3 Subjects must provide sample of archival tumor tissue (tissue block preferred, at least 5 
formalin-fixated, paraffin-embedded [FFPE] slides acceptable) collected any time before 
the general screening. A fresh biopsy will be collected if archival sample is unavailable 
or insufficient. 
2.1.1.4 Subjects must have measurable disease, 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 >20 mm with conventional techniques 
or as >10 mm with spiral CT scan.  See Section 6.3 for the evaluation of measurable 
disease. 
2.1.1.5 Subjects with resected primary tumors who have documented metastases are eligible. 
2.1.1.6 Subjects should have received at least one prior platinum based chemotherapy and an 
immune checkpoint targeted agent. Subjects with epidermal growth factor receptor 
[EGFR]-mutated and anaplastic lymphoma kinase [ALK]-translocated NSCLC should 
have received FDA-approved targeted therapies as appropriate. 
2.1.1.7 Age >18 years.  Because no dosing or adverse event data are currently available on the 
use of anetumab ravtansine in subjects <18 years of age, children are excluded from this 
study. 
2.1.1.8 ECOG performance status <2 (see Appendix B). 
2.1.1.9 Subjects must have adequate bone marrow function as assessed by the following 
laboratory test results: 
• Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L 
• Absolute neutrophil count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L  
• Platelet count ≥100,000/mm3 or ≥100 x 109/L 
2.1.1.10 Subjects must have adequate kidney function, with serum creatinine <1.5 x ULN or 
calculated glomerular filtration rate (GFR) of > 45/mL/min/1.73 m2  
2.1.1.11 Subjects must have adequate liver function as assessed by the following laboratory test 
results: 
• Total bilirubin ≤1.5 times the upper limit of normal (ULN) 
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤3.0 times ULN  in subjects without liver metastases or ≤5.0 times ULN in 
subjects with liver metastases 
2.1.1.12 Subjects must have adequate coagulation, as assessed by the following laboratory test 
results: 
• INR or PT ≤ 1.5 x ULN 
• PTT ≤ 1.5 x ULN 
2.1.1.13 Due to the lack of adequate reproductive toxicity data on anetumab ravtansine, subjects 
must use 2 forms of highly effective contraception concomitantly from the initiation of 
study therapy until 6 months after the last dose of study therapy.  Additionally, the use of 
condoms is required.  It should also be noted that, where 2 forms of effective 

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Abbreviated Title: Anetumab ravtansine in lung CA 
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contraception are required, a subject may choose to use a double-barrier method 
consisting of condom and cervical occlusive cap / diaphragm with spermicide 
2.1.1.14 Ability of subject  to understand and the willingness to sign a written informed consent 
document. 
2.1.1.15 Subjects must provide a signed informed consent before any screening procedures. 
 
2.1.2 Exclusion Criteria 
2.1.2.1 Subjects who have a previous or concurrent cancer that is distinct in primary site or 
histology from lung adenocarcinoma, except cervical carcinoma in situ, treated basal cell 
carcinoma, superficial noninvasive bladder tumors or any previous cancer curatively 
treated <2 years before the start of study treatment. 
2.1.2.2 Subjects who have a history or current evidence of bleeding disorder, i.e. any 
hemorrhage/bleeding event of CTCAE Grade ≥2 within 4 weeks before the start of study 
treatment.  
2.1.2.3 History of symptomatic metastatic brain or meningeal tumors unless the subject is > 3 
months from definitive therapy and has no evidence of tumor growth on an imaging study 
within 2 weeks prior to study entry. Subjects with brain metastases must not be 
undergoing acute corticosteroid therapy or steroid taper. Chronic steroid therapy is 
acceptable provided that the dose is stable for one month prior to screening.  
2.1.2.4 Subjects who have a history or current evidence of uncontrolled cardiovascular disease 
including but not limited to the following conditions: 
2.1.2.4.1 Congestive heart failure of New York Heart Association (NYHA) Class III or 
IV 
2.1.2.4.2 Unstable angina (symptoms of angina at rest) or new-onset angina within 
<3 months before the start of study treatment. 
2.1.2.4.3 Arterial thrombosis, deep vein thrombosis, or pulmonary embolism within 
<3 months before the start of study treatment. 
2.1.2.4.4 Myocardial infarction or stroke within <3 months before the start of study 
treatment. 
2.1.2.4.5 Pericarditis (any CTCAE grade), pericardial effusion (CTCAE Grade ≥2) or 
pleural effusion (CTCAE Grade ≥2) 
2.1.2.4.6 Cardiac arrhythmia requiring anti-arrhythmic therapy.  Subjects receiving 
digoxin, calcium channel blockers except verapamil, or beta-adrenergic 
blockers except propranolol are eligible at the investigator’s discretion if the 
dose has been stable for at least 2 weeks before the start of study treatment.  
Subjects with sinus arrhythmia and infrequent premature ventricular 
contractions are eligible at the investigator’s discretion. 
2.1.2.5 Subjects who have a left ventricular ejection fraction (LVEF) <50%, as assessed by 
echocardiogram performed at screening. 
2.1.2.6 Subjects who have a corrected QT (QTcF) interval >480 ms (CTCAE Grade >1) 
determined by the electrocardiogram (ECG) recorder’s algorithm on the screening ECG. 

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2.1.2.7 Subjects who have a history or current evidence of uncontrolled hypertension defined as 
systolic blood pressure >150 mmHg or diastolic blood pressure >95 mmHg at screening 
despite optimal medical management.  Subjects with a history of mild to moderate 
hypertension are eligible at the investigator’s discretion if the hypertension is adequately 
controlled by antihypertensive treatment used at a stable dose for at least 2 weeks before 
the start of study treatment. 
2.1.2.8 Subjects who have a heart rate ≥100 beats per minute (bpm) or ≤45 bpm determined by 
the ECG recorder’s algorithm on the screening ECG. 
2.1.2.9 Women who are pregnant or breast-feeding. Women of reproductive potential must have 
a negative serum beta human chorionic gonadotropin (β-HCG) pregnancy test obtained 
within 7 days before the start of study treatment. 
2.1.2.10 Subjects who have had a major surgery or significant trauma within 4 weeks before the 
start of study treatment. 
2.1.2.11 Subjects who have had solid organ or bone marrow transplantation. 
2.1.2.12 Subjects who have a history of hypersensitivity to any of the study drugs or their 
excipients, or a history of severe hypersensitivity to any other antigen. 
2.1.2.13 Subjects who have a history of human immunodeficiency virus (HIV) infection or 
subjects who have an active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection 
requiring treatment due to a theoretical concern that the degree of immune suppression 
associated with the treatment may result in progression of HIV infection. Subjects with 
chronic HBV or HCV infection are eligible at the investigator’s discretion if the subject 
is considered non-infectious based on serological markers. 
2.1.2.14 Subjects who have an active clinically serious infection of CTCAE Grade ≥2. 
2.1.2.15 Subjects with a non-healing serious wound, ulcer, or bone fracture unrelated to the 
primary tumor. 
2.1.2.16 Subjects with corneal epitheliopathy or any eye disorder that may predispose the subjects 
to drug-induced corneal epitheliopathy, or may interfere with diagnosis of treatment-
emergent corneal epitheliopathy at the discretion of the investigator in consultation with 
the ophthalmologist/optometrist.  Low grades of superficial punctate keratitis, within the 
range seen in the normal population, should not lead to the exclusion of the patient 
2.1.2.17 Subjects experiencing unresolved toxicity of previous antitumor therapy which is 
CTCAE Grade >1 before the start of study treatment, except for alopecia or hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/L. 
2.1.2.18 Subjects with any clinical condition that is considered unstable or might jeopardize the 
safety of the subject and/or influence the subject’s compliance in the study. 
2.1.2.19 Subjects who have received systemic anticancer therapy within 3 weeks before the start 
of study treatment.  Mitomycin C or nitrosoureas must be excluded within 6 weeks before 
the start of study treatment. 
2.1.2.20 Subjects who have received radiotherapy to tumor lesions that would be chosen as target 
lesions (measurable disease) within 4 weeks before the start of treatment, except if there 
is objective evidence of progression of the lesion by RECIST 1.1 between the prior 
radiotherapy and the screening CT or MRI scan. Palliative radiotherapy to non-target 
lesions is allowed at the investigator’s discretion.. 

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2.1.2.21 Use of drugs that inhibit renal tubular secretion (e.g. probenecid and cimetidine) within 
2 weeks before the start of study treatment. 
2.1.2.22 Use of strong cytochrome P450 3A4 (CYP3A4) inhibitors or strong CYP3A4 inducers 
within 2 weeks before the start of study treatment. 
2.1.2.23 Subjects who have previously received anetumab ravtansine. 
2.1.2.24 Subjects who are concurrently receiving any other investigational agents. 
2.2 
SCREENING EVALUATION 
Step 1: The following assessments may be performed as soon as the initial 1st line treatment cycles 
with platinum/pemetrexed are administered.  
• NCI LP confirmation of diagnosis  
• NCI LP determination of mesothelin expression 
• Medical History and Physical Examination  
 
Step 2: Once mesothelin expression and diagnosis are confirmed, then proceed with the following 
tests described below. 
The following screening assessments will occur within 28 days prior to initiation of study therapy: 
• Medical history and physical examination including vital signs 
• ECOG Performance Status 
• CT scan of chest, abdomen and/or pelvis and areas of known or suspected disease 
involvement; MRI may also be performed when appropriate 
• FDG-PET scan 
• Echocardiogram 
• Electrocardiogram 
• Viral markers – HBsAg, anti-HCV, anti-HIV 
The following screening assessments will occur within 21 days prior to initiation of study therapy: 
• Ophthalmologic exam (within 3 weeks before start of study therapy) 
o Visual acuity (BCVA according to ETDRS, or Snellen, or Landolt C or other charts) 
o Measurement of ophthalmic pressure (IOP) 
o Dry eye test [Schirmer test]  
o Slit lamp 
The following screening assessments will occur within 7 days prior to initiation of study therapy: 
• CBC with differential; Acute Care Panel (sodium, potassium, chloride, bicarbonate, 
creatinine, glucose, urea nitrogen, eGFR); Hepatic Panel (alkaline phosphatase, ALT, 
AST, Total Bilirubin, Direct Bilirubin) 
• PT, PTT 
• Urinalysis  
• β-HCG in women of childbearing potential 

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2.3 
REGISTRATION PROCEDURES 
Registration will be a two part process as patients are screened on this protocol. Authorized staff 
must register an eligible candidate with NCI Central Registration Office (CRO) within 24 hours 
of signing consent. To initially register a subject after the participant has signed the consent, 
complete the top portion the registration Eligibility Checklist from the website 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) indicating that the patient is being 
registered for screening and send via encrypted email to: NCI Central Registration Office  
ncicentralregistration-l@mail.nih.gov. Once eligibility is confirmed after completion of Step 2 
screening studies, complete the remainder of the form which is the eligibility checklist, indicating 
that the patient is being registered for treatment and email the completed registration checklist to 
the CRO at NCI Central Registration Office ncicentralregistration-l@mail.nih.gov.  After 
confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to advise 
them of the acceptance of the patient on the protocol prior to the release of any investigational 
agents.  Verification of Registration will be forwarded electronically via e-mail to the research 
team. A recorder is available during non-working hours.  
Subjects that do not meet screening criteria should be removed from the study following the 
procedure in section 3.5.3. 
 
2.4 
TREATMENT ASSIGNMENT AND RANDOMIZATION/STRATIFICATION PROCEDURES 
Cohorts 
Number Name 
Description 
1 
Safety Run-in Cohort,  
The first 6 evaluable subjects enrolled in whom the 
higher of 2 de-escalating doses of anetumab ravtansine 
will be evaluated in order to determine the recommended 
phase 2 dose 
2 
Phase 2 Cohort 
Subjects enrolled after the recommended Phase 2 dose 
has been determined 
 
Arms 
Number Name 
Description 
1 
Safety Run-in Arm 
Subjects will be dosed with the higher of the 2 possible 
anetumab ravtansine doses (dose level 1) evaluated on 
the study 
2 
Phase 2 Arm 
Subjects will be dosed with anetumab ravtansine at the 
recommended phase 2 dose (dose level 1 if no more than 
1 DLT occurred in the safety run in arm, or at dose level 
-1 otherwise) 
 

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Stratifications
None 
Randomization and Arm Assignment 
This is not a randomized study.  Subjects in Cohort 1 will be assigned directly to Arm 1.  Subjects 
in Cohort 2 will be assigned directly to Arm 2. 
2.5 
BASELINE EVALUATION
Screening evaluations performed within 28 days prior and within 7 days prior to treatment 
initiation will be used as baseline.  
3
STUDY IMPLEMENTATION 
3.1
STUDY DESIGN 
This is an open label, single center, phase I/II study of anetumab ravtansine in subjects with 
mesothelin positive lung adenocarcinoma. During the safety run-in portion of the study a 
recommended phase 2 dose (RP2D) will be determined in up to 2 dose levels of up to 6 patients 
each.  In the phase 2 portion of the study, 20 evaluable subjects will be evaluated at the RP2D 
including the 6 subjects treated at this dose during the dose de-escalation study.   
3.1.1 Study Schema 
Safety Run-in 
 
 
 
 
0/6 or 1/6 DLTs 
 
 
 
 
2/6 DLTs 
 
 
 
Anetumab ravtansine 
IV q3 weeks 
Patients with previously treated 
mesothelin expressing advanced lung 
adenocarcinoma 
Initial cohort = 6 pts at DL 1 
Phase 2 will proceed at 
DL 1 
Phase 2 will proceed at DL 
-1 with additional 6 
patients 
If at any time in the study DLT exceeds 1/3 of 
patients treated at the RP2D, accrual will be 
held and an amendment will be considered 

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Phase 2 – Simon Stage 2 Design 
 
 
 
 
 
0/13 with clincial reponse 
 
 
1 or more of 13 with 
clinical repsonse 
 
 
 
 
Anetumab 
ravtansine IV q3 
weeks 
Patients with previously treated 
mesothelin expressing advanced lung 
adenocarcinoma 
(13 patients enrolled initially (may 
include patients from safety run-in 
portion) 
No further accrual 
An additional 7 patients are 
enrolled for a total of 20 

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Treatment Schedule 
 
Anetumab ravtansine – every 3 weeks 
 
 
Blood for correlative studies – at baseline, end of cycle 2 (week 
6) and at end of treatment 
 
Tumor biopsy (optional) – at baseline and at the end of cycle 2 
(week 6) 
 
CT Scans/MRIs and FDG PET scans will be obtained every 6 weeks for the first 6 months, every 
9 weeks from then until year 2 and every 12 weeks thereafter 
Base-
line 
Week 3 
Week 6 
Week 9 
Week 
12 
Week 
15 
Every 3 weeks until  
disease progression in the 
absence of clinical 
benefit, patient 
withdrawal or toxicities  
End of 
treatmen
t 
 
3.1.2 Dose Limiting Toxicity 
For the TEAEs of corneal epitheliopathy and the best corrected visual acuity (BCVA) changes 
potentially fulfilling the DLT criteria for anetumab ravtansine, the grading systems in Table 9 and 
Table 10 respectively will be used.  All other criteria will be assessed per section 6.4.2. 
Any TEAE listed below occurring during Cycle 1 and regarded to be at least possibly related to 
anetumab ravtansine will represent a DLT for anetumab ravtansine treatment. 
3.1.2.1 Hematological 
• ANC <500/mm3 (CTCAE Grade 4) for ≥7 days 
• Febrile neutropenia (ANC < 1000/mm3 and a single body temperature reading of > 38.3°C 
(≥101 °F) or a sustained body temperature of ≥38.0 °C (≥100.4 °F) for more than 1 hour 
• Platelet count < 25000/mm3 (CTCAE Grade 4) for ≥7 days regardless of the presence of 
active bleeding or platelet count <50000/mm3 (Grade ≥3) with clinically significant 
bleeding, i.e. bleeding requiring platelet transfusion 
3.1.2.2 Non-hematological 
• AST and/or ALT increase > 5.0 times ULN (CTCAE Grade ≥ 3) 

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• AST and/or ALT increase > 3.0 times ULN (CTCAE Grade ≥ 2) with concomitant increase 
in total bilirubin >1.5 times ULN (CTCAE Grade ≥ 2) 
• Total bilirubin > 3.0 times ULN (CTCAE Grade ≥ 3) 
• Grade ≥3 corneal epitheliopathy according to the Bayer severity grading for this type of 
TEAE (Table 9) 
• Any other CTCAE Grade ≥ 3 non-hematological toxicity excluding the following: 
- 
Nausea, vomiting, or diarrhea if manageable with antiemetic or antidiarrheal agents 
within 7 days 
- 
Hair loss 
- 
Fatigue lasting ≤ 72 hours 
- 
Certain asymptomatic laboratory assessments without a clear clinical correlate, if the 
investigator determines that this TEAE should not be assessed a DLT. 
- 
CTCAE Grade ≥2 infusion reactions and other CTCAE Grade ≥2 hypersensitivity 
events deemed at least possibly related to anetumab ravtansine would not be considered 
a DLT, because hypersensitivity is not directly related to the dose. Nevertheless, these 
events would require treatment modification or discontinuation. 
• Any other toxicity irrespective of the type or severity that represents a clinically significant 
risk to subject in the investigator’s opinion. 
If a medically important TEAE not listed above, which is at least possibly related to anetumab 
ravtansine, has been observed more frequently after Cycle 1, then this TEAE may be declared a 
DLT in the remainder of the study at the investigator’s discretion. 
3.1.3 Safety Run-in 
The first 6 subjects will be enrolled at dose level 1. If <2 of 6 subjects experience a DLT, dose 
level 1 will be established as the RP2D and up to 20 evaluable subjects (including the first 6) will 
be enrolled at this dose level.  If 2 or more subjects experience DLT at dose level 1, the RP2D is 
established at dose level -1 and up to 20 evaluable subjects will be enrolled at this dose level. If a 
patient did not experience DLT and did not finish treatment, he or she will not be evaluable for 
toxicity and will be replaced in the dose level.  If at any time during the trial, the cumulative 
fraction of patients treated at the dose used in the phase II portion of the trial who have a DLT 
exceeds 1/3, then no further accrual will take place unless a treatment modification is provided via 
an amendment. 
Table 3: Dose De-escalation Schedule 
Dose Level 
Dose of anetumab ravtansine IV q 3 weeks  
Level 1 
6.5 mg/kg 
Level -1 
5.5 mg/kg 
 

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Table 4: Dose de-escalation will follow the rules outlined in the Table below. 
Number of Patients with 
DLT 
at Dose Level  
De-escalation Decision Rule 
0 or 1 out of 6 
This will be the recommended phase 2 dose 
≥ 2 out of 6 
The next lower dose level (DL -1) is established as the 
recommended phase 2 dose   
 
3.2 
DRUG ADMINISTRATION 
After reconstitution and dilution as described in section 11.1.3, anetumab ravtansine will be 
administered at a dose of 6.5 mg/kg or 5.5 mg/kg of body weight every 3 weeks as an intravenous 
infusion over 1 hour (+/- 15 minutes). Note: longer infusions are permitted if following dose 
modification guidelines; however, diluted anetumab ravtansine must be used within 6 hours. In 
obese patients, anetumab ravtansine dose should be calculated considering a maximum weight of 
100 kg. Patients will continue on treatment until death, or occurrence of progressive disease (PD) 
in the absence of clinical benefit as defined by Response Evaluation Criteria in Solid Tumors 
(RECIST), version 1.1 (RECIST 1.1) or drug-related toxicity that requires discontinuation of 
treatment, or until another criterion for withdrawal from study is met. 
3.3 
DOSE MODIFICATIONS 
Table 5 - Dose modification levels 
Dose level 1 (starting dose): 6.5 mg/kg Q3W 
Dose level -1 
5.5 mg/kg Q3W  
Dose level -2 
4.5 mg/kg Q3W 
3.3.1 Hematological toxicities  
Dose modifications for hematological toxicity  
• If treatment modification is required due to a hematological TEAE, and the continuation 
of treatment is appropriate, the anetumab ravtansine dose will be adjusted as described in 
Table 6 and Table 7 below.  
• 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 CSF17 or at the discretion of the 
investigator; however they may not be substituted for a required dose reduction.  
• Blood transfusions and therapy with IV or subcutaneous erythropoietin-stimulating 
agents (epoetin alpha, darbepoetin alpha) are allowed per institution guidelines but may 
not be used as substitute for a required dose reduction (see also section 4.1).  

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• Platelet transfusion may be used during the study in the management of acute toxicity 
such as hemorrhage or bleeding events, however they may not be used as substitute for a 
required dose reduction.  
Table 6 - Dose adjustments in response to neutrophil and platelet nadira counts of the 
previous cycle 
Absolute neutrophil nadir count 
of the previous cycle (/mm3) 
Platelet 
nadir 
count 
of 
the 
previous cycle (/mm3) 
Anetumab 
ravtansine 
dose 
adjustment b 
≥ 500 or < 500 for < 7 days and 
≥ 25,000 
No change 
< 500 for ≥ 7 days  
and/or 
< 25,000 regardless of the 
presence of active bleeding (or ≥ 
25,000 with clinically 
significant bleeding, i.e. 
bleeding requiring platelet 
transfusion) 
Decrease 1 dose level b 
Febrile neutropenia c  
and/or 
< 25,000 regardless of the 
presence of active bleeding (or ≥ 
25,000 with clinically 
significant bleeding, i.e. 
bleeding requiring platelet 
transfusion) 
Decrease 1 dose level b 
ANC = Absolute neutrophil count; C = Cycle; CBC = Complete blood count; D = Day; Q3W = Every 3 weeks  
a) Clinic visits and blood test for CBC (and biochemistry) on D8 and D15 will be performed on C1, C2 and 
C3 only. From Cycle 4 onwards, visits and procedures on D8 and D15 are no longer required.  
b) Dose reduction by 1 dose level translates to a change from 6.5 mg/kg Q3W to 5.5 mg/kg Q3W, or from 
5.5 mg/kg Q3W to 4.5 mg/kg Q3W. Not more than 2 dose reductions from the starting dose level are 
permitted.  c Febrile neutropenia is defined as ANC < 1000/mm3 and fever (a single body temperature 
reading of  > 38.3°C [101°F] or a sustained body temperature of ≥ 38°C [100.4°F] for more than 1 hour). 
 
Table 7 - Dose adjustments in response to pre-infusion values 
Absolute 
neutrophil 
count (/mm3) 
 
Platelets 
(/mm3) 
Hemoglobin 
(g/dL) 
Timing 
Anetumab 
ravtansine 
dose 
adjustment 
≥ 1,000 
and 
≥ 75,000 
 
Treat on time 
Adjust dose by 
nadir a counts in 
previous cycle 
per investigator’s 
discretion 
< 1,000 
and/ or 
< 75,000 
 
Delay until 
ANC ≥ 1.0 and 
platelets  ≥ 
75,000 b 
Decrease by 1 
dose level c 
 
 
 
< 8 
Delay until Hb 
≥ 8 b 
Re-start at the 
same dose or 
decrease by 1 

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dose level c (at 
investigator’s 
discretion) 
ANC = Absolute neutrophil count; C = Cycle; CBC = Complete blood count; D = Day; Hb = Hemoglobin; Q3W 
= Every 3 weeks; TEAE = Treatment-emergent adverse event  
a) Site visits and blood test for CBC (and biochemistry) on D8 and D15 will be performed on C1, C2 and 
C3 only. From Cycle 4 onwards, visits and procedures on D8 and D15 are no longer required.  
b) Treatment will be discontinued if the TEAE fails to resolve to Grade ≤ 1 (or Hb ≥ 9 g/dL in case of 
anemia) within 6 weeks after the last dose of anetumab ravtansine.  
c) Dose reduction by 1 dose level translates to a change from 6.5 mg/kg Q3W to 5.5 mg/kg Q3W, or from 
5.5 mg/kg Q3W to 4.5 mg/kg Q3W. Not more than 2 dose reductions from the starting dose level are 
permitted.  
 
3.3.2 Non-hematological toxicities  
3.3.2.1 Non-hematological toxicities requiring dose modification  
• CTCAE Grade  2 anetumab ravtansine infusion-related reaction or other CTCAE Grade  
2 hypersensitivity events  (See section 3.3.3.2) 
• AST and/or ALT increase >5.0 x ULN (CTCAE Grade ≥ 3)  
• AST and/or ALT increase >3.0 x ULN (CTCAE Grade ≥ 2) with concomitant increase in 
total bilirubin >1.5 x ULN (CTCAE Grade ≥ 2)  
• Total bilirubin ≥ 3.0 x ULN (CTCAE Grade ≥ 3)  
• Bayer Grade ≥ 3 corneal epitheliopathy (see below and Table 9)  
• Any other Grade ≥ 3 non-hematological toxicity that, in the investigator’s opinion, 
warrants treatment modification (see Table 8), excluding the following:  
o Nausea, vomiting, or diarrhea if manageable with anti-emetics or anti- diarrheals 
within 7 days  
o Hair loss  
o Fatigue lasting ≤ 72 h  
• Any other toxicity irrespective of the type or severity that represents a clinically 
significant risk to patient in the investigator’s opinion.  
3.3.2.2 Dose modifications for non-hematological toxicity 
If treatment modification is required due to Grade ≥ 3 non-hematological TEAE, other than 
corneal epitheliopathy and infusion-related reaction/hypersensitivity events, and the continuation 
of treatment is appropriate, the anetumab ravtansine dose will be either reduced or maintained as 
is at investigator’s discretion (see Table 8). 
Table 8 - Dose adjustments in response to non-hematologic toxicities 
CTCAE v4.0 grade 
Anetumab ravtansine dose delay / 
interruption 
Anetumab ravtansine dose 
modification 
Grade 1 – 2 a 
Treat on time 
No change required 

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CTCAE v4.0 grade 
Anetumab ravtansine dose delay / 
interruption 
Anetumab ravtansine dose 
modification 
Grade 3 
1st appearance: Delay /Interruption 
until Grade ≤ 2 b 
Re-start at the same dose or 
decrease by 1 dose level c (at 
investigator’s discretion) 
2nd appearance: Delay /Interruption 
until Grade ≤ 2 b 
Decrease by 1 more dose level c 
3rd appearance: Permanently 
discontinue 
 
Grade 4 
Permanently discontinue 
 
ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; CTCAE = Common Terminology Criteria 
for Adverse Events; Q3W = Every 3 weeks; TEAE = Treatment-emergent adverse event  
a) AST and/or ALT increase of CTCAE Grade 2 with concomitant increase in total bilirubin of CTCAE 
Grade 2 will be treated as a CTCAE Grade 3 event.  
b) Treatment will be discontinued if the TEAE fails to resolve to Grade ≤ 1 within 6 weeks after the last 
dose of anetumab ravtansine.  
c) Dose reduction by 1 dose level translates to a change from 6.5 mg/kg Q3W to 5.5 mg/kg Q3W, or from 
5.5 mg/kg Q3W to 4.5 mg/kg Q3W. Not more than 2 dose reductions from the starting dose level are 
permitted.  
The anetumab ravtansine dose reduction due to non-hematological TEAE will be done as described 
below:  
• If the patient experienced a TEAE requiring dose reduction at the 6.5 mg/kg Q3W dose 
level, the subsequent anetumab ravtansine dose should be reduced to 5.5 mg/kg Q3W.  
• If the patient experienced a TEAE requiring dose reduction at the 5.5 mg/kg Q3W dose 
level, the subsequent anetumab ravtansine dose should be reduced to 4.5 mg/kg Q3W.  
After dose reduction for TEAE, there could be no intra-patient dose re-escalation irrespective of 
the type of TEAE that has led to dose reduction in this patient with the exception of grade 3 corneal 
epitheliopathy as per Table 9. 
3.3.3 Miscellaneous toxicities  
3.3.3.1 IV infusion-related reaction and other hypersensitivity events  
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-related 
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.  
In case of a CTCAE Grade ≥ 3 hypersensitivity and acute infusion reaction, treatment must be 
permanently withdrawn. 

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3.3.3.2 Miscellaneous toxicities requiring dose modification  
For any toxicity ≤ Grade 2 assessed as related to anetumab ravtansine by the investigator, dose 
modification should be considered. Such toxicities might be ≤ Grade 2 toxicities which interfere 
with the activities of daily life, such as long lasting fatigue, or anorexia, or corneal epitheliopathy 
with vision impairment etc. A dose change might be necessary in order to ensure the patient’s 
compliance. These toxicities may be declared “TEAE requiring treatment modification” after per 
investigator discretion.  
3.3.3.3 Dose modifications for corneal epitheliopathy  
For the TEAE of corneal epitheliopathy and the best corrected visual acuity (BCVA) changes 
(blurred vision), the Bayer severity grading system (see Table 9 and Table 10) will be used to 
assess the severity of TEAEs requiring modification of anetumab ravtansine treatment.  
TEAE of corneal epitheliopathy deemed to be at least possibly related to anetumab ravtansine 
would require modification of anetumab ravtansine treatment (dose reduction or permanent 
discontinuation of treatment) according to the following principles (see Table 9). 
Table 9 - Bayer classification and management of corneal epitheliopathy 
 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Corneal 
morphology 
No pathologic 
changes 
Any stage of 
superficial 
punctate keratitisa 
Epithelial 
opacities  
 
Micro-cysts 
Micro-deposits 
Corneal erosion 
Stromal opacity: 
non-central 
Corneal ulcer 
without risk of 
acute rupture  
 
Stromal 
opacity: central 
Corneal ulcer 
more severe 
than Grade 3 
Eye 
treatmentb 
Ocular lubricants at 
the discretion of 
investigator in 
consultation with  
ophthalmologist/ 
optometrist 
Ocular lubricants; 
add topical 
steroids if 
superficial 
punctate keratitis 
shows treatment- 
emergent 
progression by ≥ 
2 SPK Grades 
Intensive 
treatment with 
ocular lubricants 
enhanced with 
ointments; 
topical steroids; 
therapeutic 
contact lens may 
be considered at 
the discretion of 
investigator in 
consultation with 
ophthalmologist/ 
optometrist 
Intensive 
therapy with 
ointments; 
topical steroids; 
therapeutic 
contact lens or 
occlusion 
recommended 
at the discretion 
of investigator 
in consultation 
with  
ophthalmologist
/optometrist 
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 in 
consultation 
with  
ophthalmologist
/ optometrist 

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Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Anetumab 
ravtansinec 
No change 
No change 
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 in 
consultation with  
ophthalmologist/ 
optometrist 
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) 
Discontinue 
treatment 
SPK = Superficial punctate keratitis  
a) Oxford Schema must be used for grading SPK from stage 0 to VI.  
b) Other remedial therapies for corneal epitheliopathy may be added or substituted at investigator's discretion 
or according to the institutional standards.  
c) Treatment decisions are based on corneal epitheliopathy only, not on visual acuity changes.  
 
Table 10 - Bayer classification of visual acuity changes 
 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Visual acuity 
No findings, 
no reporting 
from the 
patient 
Symptomatic 
visual 
acuity 
loss < 3 lines 
(ETDRS 
equivalenta) 
Visual 
acuity 
loss ≥ 3 lines, 
but < 6 lines 
(ETDRS 
equivalenta) 
Visual 
acuity 
loss ≥ 6 lines, 
(ETDRS 
equivalenta) 
Visual 
acuity 
loss ≥ 6 lines, 
(ETDRS 
equivalenta) 
leading 
to 
blindness 
ETDRS = Early Treatment Diabetic Retinopathy Study  
a) In the ETDRS chart, each loss of 3 lines corresponds to halving the visual acuity. In other charts, an 
equivalent amount of visual acuity loss must be reached in order to meet this threshold. 
 
3.3.3.3.1 Recommended measures in case of eye dryness and ocular hypertension  

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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/ optometrist. 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 standard of care. 
Ophthalmological monitoring should be maintained until the IOP has returned to normal values.  
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/ optometrist to provide adequate protection to the corneal 
epithelium. The remedial therapy for the treatment-emergent changes in the Schirmer 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 standard of care. 
3.3.4 Continuation of treatment with anetumab ravtansine  
Treatment with anetumab ravtansine could be re-started at the appropriate dose if the TEAE 
requiring dose modification has resolved to Grade ≤ 2 within 6 weeks after the last dose of 
anetumab ravtansine.  
3.3.5 Permanent discontinuation of anetumab ravtansine due to TEAEs  
• CTCAE Grade 4 non-hematological AE and Bayer Grade 4 corneal epitheliopathy (see 
Table 9) (except at the investigator’s discretion in case of certain Grade 4 abnormality of 
laboratory assessments, such as abnormal laboratory assessments without corresponding 
clinical symptoms, or abnormal laboratory assessments that can be easily clinically 
managed). 
• If any type of TEAE requiring dose modification does not resolve to Grade ≤ 1 (or Hb ≥ 9 
g/dL in case of anemia) within 6 weeks after the last dose of anetumab ravtansine. 
• Delay in anetumab ravtansine administration of 3 weeks (max. 6 weeks between 2 
infusions of study drug). 
• TEAE requiring dose reduction when already at the 4.5 mg/kg Q3W dose level (minimum 
dose). 
• More than 2 dose reductions required due to a TEAE. 
 
 

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3.4 
STUDY CALENDAR 
1 cycle = 3 weeks (21 days) 
Screening and baseline evaluations are performed per the timeframes indicated in sections 2.2 and 2.4 respectively.  
On therapy assessments may be performed up to 5 days prior to indicated time; safety follow up may occur up to 7 days after indicated 
time; long term follow up phone calls may be performed within ± 14 days of indicated time. 
Dosing cycles after cycle 1 may be delayed for up to two weeks to accommodate schedule conflicts, Federal holidays and inclement 
weather, etc. 
Procedure 
Screening/ 
Baseline 
Cycle 1 
Subsequent Cycles 
End of 
Treatment 
Post Therapy 
Follow-up 
Day 
1 
Day 
8 
Day 15 
Day 1 
Day 8 
Day 15  
30 day 
safety 
follow up 
Long 
term 
follow up 
History and PE1 
X 
X 
X 
 
X 
 
 
 
X 
 
Weight 
 
X 
 
 
X 
 
 
 
X 
 
Vital signs 
X 
X 
X 
 
X 
 
 
 
X 
 
ECOG Performance 
Score 
X 
 
 
 
 
 
 
 
 
 
Confirmation of dx 
and mesothelin 
expression 
X 
 
 
 
 
 
 
 
 
 
Imaging assessments2 
X 
Every 6 weeks (first 6 months), every 9 weeks (until end of 
year 2), every 12 weeks thereafter  
 
 
 
Echocardiogram 
X 
Every 6 weeks  for the first 6 months, then every 12 weeks 
thereafter 
 
 
 
12 lead ECG3 
X 
X 
 
 
X (cycle 2 
only) 
 
 
 
X 
 
HBsAg, anti-HCV, 
anti-HIV 
X 
 
 
 
 
 
 
 
 
 
Ophthalmologic 
exam4 
X 
 
 
 
X 
 
 
 
X 
 

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Procedure 
Screening/ 
Baseline 
Cycle 1 
Subsequent Cycles 
End of 
Treatment 
Post Therapy 
Follow-up 
Day 
1 
Day 
8 
Day 15 
Day 1 
Day 8 
Day 15  
30 day 
safety 
follow up 
Long 
term 
follow up 
CBC with 
differential, Hepatic 
Panel;  
X 
 
X 
X5 
X 
X5 
 
 
X 
 
Acute Care Panel 
X 
 
 
 
 
 
 
 
 
 
PT/PTT 
X 
 
 
 
X 
 
 
 
X 
 
Urinalysis  
X 
 
 
 
X 
 
 
 
 
 
β-HCG in women of 
childbearing potential 
X 
 
 
 
X 
 
 
 
X 
 
Optional biopsy 
X 
 
 
 
Cycle 3 
only 
 
 
 
 
 
Correlative Research 
Studies6 
 
X 
 
 
Cycle 3 
only 
 
 
X 
 
 
NIH Advance 
Directives Form 
X7 
 
Adverse Events 
 
Continuous assessment 
Concomitant 
Medications 
 
Continuous assessment 
Phone calls q 3 
months for survival 
status and new anti-
cancer treatment 
 
 
 
 
 
 
 
 
 
X 
 
1 
A complete physical exam is performed at screening.  Thereafter, brief physical exams will be performed as per schedule above. 
2 
The following imaging assessments will be performed: CT scan, MRI (if appropriate) and FDG PET.  Assessments will continue until 
confirmatory scans for progressive disease have been obtained. 
3 
All ECGs will be recorded as single digital 12-lead ECG obtained after 5-10 minutes’ rest in supine or semi-recumbent position. Personnel are 
instructed to ensure a relaxed and quiet environment with the subjects being awake and at complete rest prior and during the recordings. On day 

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1 of cycle 1, the ECG will be recorded within 1 hour (+15 minutes) after the end of the infusion.  On day 1 of cycle 2, an ECG will be recorded 
at two time points: pre-dose and within 1 hour (+15 minutes) after the end of the infusion.     
4 
A detailed ophthalmologic examination (visual acuity, IOP, Schirmer test and slit lamp) will be done for all patients during screening within 3 
weeks before the start of study treatment. After study therapy is initiated, visual acuity and slit lamp exam will be repeated before infusion in 
every cycle except C1D1, and at safety follow-up visit, or more frequently at investigator’s and ophthalmologist/ optometrist’s discretion. IOP 
measurement is to be repeated during anetumab ravtansine therapy if the patient receives steroid eye drops as treatment for eye toxicity; dry eye 
(Schirmer) test may be repeated during treatment at investigator’s discretion (e.g. in case of eye dryness during anetumab ravtansine therapy). 
During treatment period, ophthalmologic examination can be done up to 7 days before anetumab ravtansine infusion. 
5 
Assessment may be performed by local laboratory if patient is unable to return to NIH. 
6 
At each collection: 4 mL of blood in 10 mL tiger top tube to Figg lab; three 10 mL sodium heparin (green top) tubes to NIH Flow lab. 
7 
As indicated in section 10.3, all subjects ≥ age 18 will be offered the opportunity to complete an NIH advanced directives form.  This should be 
done preferably at baseline but can be done at any time during the study as long as the capacity to do so is retained.  The completion of the form 
is strongly recommended, but is not required. 
 

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3.5 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy. 
3.5.1 Criteria for removal from protocol therapy 
• Requirement for therapy prohibited by protocol (see section 4.2) 
• Progressive disease; however, treatment may be continued provided that the patient 
derives clinical benefit as determined by the investigator 
• Development of secondary malignancy 
• Participant becomes pregnant 
• Participant requests to be withdrawn from active therapy 
• Unacceptable toxicity as defined in section 3.3  
• Investigator discretion 
3.5.2 Off-Study Criteria 
• Screening failure 
• Participant requests to be withdrawn from study 
• Lost to follow up 
• The investigator decides to stop the study 
• Death 
3.5.3 Off Protocol Therapy and Off Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office 
ncicentralregistration-l@mail.nih.gov. 
4 
CONCOMITANT MEDICATIONS/MEASURES 
Any medication which is considered necessary for the patient’s welfare, and which is not expected 
to interfere with the evaluation of the study treatment or listed in section 4.2 below, may be given 
at the discretion of the investigator. In general, patients should be closely monitored for side effects 
of all concomitant medications regardless of elimination path, especially those with narrow 
therapeutic indices, such as warfarin, phenytoin, quinidine, carbamazepine, phenobarbital, 
cyclosporine, and digoxin. All concomitant medications used while patient is on study therapy 
(including start/stop dates, dose, frequency, route of administration and indication) must be 
recorded. 

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4.1 
SUPPORTIVE CARE 
4.1.1 Biologic response modifiers, such as filgrastim 
Filgrastim 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 CSF17 or at the discretion of the investigator (if 
medically necessary, growth factors may be administered at recommended doses; however they 
may not be substituted for a required dose reduction 
4.1.2 Blood products 
Blood transfusions and chronic therapy with IV or subcutaneous erythropoietin- stimulating agents 
(epoetin alpha, darbepoetin alpha): These are allowed, but may not be used as a substitute for 
required dose reduction. 
4.1.3 Other 
Further supportive per NIH CC Pharmacy guidelines is permitted with the exception of 
interventions appearing in section 4.2. 
4.2 
PROHIBITED THERAPIES 
• Platinum/pemetrexed/bevacizumab 
• Other systemic anti-cancer therapy (cytotoxic therapy, targeted therapies, immunotherapy, 
hormonal therapy, or any other experimental or approved therapy) 
• Acute steroid therapy 
• Anti-arrhythmic therapy other than beta blockers of digoxin 
• Any drugs with known bone marrow toxicity 
• Strong inhibitors and strong inducers of CYP3A4 (listed in Appendix C). Moderate and 
weak CYP3A4 inhibitors should be used with caution as decrease in plasma concentrations 
of DM4 cannot be ruled out. 
• Any drugs that inhibit renal tubular secretion (e.g. probenecid and cimetidine). 
5 
BIOSPECIMEN COLLECTION 
5.1 
CORRELATIVE STUDIES FOR RESEARCH 
5.1.1 Induction of anti-mesothelin humoral immune response  
We have previously shown that in some patients with mesothelioma and ovarian cancer there is 
loss of tolerance to mesothelin as reflected by development of anti-mesothelin antibodies. We 
propose evaluating serum samples from all patients enrolled on this study and determine if 
treatment with anetumab ravtansine induces a humoral immune response to mesothelin and if so 
correlating induction of anti-mesothelin humoral immune response with tumor characteristics 
(such as tumor mesothelin expression, serum mesothelin and megakaryocyte-potentiating factor 
(MPF) levels) as well as clinical outcome including overall survival. 

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5.1.1.1 Sample Collection   
Samples will be collected at baseline, at the end of cycle 2 and at the end of treatment. 
All blood samples will be taken by either direct venipuncture or an indwelling venous access.  At 
each sample collection time, blood (4mL) will be drawn into a 10-mL serum separator tube (tiger 
top tube) labeled as follows:  
- Subject ID Number  
- Study Number   
- Time and date of collection  
5.1.1.2 Sample Processing  
Please e-mail Julie Barnes at Julie.barnes@nih.gov and Paula Carter pcartera@mail.nih.gov at 
least 24 hours before transporting samples (the Friday before is preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact Julie Barnes by e-mail or at 240-760-6044. 
   
Upon arrival in the CPP, each sample should be processed in the following manner:  
Allow blood to clot for 10 minutes and centrifuge to separate the serum within 30 minute of 
collection.  If necessary whole blood may be stored in the collection tubes upright and refrigerated 
at 4-8°C for up to 24 hours prior to centrifugation and processing.  Processing within 30 minutes 
is strongly preferred.  Transfer the serum into two (2) pre-labeled cryotubes and immediately 
freeze by placing on dry ice. Transfer frozen serum samples into a – 80°C freezer for storage.   
Autoantibody levels will be retrospectively assessed. 
5.1.1.3 Sample Storage 
All serum samples will be stored frozen at approximately –80°C in the Clinical Pharmacology 
Program.   
5.1.2 Gene expression-based characterization of the immune landscape before and after 
treatment with anetumab ravtansine 
We will evaluate tumor biopsies before and after treatment with anetumab ravtansine using a 
hybridization-based digital gene expression platform nCounter (NanoString Technologies). This 
platform allows for unbiased multiplexed quantification of RNA transcripts achieving sensitivity 
comparable to quantitative reverse-transcription polymerase chain reaction (Q-RT-PCR), without 
any enzymatic reaction involved in the process. We have expertise in the use of this technology 
for the characterization of purified cell subsets and also for the study of the changes that occur in 
human tumors, as a consequence of a given treatment, using tumor core biopsy tissues. This 
analysis can be performed on flash frozen biopsies without any further isolation or enrichment of 
specific cell types. We will also use immunohistochemistry and immunofluorescence techniques 
to characterize diverse immune cell subpopulations and alterations with tumor biopsies of patients 
before and after treatment. 

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For the present study, we will screen pre- and post-treatment samples for the expression of markers 
of immune cell subsets (CD3, CD8, CD4, etc.), local production of cytokines (interferon-gamma, 
tumor necrosis factor-alpha, etc.) and chemokines (CXCL13, CCL5, etc.), adhesion molecules and 
others. The purpose of this study is to characterize the molecular changes that occur within the 
tumors following treatment with anetumab ravtansine. The ultimate goal is to gain a better 
understanding of the mechanism of action of this treatment, and to identify molecular correlates 
of clinical outcomes such as objective responses and/or improved survival.  
In order to achieve these goals, flash frozen samples will be subjected to total RNA isolation 
followed by hybridization with capture and detection probes specific for 620 transcripts, including 
genes involved in the regulation of the immune function and also markers expressed by tumor cells 
and tumor stroma. To cover those target transcripts, a combination of a commercially available 
pre-designed probe set (GX Human Immunology v2, NanoString Technologies) will be used in 
combination with a custom-designed code set of thirty additional targets (Panel Plus, NanoString 
Technologies). Hybridization complexes will be quantified using a NanoString nCounter Analysis 
System, at the Genomics Core Facility of the Center for Cancer Research, NCI.  
Results obtained by this approach will be correlated with data obtained from 
immunohistochemistry and pathology analysis of tumor biopsies as well as with data from analysis 
of peripheral blood populations, for a comprehensive study of the mechanism of action of 
anetumab ravtansine in lung cancer and mesothelioma patients. 
5.1.2.1 Collection 
Optional biopsies will be collected at baseline (if a sample was not collected at screening) and at 
the end of cycle 2.  Archival samples may be used if patient refuses biopsy. 
Collection of biopsy should be guided by ultrasound, CT scan, or other method according to the 
location of the selected lesion using a ≤ 18 gauge needle to provide cores ideally of at least 20 mm 
in length or equivalent size. At least 2, ideally 4 core biopsies will be obtained. Fine needle 
aspiration and biopsy of bone lesions are not acceptable.  
The first core will be stored in the Laboratory of Pathology.  Remaining samples will be stored in 
the Laboratory of Dr. Raffit Hassan, Building 10, Room 3B51. In general, Betsy Morrow (phone: 
301 402 5688; email: morrowbj@mail.nih.gov), a biologist in Dr. Hassan’s lab will pick up the 
samples.  If she is unavailable, another biologist will do so. 
5.1.3 Assessment of Mesothelin Expression over Time 
Fresh tumor tissue collected at baseline (optional) will be compared to archival material in order 
to determine whether mesothelin protein levels change over time and with disease progression. 
Mesothelin 
expression 
will 
be 
assessed 
by 
the 
Laboratory 
of 
Pathology 
using 
immunohistochemistry. Immunohistochemical staining will be evaluated by a pathologist and 
scored based on the intensity of staining as weak 1+, moderate 2+, and strong 3+, and the 
percentage of tumor cells that are positive.  
5.1.3.1 Collection 
Samples collected at screening (archival) and baseline (optional) as described previously will be 
used for this analysis. 
 

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5.1.4 Assessment of Myeloid Derived Suppressor Cells (MDSC) in Subjects with Lung 
Adenocarcinoma 
5.1.4.1 Sample collection 
Samples will be collected at baseline prior to first dose of anetumab ravtansine and the end of cycle 
2 and at the end of treatment. All blood samples will be taken by either direct venipuncture or an 
indwelling venous access. At each sample collection time, blood (30 mL) will be drawn into three 
10 mL sodium heparin (green top) tubes. 
The tube should be labeled with the following information: 
- Subject ID Number  
- Study Number   
- Time and date of collection  
-Specimen type: peripheral blood 
5.1.4.2 Sample processing 
The samples will be sent to NIH Flow Cytometry lab located at 3S240, South part of Building 10. 
All specimens for flow cytometry will be scheduled in advance by contacting Dr. Stetler-
Stevenson stetler@mail.nih.gov and/or Dr. Yuan yuanc@mail.nih.gov by email. Peripheral blood 
samples should arrive no later than 1 pm to the flow cytometry laboratory on the day scheduled. 
Specimens are received in the laboratory via escort or via delivery by someone from the clinical 
team. Specimens for delivery AFTER HOURS ONLY may also be placed in the secure specimen 
drop box located in Laboratory of Pathology 3N hallway. Peripheral blood specimens are collected 
in sodium heparin tubes, and are stored at room temperature until delivery.  
The specimens should be delivered as soon as possible after collection, and cannot be evaluated if 
> 48 hours old.   
Upon receipt in the flow lab, the sample will be checked for correct labeling with appropriate 
patient identifiers and specimen type (e.g. peripheral blood).  
5.2 
SAMPLE COLLECTION SUMMARY 
Test/assay 
Sample 
Type of 
tube (if 
applicable) 
Collection point 
(within ) 
Location of 
specimen analysis 
Anti-mesothelin 
humoral immune 
response 
4 mLs blood 
10 mL 
serum 
Separator  
 
Baseline, C3D1, 
EOT 
Clinical 
Pharmacology 
Program 
Gene expression 
characterization of 
the immune 
landscape  &  
Optional tumor 
biopsy 
NA 
Baseline, C3D1 
Dr. Hassan’s lab 

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Test/assay 
Sample 
Type of 
tube (if 
applicable) 
Collection point 
(within ) 
Location of 
specimen analysis 
Assessment of 
Mesothelin 
Expression Over 
Time 
Archival 
sample and 
optional tumor 
biopsy 
NA 
Archival sample 
collected at 
screening, and on 
study biopsies 
collected for 
Gene expression 
characterization 
study 
Laboratory of 
Pathology 
Assessment of 
MDSC 
30 mL blood 
Three 10 
mL sodium 
heparin 
tubes 
Baseline, C3D1, 
EOT 
NIH Flow 
Cytometry Lab 
 
5.3 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  Samples 
will not be sent outside NIH without IRB notification and an executed MTA. 
5.3.1 Clinical Pharmacology Program 
Upon arrival in the Clinical Pharmacology Program (CPP), OCD, CCR, NCI, all samples are 
barcoded, with data entered and stored in Patient Sample Data Management System (PSDMS), 
also known as Labrador, the system utilized by the CPP. This is a secure program, with access to 
the PSDMS system limited to defined CPP personnel, who are issued individual user accounts. 
PSDMS creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without PSDMS access. The data recorded for each sample includes the patient 
ID, name, trial name/protocol number, time drawn, cycle, time point, dose, material type, as well 
as box and freezer location. There are patient demographics that can be obtained to correlate with 
the samples through PSDMS. For each sample, there are notes associated with processing method 
(delay in sample processing, storage conditions on the ward, etc.) 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20°C or -80°C 
according to stability requirements. These freezers are located onsite in the CPP and offsite at NCI 
Frederick Central Repository Services in Frederick, MD. Samples will be stored until requested 
by the researcher assigned to the protocol. All requests are monitored and tracked in PSDMS. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per IRB approved protocol) and that any unused samples 
must be returned to the CPP. 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting the 
rights to use the material. 

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5.3.2 Laboratory of Dr. Raffit Hassan 
This study will follow storage, handling and labeling procedures to ensure that security, 
confidentiality and sample integrity are maintained. All samples (blood or tissue) are tracked by 
distinct identification labels generated by Labmatrix that include a unique patient identifier and 
date of specimen collection. Thus samples will be de-identified of personal data, with access to 
personal data restricted to the study investigators.   
Depending on specimen type, samples are stored in liquid nitrogen, in monitored 
freezers/refrigerators at either -20 or -80°C according to stability requirements or in a slide cabinet 
in the research Laboratory of Dr. Raffit Hassan (Building 10, Room 3B51). 
5.3.3 Laboratory of Pathology 
Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) 
where they are examined grossly and relevant portions are fixed, embedded in paraffin and 
sectioned and stained for diagnostic interpretation.  Unutilized excess tissues are stored for up to 
three months, in accordance with College of American Pathologists/Joint Commission on 
Accreditation 
of 
Healthcare 
Organizations 
(CAP/JCAHO) 
guidelines, 
and 
then 
discarded.  Following completion of the diagnostic workup, the slides and tissue blocks are stored 
indefinitely in the LP’s clinical archives.  All specimens are catalogued and retrieved utilizing the 
clinical laboratory information systems, in accordance with CAP/JCAHO regulations.  The use of 
any stored specimens for research purposes is only allowed when the appropriate IRB approval 
has been obtained.  In some cases, this approval has been obtained via the original protocol on 
which the patient was enrolled.  
5.3.4 NIH Flow Cytometry Laboratory 
Specimens received in the flow cytometry laboratory are accessible only to the flow cytometry 
laboratory team, as the laboratory door is locked and key access is only provided to the flow 
cytometry laboratory members.  Additionally, the flow cytometry laboratory is set behind a set of 
double doors that are accessible only by badge/key card access. 
5.3.5 Protocol Completion/Sample Destruction 
All specimens obtained in the protocol are used as defined in the protocol. Any specimens 
remaining at the completion of the protocol will be stored in the conditions described above. The 
study will remain open as long as sample or data analysis continues. Samples from consenting 
subjects will be stored until they are no longer of scientific value or until a subject withdraws 
consent for their continued use, at which time they will be destroyed and data from the. Once 
primary research objectives for the protocol are achieved, intramural researchers can request 
access to remaining samples, provided they have an IRB-approved protocol and patient consent or 
an exemption from OHSRP.  
The PI will report any loss or destruction of samples to the NCI IRB as soon as he/she is made 
aware of such loss. The PI will report destroyed samples to the IRB if samples become 
unsalvageable because of environmental factors such as a broken freezer or lack of dry ice in a 
shipping container, or if a patient withdraws consent. Samples will also be reported as lost if they 
are lost in transit between facilities or misplaced by a researcher. Freezer problems, lost samples, 
or other problems associated with samples will also be reported to the IRB, the NCI Clinical 
Director and the office of the CCR, NCI. 

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6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
Data obtained on the study will be stored in C3D and Labmatrix. 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts. All data obtained during the conduct of the protocol will be kept 
in secure network drives or in approved alternative sites that comply with NIH security standards. 
Primary and final analyzed data will have identifiers so that research data can be attributed to an 
individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified.  
6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows: 
_X_ De-identified data in an NIH-funded or approved public repository.   
_X_ De-identified data in BTRIS  
_X_ De-identified or identified data with approved outside collaborators under appropriate 
agreements. 
 
How and where will the data be shared?  

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Data will be shared through: 
_X_ An NIH-funded or approved public repository.  _clinical trials.gov. 
_X_ BTRIS 
_X_ Approved outside collaborators under appropriate individual agreements. 
_X_ Publication and/or public presentations. 
 
When will the data be shared? 
_X_ Before publication. 
_X_ At the time of publication or shortly thereafter. 
6.2.2 Genomic Data Sharing Plan 
No large scale genomic data will be generated on this study. 
6.3 
RESPONSE CRITERIA 
For the purposes of this study, patients should be re-evaluated for response every 6 weeks in the 
first 6 months, every 9 weeks until the end of year 2 and every 12 weeks thereafter.  In addition to 
a baseline scan, confirmatory scans should also be obtained not less than 4 weeks following initial 
documentation of objective response. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1)18.  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. 
6.3.1 Definitions 
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first 
treatment with anetumab ravtansine. 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified according 
to the definitions stated below.  (Note:  Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response:  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
6.3.2 Disease Parameters 
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 by chest x-ray, as >10 mm 

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with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured 
and followed. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable 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. 
Target lesions.  All measurable lesions 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 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. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 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.  
6.3.3 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. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 

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(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater 
than 5 mm, 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).   
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. 
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.   
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. 
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. 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published19-21.  In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with 
objective tumor assessment for use in first-line trials in ovarian cancer22]. 

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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. 
 
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. 
 
6.3.4 Response Criteria 
6.3.4.1 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. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum of 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.  (Note:  the appearance of one or more new lesions is also considered 
progressions). 

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Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study. 
 
6.3.4.2 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 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). 
 
6.3.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
No 
SD 
Documented at least once >4 
wks. from baseline** 

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PD/not 
evaluated 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
6.3.5 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 
recurrent or 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 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised 

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6.3.6 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
6.4 
TOXICITY CRITERIA 
6.4.1 Corneal Epitheliopathy and Best Corrected Visual Acuity 
For the adverse event of corneal epitheliopathy and the best corrected visual acuity (BCVA) 
changes potentially fulfilling the DLT criteria for anetumab ravtansine, the grading systems in 
Table 9 and Table 10 respectively will be used.  All other criteria will be assessed per section 6.4.2 
below. 
6.4.2 All Other Adverse Events 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
7.1 
DEFINITIONS 
7.1.1 Adverse Event 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.. 
7.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
7.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. "Unexpected” 
also refers to adverse events or suspected adverse reactions that are mentioned in the investigator 
brochure as occurring with a class of drugs or as anticipated from the pharmacological properties 
of the drug, but are not specifically mentioned as occurring with the particular drug under 
investigation. 

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7.1.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.1.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
7.1.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
7.1.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that had it occurred in a more severe form, might have caused death. 
7.1.8 Hospitalization 
In general, hospitalization means that the subject has been detained at the hospital or emergency 
ward for observation or treatment that would not have been appropriate in the physician’s office 
or out-patient setting.  Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious.  When in doubt 
as to whether hospitalization occurred or was necessary, the AE should be considered serious.  
Hospitalization for elective treatment planned prior to study enrollment is neither an SAE nor an 
AE. 
7.1.9 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.   
7.1.10 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) policies, 
IRB requirements, or regulatory requirements for the protection of human research subjects. 
7.1.11 Unanticipated Problem 
Any incident, experience, or outcome that: 

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•  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
7.2 
NCI-IRB AND CLINICAL DIRECTOR (CD) REPORTING 
7.2.1 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths 
The Protocol PI will report on the NIH Problem Form to the NCI-IRB and NCI Clinical Director: 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
7.2.2 NCI-IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
• All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
• All Grade 3 and 4 events that are possibly, probably or definitely related to the research;  
• All Grade 5 events regardless of attribution;  
• All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.2.3 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB. 

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7.3 
IND SPONSOR REPORTING CRITERIA  
During the first 30 days after the subject receives investigational agent/intervention, the 
investigator must immediately report to the sponsor, using the mandatory MedWatch form 3500a 
or equivalent, any serious adverse event, whether or not considered drug related, including those 
listed in the protocol or investigator brochure and must include an assessment of whether there is 
a reasonable possibility that the drug caused the event. For serious adverse events that occur more 
than 30 days after the last administration of investigational agent/intervention, only report those 
that have an attribution of at least possibly related to the agent/intervention. 
Required timing for reporting per the above guideline: 
• Deaths (except death due to progressive disease) must be reported via email within 
24 hours.  A complete report must be submitted within one business day.  
• Other serious adverse events as well as deaths due to progressive disease must be 
reported within one business day. 
Events will be submitted to Center for Cancer Research (CCR) at: CCRsafety@mail.nih.gov and 
to the CCR PI and study coordinator. 
7.3.1 Reporting Pregnancy 
7.3.1.1 Maternal exposure 
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately and the pregnancy reported to the Sponsor. The potential risk of 
exposure of the fetus to the investigational agent(s) or chemotherapy agents (s) should be 
documented in box B5 of the MedWatch form “Describe Event or Problem”. 
Pregnancy itself is not regarded as an SAE. However, as patients who become pregnant on study 
risk intrauterine exposure of the fetus to agents which may be teratogenic, the CCR is requesting 
that pregnancy should be reported in an expedited manner as Grade 3 “Pregnancy, puerperium 
and perinatal conditions - Other (pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC.  
Congenital abnormalities or birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented. 
If any pregnancy occurs in the course of the study, then the investigator should inform the Sponsor 
within 1 day, i.e., immediately, but no later than 24 hours of when he or she becomes aware of 
it. 
The designated Sponsor representative will work with the investigator to ensure that all relevant 
information is provided to the Sponsor within 1 to 5 calendar days for SAEs and within 30 days 
for all other pregnancies. 
The same timelines apply when outcome information is available. 
7.3.1.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for six 
months after the last dose of anetumab ravtansine. 

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Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 6 months after the last dose 
should, if possible, be followed up and documented. 
 
7.4 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
All events listed below must be reported in the defined timelines to CCRsafety@mail.nih.gov.  
The CCR Office of Regulatory Affairs will send all reports to the manufacturer as described below. 
 
All SAEs must be reported to Bayer within 24 hours of the CCR Office of Regulatory Affair’s 
awareness and must include the following minimum information:  
1.  The name and contact information of the reporter 
2.  The name of the study drug(s) 
3.  A description of the reported SAE 
4.  A patient identified by one or more of the following:  
a.  Patient initials 
b.  Patient number  
c.  Knowledge that a patient who experienced the adverse event exists 
d.  Age 
e.  Sex 
5.  An investigator assessment of study drug causality.   
Additional data which would aid the review and causality assessment of the case include but are 
not limited to:   
• The date of onset 
• The severity 
• The time from administration of study drug(s) to start of the event 
• The duration and outcome of the event 
• Any possible etiology for the event 
• The final diagnosis or syndrome, if known 
• Action(s) taken, if any 
7.4.1.1 Expedited Reporting of Other Safety Information 
The Sponsor shall report to Bayer within 24 hours of the CCR Office of Regulatory Affair’s 
awareness of other events such as:   
• An adverse event related to study specific procedures  
• Any new and important event related to treatment with the study drug(s). 
• Any pregnancy during which a female patient was exposed to the study drug(s) 

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• Any pregnancy in the partner of a male patient, where the male patient was exposed to 
study drug at the time of conception or conception occurred within two weeks of the last 
dose of study drug(s). 
• Any other relevant safety information including but not limited to reports on drug 
interaction, overdose, drug abuse or misuse, drug dependency, withdrawal syndrome, 
medication error, occupational exposure and lack of drug effect (LODE) occurring at any 
time during the treatment phase; 
• Any communication concerning safety related information to regulatory authorities or 
ethics committees including but not limited to: 
• Development Safety Update Reports (DSUR) / relevant parts of IND reports for the 
STUDY; 
• Any other safety related reports, issues and queries that are either raised by or 
communicated to regulatory authorities or ethics committees. 
 
The Investigator/Sponsor may report SAEs using: 
A MedWatch form available at http://www.fda.gov/medwatch/ 
All reports shall be sent electronically to: 
Electronic Mailbox: DrugSafety.GPV.US@bayer.com  
Facsimile:                  (973) 709-2185  
Address:                 
Global Pharmacovigilance - USA  
Mail only         
Bayer HealthCare         
P.O. Box 915  
Whippany, NJ 07981-0915  
Address: 
 
100 Bayer Blvd., Whippany, NJ 07981 
FDX or UPS only 
67 Whippany Road, Whippany NJ 07981 for UPS 
 
Reports for all Bayer products can also be phoned in via our Medical Communications Department 
Phone:                  
1-888-842-2937 
The Principal Investigator commits to respond promptly to any query from Bayer regarding SAE 
reports. 
7.5 
DATA AND SAFETY MONITORING PLAN 
7.5.1 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis when patients are being actively treated on 
the trial to discuss each patient. Decisions about dose level enrollment and dose de-escalation will 
be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or protocol 
deviations will be immediately reported to the IRB using iRIS and to the Sponsor.  

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The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
7.5.2 Sponsor Monitoring Plan 
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary study endpoints; adherence to the protocol, regulations, and 
SOPs; and human subjects protection. This is done through independent verification of study 
data with source documentation focusing on: 
• Informed consent process 
• Eligibility confirmation 
• Drug administration and accountability 
• Adverse events monitoring 
• Response assessment. 
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center. 
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct. 
8 
STATISTICAL CONSIDERATIONS   
The primary objectives of this trial are to assess the safety and tolerability of anetumab ravtansine 
in patients with unresectable mesothelin expressing previously treated advanced lung 
adenocarcinoma (stage IIIB or IV), and to determine a preliminary estimate of the response rate of 
the treatment.  Based on the mechanisms of action of anetumab ravtansine, at least minimal tumor 
expression of mesothelin would be required to anticipate clinical activity. As such, patients to be 
enrolled on the trial will first be screened for the presence of mesothelin membrane intensity score 
of 2+ or 3+ (on the 0-3 scale) expressed on the membrane of ≥10% of tumor cells.  For this assay, 
subjects must provide sample of archival tumor tissue collected any time before the general 
screening.  Additionally, optional tumor biopsies will be performed before and after 2 doses of 
anetumab ravtansine.  
The first 6 patients enrolled on the trial will receive anetumab ravtansine at a dose of 6.5 mg/kg. 
If 0 or 1 of the first 6 patients experiences a dose-limiting toxicity (DLT), then the remainder of 
the patients on the trial will be treated at that dose. If 2 or more patients within the first 6 experience 
a DLT, then the remaining patients will be treated at 5.5 mg/kg. If at any time during the trial, the 
cumulative fraction of patients treated at the dose used in the phase II portion of the trial who have 
a DLT exceeds 1/3, then no further accrual will take place unless a treatment modification is 
provided via an amendment. 
The phase II portion of the trial will be conducted incorporating either the 6 patients treated at 6.5 
mg/kg or 5.5 mg/kg as appropriate. Given the expected rarity of responses, the goal would be to 
determine if using anetumab ravtansine would rule out a 5% response rate and target a rate of 25%. 
For these patients, the trial will be conducted using a Simon Minimax two-stage phase II trial 
design in order to rule out an unacceptably low partial response (PR)+ complete response (CR) 

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rate of 5% (p0=0.05) in favor of an improved response rate of  25% (p1=0.25). With alpha=0.10 
(probability of accepting a poor treatment=0.10) and beta = 0.10 (probability of rejecting a good 
treatment=0.10), this first stage will enroll 13 evaluable patients (including patients treated at the 
safe dose found in the initial 6 patients), and if 0 of the 13 have a clinical response, then no further 
patients will be accrued. If 1 or more of the first 13 patients have a response, then accrual would 
continue until a total of 20 evaluable patients have been treated. As it may take up to several 
months to determine if a patient has experienced a response, a temporary pause in the accrual may 
be necessary to ensure that enrollment to the second stage is warranted. If there are 1 to 2 patients 
with a response out of 20 patients, this would be an uninterestingly low response rate. If there were 
3 or more of 20 (15%) who experienced a response, this would be sufficiently interesting to warrant 
further study in later trials. Under the null hypothesis (5% response rate), the probability of early 
termination is 51%. 
Assessment of serum samples and tumor biopsies will be exploratory and will be summarized 
descriptively. 
The initial portion of the trial may require up to 6 patients who may not be included in the phase 
II portion if 2 or more of them experience DLTs at 6.5 mg/kg. The phase II portion may require 
up to 20 evaluable patients. Thus, if 5.5 mg/kg is the selected dose, then up to 26 evaluable patients 
may be required while if 6.5 mg/kg is selected, only up to 20 evaluable patients may be required. 
It is anticipated that approximately 50% of screened patients will have <5% mesothelin level and 
will not be treated on the protocol. Thus, in order to allow for 50% drop-outs for that reason as 
well as a small number of inevaluable patients, the accrual ceiling will be set at 55 patients. If 2 
patients per month enroll on this trial, accrual would be expected to be completed in approximately 
28 months.  
9 
COLLABORATIVE AGREEMENTS 
9.1 
COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) 
The study drug, anetumab ravtansine, will be supplied by the manufacturer, Bayer HealthCare 
Pharmaceuticals under a CRADA agreement (CRADA #03084) between the manufacturer and the 
Center for Cancer Research. 
10 HUMAN SUBJECTS PROTECTIONS  
10.1 RATIONALE FOR SUBJECT SELECTION 
This study will be open to all individuals with mesothelin expressing lung adenocarcinoma 
regardless of gender, ethnicity, or race provided that the aforementioned inclusion and exclusion 
criteria are met.  The selection criteria reflect all available nonclinical and clinical safety 
experience with anetumab ravtansine. Further, the selection criteria address the potential 
pharmacokinetics issues that may confound the reliable assessment of the study objective related 
to the pharmacokinetic drug-drug interaction.  
The treatment of men as well as women is justified because of the severity of the underlying 
neoplastic disease. Men and women who use appropriate contraception or women who are not of 
child-bearing potential will be enrolled into this study. The proportion of men and women enrolled 
into the dose-safety run-in cohorts of this study depends only on the availability of subjects at the 
NIH Clinical Center. 

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This study will be recruited through internal referral, our local physician referral base, and will be 
posted on clinicaltrials.gov. 
10.2 PARTICIPATION OF CHILDREN 
There are no dosing or adverse event data are currently available on the use of BAY 94-9343 / 
anetumab ravtansine in patients <18 years of age; therefore, children are excluded from this 
study. 
10.3 PARTICIPATION OF SUBJECTS UNABLE TO PROVIDE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol.  However re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 10.4), all subjects ≥ age 18 will be offered the opportunity to fill in 
their wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or cognitively 
impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent 
Assessment Team for evaluation.  For those subjects that become incapacitated and do not have 
pre-determined substitute decision maker, the procedures described in MAS Policy 87-4 for 
appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) 
who do not have a legal guardian or durable power of attorney, will be followed. 
 
10.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
10.4.1 Risks  
10.4.1.1 Study Drug 
Potential risks of the study include the possible occurrence of any of a range of side effects as 
listed in section 11.1.2 and the consent document. The procedure for protecting against or 
minimizing risks will be to medically evaluate patients on a regular basis, provide premedications 
and supportive therapies as described earlier.  
10.4.1.2 Biopsy 
Needle biopsy is minimally invasive and is typically a very safe procedure. Depending upon the 
site being biopsies and the type of biopsy being performed, risks can include infection of the biopsy 
site, development of a hematoma, and bleeding. Rarely more significant complications can occur 
when structures near the biopsy target are entered with the needle (e.g. puncture of lung or bowel). 
Furthermore, the optional biopsies collected at baseline and after the end of cycle 2 (which may 
be CT guided) will be for research purposes only. This will result in exposure to approximately 
0.27 rem. This amount is below the guideline of 5 rem per year allowed for adult research subjects 
by the NIH Radiation Safety Committee. 
10.4.1.3 Research Blood Sampling 
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 

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10.4.2 Benefits 
The potential benefit to a patient who enters the study is a reduction in the bulk of his/her tumor, 
which may or may not have a favorable impact on symptoms and/or survival. 
10.5 CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
An associate or principal investigator on the trial will inform patients of the purpose, alternatives, 
treatment plan, research objectives and follow-up of this trial.  The patient will be provided an 
IRB-approved consent for review and signature and his/her questions will be answered.  After a 
decision is made to enroll into the study, a signature will be obtained from the patient at a 
subsequent visit.  The original of the signed informed consent will be placed in the patient's 
medical record and a copy will be held in the research record. 
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before receiving study therapy.  
Consent for the optional biopsies on this study will be obtained at the time of the procedure, using 
the procedure consent.  If the patient refuses the optional biopsy at that time, the refusal will be 
documented in the medical record and in the research record. 
10.5.1 Telephone re-consent procedure 
Re-consent on this study may be obtained via telephone according to the following procedure: the 
informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent. A witness to the subject’s signature will sign 
and date the consent.  The original informed consent document will be sent back to the consenting 
investigator who will sign and date the consent form with the date the consent was obtained via 
telephone.  A fully executed copy will be returned via mail for the subject’s records.  The informed 
consent process will be documented on a progress note by the consenting investigator. 
10.5.2 Informed consent of non-English speaking/writing subjects 
If there is an unexpected enrollment of a research participant for whom there is no translated extant 
IRB approved consent document, the principal investigator and/or those authorized to obtain 
informed consent will use the Short Form Oral Consent Process as described in MAS Policy M77-
2, OHSRP SOP 12, 45 CFR 46.117 (b) (2), and 21 CFR 50.27 (b) (2).  The summary that will be 
used is the English version of the extant IRB approved consent document.  Signed copies of both 
the English version of the consent and the translated short form will be given to the subject or their 
legally authorized representative and the signed original will be filed in the medical record. 
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation. Preferably someone who is independent of the subject (i.e., not a family 
member) will assist in presenting information and obtaining consent. Whenever possible, 
interpreters will be provided copies of the relevant consent documents well before the consent 
conversation with the subject (24 to 48 hours if possible).  
We request prospective IRB approval of the use of the short form process and will notify the IRB 
at the time of continuing review of the frequency of the use of the Short Form. 

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11 PHARMACEUTICAL INFORMATION   
11.1 ANETUMAB RAVTANSINE (IND #: 130915) 
11.1.1 Source  
Anetumab ravtansine will be supplied by the manufacturer, Bayer Healthcare Pharmaceuticals 
under a CRADA agreement between the manufacturer and the Thoracic and GI Oncology Branch. 
11.1.2 Toxicity  
The clinical experience with anetumab ravtansine available to date comes from the ongoing Study 
15051 entitled “An open label Phase 1 dose-escalation study to evaluate the safety, tolerability, 
pharmacokinetics, pharmacodynamics, and MTD of the anti-mesothelin ADC anetumab 
ravtansine in subjects with advanced solid tumors.” (NCT01439152) 
Data are available from 147 subjects evaluated on this study, including: 10 dose escalation cohorts 
(45 subjects), two expansion cohorts in mesothelioma and ovarian cancer at a dose of 6.5 mg/kg 
every 3 weeks (32 subjects); two further expansion cohorts in mesothelioma and ovarian cancer at 
doses of 1.8 mg/kg weekly (35 subjects, but data from 1 individual was not available) and 2.2 
mg/kg weekly (36 subjects). 
One hundred nine subjects (74.1%) had treatment emergent adverse events (TEAEs) considered 
to be at least possibly related to the study drug. The most common TEAEs at least possibly related 
to anetumab ravtansine are presented in Table 11 by the number of subjects who reported an event 
in decreasing order. 
A total of 16 subjects died within 30 days of the drug being stopped and none of these events were 
related to the study drug. 
Table 11: Treatment-emergent adverse events at least possibly related to anetumab ravtansine, 
>5% by cohort (with separation of higher and lower dose-escalation cohorts) 
Number of subjects with drug related TEAE 
MedDRA 
Preferred 
Term 
Escalation 
1-8A 
(n=35) 
Escalation 
9 
6.5 mg/kg 
Q3W (n=6) 
Escalation 
10 
7.5 mg/kg 
Q3W (n=4) 
Exp 
6.5 mg/kg 
Q3W 
(n=32) 
Exp 
1.8 mg/kg 
QW (n=34) 
Exp 
2.2 mg/kg 
QW (n=36)  
Total 
(n=147) 
All 
29  
(64.4%) 
n/a 
n/a 
30  
(93.8%) 
26  
(76.5%) 
24  
(66.7%) 
109 
 (74.1%) 
Nausea 
8 (22.8%) 
3 (50.0%) 
2 (50.0%) 
19 (59.4%) 
10 (29.4%) 
8 (22.2%) 
50 (34.0%) 
Fatigue 
10 (28.6%) 
2 (33.3%) 
1 (25.0%) 
16 (50.0%) 
9 (26.5%) 
11 (30.6%) 
49 (33.3%) 
Diarrhea 
1 (2.9%) 
3 (50.0%) 
0 
10 (31.3%) 
6 (17.6%) 
5 (13.9%) 
25 (17.0%) 
Vomiting 
5 (14.3%) 
3 (50.0%) 
1 (25.0%) 
9 (28.1%) 
2 (5.9%) 
4 (11.1%) 
24 (16.3%) 
Decreased 
appetite 
4 (11.4%) 
2 (33.3%) 
0 
10 (31.3%) 
2 (5.9%) 
3 (8.3%) 
21 (14.3%) 
AST 
increase 
0 
1 (16.7%) 
2 (50.0%) 
7 (21.9%) 
5 (14.7%) 
5 (13.9%) 
20 (13.6%) 

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Number of subjects with drug related TEAE 
MedDRA 
Preferred 
Term 
Escalation 
1-8A 
(n=35) 
Escalation 
9 
6.5 mg/kg 
Q3W (n=6) 
Escalation 
10 
7.5 mg/kg 
Q3W (n=4) 
Exp 
6.5 mg/kg 
Q3W 
(n=32) 
Exp 
1.8 mg/kg 
QW (n=34) 
Exp 
2.2 mg/kg 
QW (n=36)  
Total 
(n=147) 
Neuropath
y 
peripheral 
3 (8.6%) 
0 
1 (25.0%) 
9 (28.1%) 
3 (8.8%) 
3 (8.3%) 
19 (12.9%) 
ALT 
increase 
1 (2.9%) 
1 (16.7%) 
1 (25.0%) 
5 (15.6%) 
2 (5.9%) 
6 (16.7%) 
16 (10.9%) 
Vision 
blurred 
0 
0 
2 (50.0%) 
6 (18.8%) 
2 (5.9%) 
4 (11.1%) 
14 (9.5%) 
Platelet 
decrease 
0 
1 (16.7%) 
1 (25.0%) 
6 (18.8%) 
2 (5.9%) 
3 (8.3%) 
13 (8.8%) 
Alk phos 
increase 
0 
0 
1 (25.0%) 
4 (12.5%) 
0 
5 (13.9%) 
10 (6.8%) 
Lymphocy
te 
decrease 
2 (5.7%) 
1 (16.7%) 
0 
2 (6.3%) 
2 (5.9%) 
1 (2.8%) 
8 (5.4%) 
Corneal 
disorder 
0 
0 
2 (50.0%) 
5 (15.6%) 
0 
0 
7 (4.8%) 
Dry eye 
0 
0 
0 
2 (6.3%) 
2 (5.9%) 
3 (8.3%) 
7 (4.8%) 
Asthenia 
2 (5.7%) 
0 
0 
5 (15.6%) 
0 
0 
7 (4.8%) 
Non 
cardiac 
chest pain 
1 (2.9%) 
0 
1 (25.0%) 
2 (6.3%) 
1 (2.9%) 
0 
5 (3.4%) 
Peripheral 
sensory 
neuropath
y 
0 
0 
0 
1 (3.1%) 
3 (8.8%) 
1 (2.8%) 
5 (3.4%) 
Flushing 
1 (2.9%) 
1 (16.7%) 
1 (25.0%) 
1 (3.1%) 
1 (2.9%) 
0 
5 (3.4%) 
Dyspepsia 
1 (2.9%) 
1 (16.7%) 
0 
1 (3.1%) 
2 (5.9%) 
0 
5 (3.4%) 
Pyrexia 
1 (2.9%) 
0 
1 (25.0%) 
0 
1 (2.9%) 
2 (5.6%) 
5 (3.4%) 
Anemia 
0 
0 
0 
1 (3.1%) 
3 (8.8%) 
1 (2.8%) 
5 (3.4%) 
Hypothyro
idism 
0 
0 
0 
0 
2 (5.9%) 
3 (8.3%) 
5 (3.4%) 
Lipase 
increase 
0 
0 
1 (25.0%) 
2 (6.3%) 
1 (2.9%) 
1 (2.8%) 
5 (3.4%) 
Rash 
1 (2.9%) 
0 
0 
1 (3.1%) 
2 (5.9%) 
0 
4 (2.7%) 
Chills 
2 (5.7%) 
0 
1 (25.0%) 
0 
0 
1 (2.8%) 
4 (2.7%) 

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Number of subjects with drug related TEAE 
MedDRA 
Preferred 
Term 
Escalation 
1-8A 
(n=35) 
Escalation 
9 
6.5 mg/kg 
Q3W (n=6) 
Escalation 
10 
7.5 mg/kg 
Q3W (n=4) 
Exp 
6.5 mg/kg 
Q3W 
(n=32) 
Exp 
1.8 mg/kg 
QW (n=34) 
Exp 
2.2 mg/kg 
QW (n=36)  
Total 
(n=147) 
Corneal 
epithelial 
microcysts 
0 
0 
0 
2 (6.3%) 
2 (5.9%) 
3 (8.3%) 
7 (4.8%) 
Hyponatre
mia 
1 (2.9%) 
0 
0 
2 (6.3%) 
0 
1 (2.8%) 
4 (2.7%) 
Dyspnea 
0 
0 
0 
1 (3.1%) 
2 (5.9%) 
1 (2.8%) 
4 (2.7%) 
Arthralgia 
0 
0 
0 
2 (6.3%) 
1 (2.9%) 
1 (2.8%) 
4 (2.7%) 
Cholestero
l increased 
0 
1 (16.7%) 
0 
0 
0 
0 
1 (0.7%) 
Exp = expansion cohort 
Cohorts 1 – 8A were dosed every 3 weeks.  The doses were as follows: cohort 1 (n=3) - 0.15 mg/kg; cohort 2 (n=3) 
– 0.3 mg/kg; cohort 3 (n=4)  - 0.6 mg/kg; cohort 4 (n=4)  – 1.2 mg/kg; cohort 5 (n=4)  – 2.4 mg/kg; cohort 6 (n=4)  
– 3.6 mg/kg, cohort 7 (n=4)  – 4.5 mg/kg; cohorts 8+8A* (n=9)  – 5.5 mg/kg 
 
* including cohort 8A (anetumab ravtansine produced from a new cell line) 
) 
 
Describe all toxicities observed in patients and/or relevant animal studies 
11.1.3 Formulation and preparation  
The drug product is available as a lyophilizate. Each vial contains 62.5 mg of anetumab ravtansine; 
the amount available for administration, based on retractable volume of reconstituted solution, is 
60 mg of anetumab ravtansine. It should be reconstituted in water for injection and diluted in 0.9% 
sodium chloride solution (normal saline) or dextrose 5% solution prior to administration as IV 
infusion. 
The drug product is to be stored at 2°C to 8°C (36°F to 46°F). 
The reconstitution and dilution of the anetumab ravtansine solution and the associated stability 
information is described in detail in a separate manual “Anetumab ravtansine storage and handling 
instructions”. 
 
11.1.4 Administration procedures 
Please see section 3.2. 
11.1.5 Incompatibilities   
None have been confirmed in a clinical study. 

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11.1.5.1 Chemical Structure 
 
Anetumab ravtansine is an ADC consisting of a fully human IgG1 antibody (MF-T, BAY 86-1903) 
directed at the mesothelin antigen and conjugated to a synthetic cytotoxic anticancer agent, 
maytansine derivative (DM4, BAY 100-6640) as toxophore through an SPDB.  
Based on the reference by Davis et al.23, DM4 is a substrate of metabolizing enzymes CYP3A4, 
3A5, and 2D6. Further the package insert of ado-trastuzumab emtansine, which also uses 
maytansine (referred to as DM1) conjugated to trastuzumab, indicates that the cytotoxic 
component is mainly metabolized by 3A4 and to a lesser extent by 3A5. Therefore, concomitant 
administration of strong inhibitors and inducers of CYP3A4 are prohibited in patients receiving 
anetumab ravtansine. 
DM4-Me is a substrate of P-gp transporter and it is possible that medications that are potent 
inhibitors of P-gp transporter could alter the pharmacokinetic profile of DM4-Me in plasma. 
 
 

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Tumor Aggressiveness and Is Associated with Reduced Recurrence-Free and Overall Survival in 
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Golfier S, Kopitz C, Kahnert A, et al. Anetumab ravtansine: a novel mesothelin-targeting 
antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander 
effect. Molecular cancer therapeutics 2014;13:1537-48. 
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Hassan R, Bendell JC, Blumenschein Jr. G, et al. Phase I Study of Anti-Mesothelin 
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Davis JA, Rock DA, Wienkers LC, Pearson JT. In vitro characterization of the drug-drug 
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13 APPENDICES 
13.1 APPENDIX A: NON SIGNIFICANT RISK REQUEST AND DETERMINATION FOR MESOTHELIN 
EXPRESSION TESTING  
13.1.1 NSR Determination Request to FDA 
 

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13.1.2 NSR Designation from FDA 
 

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13.2 APPENDIX B: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance 
without restriction. 
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). 
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. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
Dead. 
 

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13.3 APPENDIX C: CYP3A4 INHIBITORS AND INDUCERS 
Strong CYP3A4 inhibitors 
Strong CYP3A4 inducers 
Boceprevir 
Avasimibe 
Clarithromycin 
Carbamazepine 
Conivaptan 
Phenytoin 
Grapefruit juice 
Rifampin 
Indinavir 
St. John’s wort 
Itraconazole 
 
Ketoconazole 
 
Lopinavir / Ritonavir 
 
Mibefradil (withdrawn in US) 
 
Nefazodone  
 
Nelfinavir 
 
Posaconazole 
 
Ritonavir 
 
Saquinavir 
 
Telaprevir 
 
Telithromycin 
 
Voriconazole 
 
CYP3A4 = Cytochrome P450, family 3, subfamily A, polypeptide 4