Clinical trial NCT03023722
Conditions: Pancreatic Cancer
Sponsor: Yale University
Start date: 2017-05-11; Completion date: 2019-12-11
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to:

-Test the activity/response rate per RECIST 1.1 criteria of anetumab ravtansine in patients with advanced pancreatic cancer who stain for mesothelin expression

The secondary objectives of this study are to:

* Time to Progression (TTP) defined as time from study treatment to RECIST 1.1 progression, or death (others going off study will be censored)
* Toxicity in pancreatic cancer patients (at 6.5 mg/kg dose)

Detailed description:
This is a non-randomized, open-label, multicenter, Phase II study to evaluate the efficacy and safety of intravenous anetumab ravtansine (BAY 94-9343), an anti-mesothelin antibody drug conjugate, in pretreated mesothelin-expressing advanced pancreatic cancer.

At the time of the start of study treatment, the patients will have pretreated advanced pancreatic cancer that also overexpresses mesothelin as determined by immunohistochemistry (IHC).

A maximum of 30 patients will be enrolled in a minimax, Simon 2-stage design with a single early stopping rule for lack of efficacy. The target population is those patients with pancreatic cancer who have failed an earlier treatment. All patients will be treated with an anti-mesothelin immuno-conjugate, in this single arm, non-randomized trial and all patients treated with at least one dose of Anetumab will be included. The endpoint is any response using the RECIST 1.1 criteria.

Arms: arm 1: Patients with advanced metastatic pancreatic cancer who have measurable disease
Interventions: intervention 1: anetumab ravtansine
Intervention descriptions: intervention 1: Patients will receive anetumab ravtansine IV infusion at a dose of 6.5 mg/kg (recommended Phase II dose) on Day 1 of a 21-day cycle

Protocol documents:
Prot_SAP_000.pdf: 
NCT03023722  
   
Unique Protocol ID: 1608018265 
 
Brief Title:  Phase II Anetumab Ravtansine in Pre-treated Mesothelin-expressing Pancreatic Cancer 
 
 19-September-2018 


  
   
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1.  
Title page  
  
An open-label, Phase II study of intravenous anetumab ravtansine (BAY 94-9343), an anti-
mesothelin antibody drug conjugate, in pretreated mesothelin-expressing advanced pancreatic 
cancer  
Phase II anetumab ravtansine in pre-treated mesothelin-expressing pancreatic cancer  
  
Test drug:  
BAY 94-9343 / anetumab ravtansine  
Study purpose:  
Assess the efficacy and safety of anetumab ravtansine as 2nd or 
3rd line treatment in advanced pancreatic cancer  
Clinical study phase:  
II 
  
Date: 
19-September-2018 
Sponsor’s study no.:  
Yale HIC# 1608018265  
  
  
Sponsor:  
Yale Cancer Center, Yale University  
Principal Investigator:          Stacey Stein, MD  
                                             
Statistician:                          Daniel Zelterman, PhD (Yale School of Public Health)  
  
  
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements.  
Confidential  
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this  
document - whether in part or in full - to parties not associated with the clinical investigation, or 
its use for any other purpose, without the prior written consent of the sponsor is not permitted.  
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.  
  
 
 
 
 
 
 


  
   
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Signature of principal investigator  
  
The signatory agrees to the content of the final clinical study protocol as presented.  
  
Name:  
  
Affiliation:    
Date:  
  
  
Signature:   
 
Signed copies of this signature page are stored in the sponsor’s study file and in the respective 
center’s investigator site file.  
 
 
 
 
 
 
 
 
 
 
 
 


  
   
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2.  
Synopsis  
Title  
An, open-label, Phase II study of intravenous anetumab ravtansine (BAY 
94-9343), an anti-mesothelin antibody drug conjugate, in pretreated 
mesothelin-expressing advanced pancreatic cancer  
Short title  
Phase II anetumab ravtansine as 2nd or 3rd line treatment for pancreatic 
cancer  
Clinical study phase  
II  
Study objective(s)  
The primary objective of this study is to:  
• 
Test the activity/response rate per RECIST 1.1 criteria of anetumab 
ravtansine in patients with advanced pancreatic cancer who stain for 
mesothelin expression  
  
The secondary objectives of this study are to:  
• 
Time to Progression (TTP) defined as time from study treatment to 
RECIST progression, or death (others going off study will be 
censored)   
• 
Toxicity in pancreatic cancer patients (at 6.5 mg/kg dose)  
Test drug(s)  
Anetumab ravtansine  
Name of active ingredient  
Anetumab ravtansine / BAY 94-9343  
Dose(s)  
6.5 mg/kg every 3 weeks (Q3W)  
Route of administration  
Intravenous (IV) infusion over 1 h  
Duration of treatment  
Patients will continue on treatment until one of the following occurs:  
• 
Progressive disease (PD) as defined by Response Evaluation Criteria 
in Solid Tumors (RECIST) v1.1 as assessed by Investigator.   
However, all scans will also be read independently by radiologists in 
Precision Metrics (previously known as Tumor Imaging Metrics 
Core [TIMC]) or an equivalent system and archived therein.   
• 
Clinical progression as assessed by investigator.   
• 
Death  
• 
Any other criterion for withdrawal from study treatment.  
Reference drug(s)  
Not applicable   
Indication  
Pre-treated advanced pancreatic cancer, Mesothelin positive by IHC  
Diagnosis and main criteria for 
inclusion /exclusion  
Patients with advanced metastatic pancreatic cancer who have measurable 
disease; must have at least one and not more than two prior chemotherapy 
regimens for advanced disease (neoadjuvant or adjuvant chemotherapy 
would not be counted as a line of therapy). If prior radiation, measurable 
lesion outside radiation portal. ECOG PS 0-1; Mesothelin positive 
(defined as 30% of cells with staining 2+ or 3+ on IHC for mesothelin).  
Must have normal organ function with LFTs <2.5 x ULN, no history of 
keratitis or corneal disease.  Excluded from study if have uncontrolled 
medical illness or infections, peripheral neuropathy interfering with 
function, history of corneal disease or keratitis  
Study design  
A nonrandomized, open-label, single arm, 2-3 center, Phase II study.  


  
   
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Patients will be treated and undergo imaging scan every 6 weeks.    
RECIST 1.1 criteria to be used for response  
Descriptive statistics of RR (response rate) + 95% CI  
Time to Progression calculated by K-M method  
All patients treated with at least one dose of Anetumab to be included  
A maximum of 30 patients will be enrolled in a minimax, Simon 2-stage 
design with a single early stopping rule for lack of efficacy.  The target 
population is those patients with pancreatic cancer who have failed an 
earlier treatment.  All patients will be treated with an anti-mesothelin 
immuno-conjugate, in this single arm, non-randomized trial.  The 
endpoint is any response using the RECIST 1.1 criteria.  
The minimax, Simon 2-stage design testing 5% null hypothesis versus a 
21% alternative requires a maximum of 30 patients.  If there are no 
patients exhibiting any response among the first 20, which indicates a 
response rate less than 5%, then the trial will terminate early.  If there is at 
least one response among the first 20 (indicating response rate of at least 
5%), then the trial will accrue an additional 10 patients for a maximum of 
30. Four or more responses out of 30 will reject the null hypothesis in 
favor of the 21% response alternative.  These criteria have significance 
level (alpha) 0.1 and power 90%.  The probability of stopping early is 
36% if the response rate is 5% or lower.  The expected sample size is 
26.4.  
Methodology  
Primary efficacy will be assessed based on radiological tumor evaluation 
by contrast-enhanced computed tomography (CT) or contrast-enhanced 
magnetic resonance imaging (MRI) of chest/abdomen/pelvis. During 
treatment as well as active follow-up, tumor imaging will be performed 
with the same modality to the extent possible, every 6 weeks during the 
first 6 months after the start of study treatment, every 9 weeks until the 
end of year 2, and every 12 weeks thereafter until RECIST confirmed 
radiological disease progression or end of study.   
Safety evaluations will be done at full screening, at each clinic visit during 
the treatment period, and at the safety follow-up visit. The National 
Cancer Institute’s Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) version 4.03 will be used to grade severity of adverse 
events (AEs).  
Type of control  
Not applicable  
Data Monitoring Committee  
Yes  
Number of patients  
A maximum of 30 patients will be enrolled  
Primary variable  
  
Response rate as measured per RECIST 1.1 criteria  
 
  
Plan for statistical analysis  
The minimax, Simon 2-stage design testing 5% null hypothesis versus a 
21% alternative requires a maximum of 30 patients.  If there are no 
patients exhibiting any response among the first 20, which indicates a 
response rate less than 5%, then the trial will terminate early.  If there is at 
least one response among the first 20 (indicating response rate of at least 
5%), then the trial will accrue an additional 10 patients for a maximum of  


  
   
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30. Four or more responses out of 30 will reject the null hypothesis in favor of 
the 21% response alternative.  These criteria have significance level (alpha) 0.1 
and power 90%.  The probability of stopping early is 36% if the response rate 
is 5% or lower.  The expected sample size is 26.4.  
  
  
  
 


  
   
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Contents 
1. 
Title page ................................................................................................................................... 1 
2. 
Synopsis .................................................................................................................................... 3 
3. 
Introduction ............................................................................................................................. 14 
3.1 
Background ....................................................................................................................... 14 
3.2 
Rationale of the study ....................................................................................................... 15 
4. 
Study objectives ...................................................................................................................... 15 
5. 
Study design ............................................................................................................................ 15 
5.1 
Design overview ............................................................................................................... 15 
5.2 
Primary variable ............................................................................................................... 16 
6. 
Study population ..................................................................................................................... 16 
6.1 
Inclusion criteria ............................................................................................................... 16 
6.1.1 
Eligibility criteria for prescreening ........................................................................... 16 
6.1.2 
Eligibility criteria for full study ................................................................................ 17 
6.2 
Exclusion criteria .............................................................................................................. 18 
6.3 
Withdrawal of patients from study ................................................................................... 20 
6.3.1 
Screening failure ....................................................................................................... 20 
6.3.2 
Withdrawal criteria .................................................................................................... 21 
6.3.3. 
Lost to follow-up patients ......................................................................................... 23 
6.3.4 
General withdrawal procedures ................................................................................. 23 
6.3.5 
Replacement .............................................................................................................. 23 
6.4 
Patient identification ......................................................................................................... 23 
7. 
Treatment(s) ............................................................................................................................ 23 
7.1 
Treatments to be administered .......................................................................................... 23 
7.2 
Identity of study treatment ................................................................................................ 23 
7.2.1 
Test drug - anetumab ravtansine ............................................................................... 23 
7.3 
Dosage and administration ............................................................................................... 25 
7.3.1 
Administration of anetumab ravtansine .................................................................... 25 
7.3.2 
Dose modification ..................................................................................................... 25 
7.4 
Drug logistics and accountability ..................................................................................... 35 
7.5 
Treatment compliance ...................................................................................................... 36 
8. 
Non-study therapy ................................................................................................................... 36 
8.1 
Prior and concomitant therapy .......................................................................................... 36 
8.2 
Post-study therapy ............................................................................................................ 39 
9. 
Procedures and variables ......................................................................................................... 40 


  
   
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9.1 
Tabular schedule of evaluations ....................................................................................... 40 
9.2 
Visit description ................................................................................................................ 42 
9.2.1 
Prescreening .............................................................................................................. 42 
9.2.2 
Full screening period ................................................................................................. 43 
9.2.3 
Treatment period ....................................................................................................... 44 
9.2.4 
Efficacy assessments ................................................................................................. 48 
9.2.5 
Follow-up periods ..................................................................................................... 48 
9.3 
Population characteristics ................................................................................................. 50 
9.3.1 
Demographic ............................................................................................................. 50 
9.3.2 
Medical history .......................................................................................................... 50 
9.3.3 
Other baseline characteristics .................................................................................... 50 
9.4 
Efficacy ............................................................................................................................. 51 
9.4.1 
Radiological tumor assessments ................................................................................ 51 
9.4.2 
Survival ..................................................................................................................... 52 
9.5 
Safety ................................................................................................................................ 53 
9.5.1 
Adverse events .......................................................................................................... 53 
9.5.2 
Pregnancies ................................................................................................................ 59 
9.5.3 
Further safety ............................................................................................................. 60 
9.6 
Other procedures and variables ........................................................................................ 62 
9.6.1 
Biomarkers ................................................................................................................ 62 
9.7 
Appropriateness of procedures / measurements ............................................................... 63 
10. 
Statistical methods and determination of sample size .......................................................... 63 
10.1 
General considerations .................................................................................................. 63 
10.2 
Variables and planned statistical analyses .................................................................... 63 
10.2.1 
Population characteristics ...................................................................................... 63 
10.2.2 
Primary efficacy variable ....................................................................................... 63 
10.2.3 
Other variables ....................................................................................................... 65 
10.3 
Planned interim analyses ............................................................................................... 65 
11. 
Data handling and quality assurance .................................................................................... 65 
11.1 
Data recording ............................................................................................................... 65 
11.1.1 
Source documentation ........................................................................................... 65 
11.1.2 
Data recorded from prescreening and full screening failures ................................ 66 
11.2 
Monitoring .................................................................................................................... 66 
11.3 
Audit and inspection ..................................................................................................... 67 
11.4 
Archiving ...................................................................................................................... 67 


  
   
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12. 
Premature termination of the study ...................................................................................... 68 
13. 
Ethical and legal aspects ...................................................................................................... 68 
13.1 
Investigator(s) and other study personnel ..................................................................... 68 
13.2 
External data evaluation bodies Data Safety Monitoring Committee (DSMC) ........... 69 
13.3 
Funding and financial disclosure .................................................................................. 69 
13.3.1 
Funding ...................................................................................................................... 69 
13.3.2 
Financial disclosure ................................................................................................... 69 
13.4 
Ethical and legal conduct of the study .......................................................................... 70 
13.5 
Patient information and consent .................................................................................... 70 
13.5.1 
Patient information and informed consent form for prescreening ............................ 70 
13.5.2 
Patient information and informed consent form for full study .................................. 70 
13.6 
Publication policy and use of data ................................................................................ 71 
13.7 
Confidentiality .............................................................................................................. 71 
14. 
Reference list ........................................................................................................................ 72 
15. 
Protocol amendments ........................................................................................................... 73 
16. 
Appendices ........................................................................................................................... 74 
16.1 
ECOG Performance Status ........................................................................................... 74 
16.2 
New York Heart Association (NYHA) functional classification ................................. 75 
16.3 
Response assessment .................................................................................................... 75 
16.4 
National Cancer Institute’s Common Terminology Criteria for Adverse Events, 
version 4.03 ................................................................................................................................. 76 
16.5 
CYP3A4 inhibitors and inducers .................................................................................. 76 
16.6 
Calculation of glomerular filtration rate by the Modification of Diet in Renal Disease 
formula 77 
16.7 
Mosteller Equation for calculation of body surface area (BSA) ................................... 77 
 
Table of tables  
Table 2 -1  
Identity of anetumab ravtansine  .................................................................................................... 24 
Table 2 -2  
Dose levels of anetumab ravtansine
 .............................................................................................. 26 
Table 2 -3  
Dose adjustments in response to neutrophil and platelet nadir 
a counts of the previous cycle
 . 27 
Table 2 -4  
Dose adjustments in response to pre
-infusion values  ................................................................... 28 
Table 2 -5  
Dose adjustments in response to non
-hematologic toxicities  ...................................................... 30 
Table 2 -6  
Bayer classification and management of corneal epitheliopathies
 .............................................. 32 
Table 2 -7  
Bayer classification of visual acuity changes
.................................................................................. 35 
Table 2 -8  
Prohibited prior and concomitant therapies
 ................................................................................. 37 
Table 2 -9  
Permitted concomitant therapies  .................................................................................................. 39 
 
Table of figures  


  
   
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Figure 2 -1 
Withdrawal criteria  ......................................................................................................................... 22  
  
 


  
   
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List of abbreviations   
5-HT3  
5-hydroxytryptamine (serotonin)  
ADC  
Antibody-drug conjugate  
AE  
Adverse event  
AG  
Joint stock company, Aktiengesellschaft  
ALP  
Alkaline phosphatase  
ALT  
Alanine aminotransferase  
ANC  
Absolute neutrophil count  
aPTT  
Activated partial thromboplastin time  
ASCO  
American Society of Clinical Oncology  
AST  
Aspartate aminotransferase  
BCVA  
Best corrected visual acuity  
β-HCG  
β subunit of human chorionic gonadotropin  
BIO  
Biomarker set  
BM  
Biomarker  
BP  
Blood pressure  
BSA  
Body surface area  
BUN  
Blood urea nitrogen  
°C  
Celcius degree(s)  
C  
Cycle  
CBC  
Complete blood count  
Cmax  
Maximum drug concentration  
CNS  
Central nervous system  
COA  
Clinical Outcomes Assessment  
CR  
Complete response  
CRF  
Case report form  
CSF  
Colony stimulating factor  
CSR  
Clinical Study Report  
CT  
Computed tomography  
CTCAE  
Common Terminology Criteria for Adverse Events  
CYP2D6  
Cytochrome P450, family 2, subfamily D, polypeptide 6  
CYP3A4  
Cytochrome P450, family 3, subfamily A, polypeptide 4  
D  
Day  
dL  
Deciliter  
DM4  
Derivatives of maytansine 4  
DM4-Me  
Methyl-DM4  
DSMC  
Data and Safety Monitoring Committee  
DNA  
Deoxyribonucleic acid  
DOR  
Duration of response  
ECG  
Electrocardiogram  
EchoCG  
Echocardiogram  
ECOG  
Eastern Cooperative Oncology Group  
ECOG PS  
Eastern Cooperative Oncology Group Performance Status  
EDC  
Electronic data capture  
eGFR  
Estimated glomerular filtration rate  
 
  
 
ENR  
Enrolled set  


  
   
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ETDRS  
Early 
Treatment 
Diabetic
Retinopathy Study  
EU  
European Union  
°F  
Fahrenheit degree(s)  
FDA  
Food and Drug Administration  
FFPE  
Formalin-fixed, paraffin-embedded 
g  
Gram(s)  
GCP  
Good Clinical Practice  
G-CSF  
Granulocyte-colony stimulating 
factor  
GFR  
Glomerular filtration rate  
GGT  
Gamma-glutamyl transferase  
GMP  
Good Manufacturing Practice  
GPV  
Global Pharmacovigilance  
h  
Hour(s)  
H0  
Null hypothesis  
HA  
Alternative hypothesis  
Hb  
Hemoglobin  
HIC  
Human Investigation Committee  
HIV  
Human immunodeficiency virus  
HR  
Heart rate  
IB  
Investigator’s brochure  
ICF  
Informed consent form  
ICH  
International Conference on 
Harmonization  
IDS  
Investigational Drug Service  
IEC  
Independent Ethics Committee  
IgG1  
Immunoglobulin G subclass 1  
IHC  
Immunohistochemistry  
ILD  
Interstitial lung disease  
IM  
Immunogenicity  
IMP  
Investigational medicinal product  
INR  
International normalized ratio  
IOP  
Intraocular pressure  
IRB  
Institutional Review Board  
ITT  
Intent-to-treat (set)  
IUD  
Intrauterine device  
IUS  
Intrauterine hormone-releasing 
system  
IV  
Intravenous  
kg  
Kilogram(s)  
LDH  
Lactic dehydrogenase   
LLN  
Lower limit of normal  
LPLV  
Last patient last visit  
LVEF  
Left ventricular ejection fraction  
m2  
Square meter(s)  
MCU  
Multi-Center Unit  
MD  
Doctor of Medicine  


  
   
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MDRD  
Modification of Diet in Renal 
Disease  
MedDRA  
Medical Dictionary for Regulatory
Activities  
mg  
Milligram(s)  
Min  
Minute(s)  
miRNA  
Micro ribonucleic acid  
mL  
Milliliter(s)   
mm3  
Cubic millimeter(s)  
mmHg  
Millimeter of mercury  
MoA  
Mechanism of action  
mRECIST  
Modified Response Evaluation Criteria in Solid 
Tumors  
MRI  
Magnetic resonance imaging  
MTD  
Maximum tolerated dose  
MUGA  
Multiple gated acquisition  
N  
Number of patients  
n  
Number of non-missing values  
N HCl  
Normal hydrochloric acid  
NC  
No change  
NCCN  
National Comprehensive Cancer Network  
NCI-CTCAE  National Cancer Institute’s Common 
Terminology Criteria for Adverse Events  
NE  
Not evaluated  
NGS  
Next generation sequencing  
NYHA  
New York Heart Association  
ORR  
Objective response rate  
OS  
Overall survival  
PD  
Progressive disease  
PET  
Positron emission tomography  
PFS  
Progression-free survival  
PFT  
Pulmonary function test  
P-gp  
Permeability glycoprotein  
PhD  
Doctor of Philosophy  
PI  
Principal Investigator  
PK(s)  
Pharmacokinetic(s)  
PR  
Partial response  
PT  
Prothrombin time  
PTT  
Partial thromboplastin time  
Q3W  
Every 3 weeks  
QA  
Quality assurance  
QW  
Once weekly  
RECIST  
Response Evaluation Criteria in Solid Tumors  
RNA  
Ribonucleic acid  
RPIID  
Recommended Phase II dose  
RR  
Respiratory rate  
RT  
Radiotherapy  
SAE  
Serious adverse event  


  
   
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SAF  
Safety set  
SAP  
Statistical Analysis Plan  
SAS  
Statistical Analysis Software  
SD  
Stable disease  
SoC  
Standard of care  
SPDB  
N-succinimidyl 
4-(2-pyridyldithio)butyrate
(reducible disulfide linker)  
SPK  
Superficial punctate keratitis  
SQR RT  
Square root (√)  
SUSAR  
Suspected, unexpected, serious adverse reaction  
T1  
Tumor invades lamina propria  
Ta  
Non-invasive tumor  
TEAE  
Treatment-emergent adverse 
event  
Temp  
Body temperature  
Tis  
Carcinoma in situ  
TMF  
Trial master file  
TTP  
Time to progression  
ULN  
Upper limit of normal  
US(A)  
United States of America  
USP  
United States Pharmacopeia  
WBC  
White blood cell count  
WOCBP  
Women of childbearing 
potential  
YCC  
Yale Cancer Center  
YCCI  
Yale 
Center 
for 
Clinical
Investigation  
 
 
  
 


  
   
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3.  
Introduction  
3.1  
Background  
Mesothelin is a membrane associated differentiation antigen present on normal mesothelial 
cells and overexpressed in a vast majority of ductal pancreatic adenocarcinomas, 
mesotheliomas, and adenocarcinomas of the ovary.  The biological function of mesothelin 
remains unknown and mesothelin-deficient mice have no obvious phenotype of defect. 
Mesothelin is an internalizing antigen and shows a restricted expression profile in normal 
tissue making it an excellent target for antibody directed cytotoxic drug delivery.  
BAY 94-9343, anetumab ravtansine, is an antibody-drug conjugate 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 
1006640) as toxophore through a reducible disulfide linker (SPDB).  Preclinical efforts have 
shown specific effects on mesothelin positive cell lines and in xenograft models including 
activity in pancreatic BxPC3 xenograft model.  Toxicology studies showed a number of 
important signals but specifically skin toxicity.  
Human phase 1 and PK studies were performed showing terminal phase half-life values of the 
ADC and Total Antibody were approximately 5.5 to 6 days. Plasma DM4 and DM4-Me 
concentrations declined with a half-life of approximately 3 days and 5.5 days at the MTD. DM4-
Me pharmacokinetics exhibited moderate to high variability and exposure increased in a 
substantially more than dose proportional manner in the dose range studied.  
The safety results from the dose escalation part of the first-in-human study 15051 in 45 
patients with advanced cancer (BAY 94-9343 dose range, 0.15-7.5 mg/kg q3w) were as 
follows: 1) The non-tolerable dose of BAY 94-9343 was 7.5 mg/kg q3w; the non-tolerable 
toxicities at 7.5 mg/kg q3w were corneal toxicity (blurry vision and keratitis due to corneal 
epitheliopathy), peripheral neuropathy and increase in serum amylase and lipase; 2) The 
maximum tolerated dose was 6.5 mg/kg q3w; the only dose-limiting toxicity observed at this 
dose level was the asymptomatic Grade 3 increase in serum AST/ALT; 3) The most common 
treatment-emergent adverse events at least possibly related to BAY 94-9343 were fatigue, 
nausea, vomiting, anorexia, peripheral neuropathy, myalgia, weakness and diarrhea. The most 
common treatment-emergent lab abnormalities were lymphopenia, hypoalbuminemia, 
hyponatremia, hyperglycemia and hypokalemia; 4) at doses below the non-tolerated dose, the 
TEAEs were mostly mild and not clinically significant except for cardiac chest pain, 
hypertension, grade 3 increase in ALT and AST, and decrease in platelets and sodium.  
The safety results from the MTD Expansion 6.5 mg/kg q3w cohort, which evaluated the MTD 
for BAY 94-9343 determined in the dose escalation cohorts were as follows: 1) BAY 94-9343 
at 6.5 mg/kg given IV once every 3 weeks was considered tolerable in the two cohorts of 
subjects with ovarian cancer (n=20) and pleural or peritoneal mesothelioma (n=12); 2) 
Overall, 16 of 32 (50%) subjects treated at 6.5 mg/kg q3w have required dose reduction to 5.5 
mg/kg q3w and 4 (25%) of these subjects required another dose reduction to 4.5 mg/kg; 3) the 
safety finding of particular relevance was the high incidence of corneal toxicity (blurred 
vision and keratitis with vision impairment due to corneal epithelial microcysts or deposits in 
12 of 32 subjects) causally attributed to BAY 94-9343; 4) although being fully reversible in 
the vast majority of cases, the corneal toxicity invariably necessitated lengthy treatment 
interruption and dose reduction; 5) otherwise the safety profile of BAY 94-9343 in the MTD 


  
   
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Expansion 6.5 mg/kg q3w cohort was very similar to that observed in dose escalation cohorts 
up to and including the Cohort 9 (6.5 mg/kg q3w), with mostly mild TEAEs and remarkably 
low incidence of drug-related SAEs.  One patient in a Japanese cohort with pancreatic cancer 
developed drug-induced liver injury.    
We will therefore pursue the 6.5 mg/kg dose, as having an acceptable incidence of corneal 
toxicity and keratitis and as the phase II dose in use for current studies.  
3.2  
Rationale of the study  
The need for new treatments for pancreatic cancer is great.  At the MTD of 6.5 mg/kg Q3W, 
anetumab ravtansine has demonstrated a tolerable safety profile and efficacy in pancreatic 
cancer.  If this study shows promise, with at least 21% of treated patients showing RECIST 
response, or prolonged delay in progression compared with historical controls, this would 
suggest the potential to impart large clinical benefit and warrant larger controlled trials.  
4.  
Study objectives  
The primary objective of this study is to:  
• 
Test the activity/response rate per RECIST 1.1 criteria of anetumab ravtansine in patients 
with advanced pancreatic cancer who stain for mesothelin expression  
  
The secondary objectives of this study are to:  
• 
Time to Progression (TTP) defined as time from study treatment to RECIST 1.1 
progression, or death (others going off study will be censored)   
• 
Toxicity in pancreatic cancer patients (at 6.5 mg/kg dose)  
5.  
Study design  
5.1  
Design overview  
This is a non-randomized, open-label, multicenter, Phase II study to evaluate the efficacy and 
safety of intravenous anetumab ravtansine (BAY 94-9343), an anti-mesothelin antibody drug 
conjugate, in pretreated mesothelin-expressing advanced pancreatic cancer.  
At the time of the start of study treatment, the patients will have pretreated advanced 
pancreatic cancer that also overexpresses mesothelin as determined by immunohistochemistry 
(IHC).  Mesothelin testing will be performed centrally.  
A maximum of 30 patients will be enrolled in a minimax, Simon 2-stage design with a single 
early stopping rule for lack of efficacy.  The target population is those patients with pancreatic 
cancer who have failed an earlier treatment.  All patients will be treated with an anti-
mesothelin immuno-conjugate, in this single arm, non-randomized trial and all patients treated 
with at least one dose of Anetumab will be included.  The endpoint is any response using the 
RECIST 1.1 criteria.  
The minimax, Simon 2-stage design testing 5% null hypothesis versus a 21% alternative 
requires a maximum of 30 patients.  If there are no patients exhibiting any response among 
the first 20, which indicates a response rate less than 5%, then the trial will terminate early. If 
there is at least one response among the first 20 (indicating response rate of at least 5%) then 
the trial will accrue an additional 10 patients for a maximum of 30. Four or more responses 
out of 30 will reject the null hypothesis in favor of the 21% response alternative.  These 


  
   
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criteria have significance level (alpha) 0.1 and power 90%.  The probability of stopping early 
is 36% if the response rate is 5% or lower.  The expected sample size is 26.4.  
The start of the treatment period is defined by first administration of study drug (anetumab 
ravtansine). Patients will receive anetumab ravtansine IV infusion at a dose of 6.5 mg/kg 
(recommended Phase II dose [RPIID]) on Day 1 of a 21-day cycle. Treatment will be 
continued until death or occurrence of PD as defined by Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 and assessed by blinded radiology review, or clinical progression, or 
until another criterion for withdrawal from the study is met.   
Patients who discontinue study treatment for any reason other than confirmed radiological PD 
will be followed for progression during active follow-up (which includes the safety follow-up 
period) until confirmed PD for this patient is observed.  
All patients who end study treatment for any reason will be followed for OS and the start of 
any new anti-cancer treatment every 3 months during the long-term follow-up period until 
data maturation for the OS final analysis is reached, or until death, consent withdrawal or end 
of study, whichever occurs first.  
Primary efficacy will be assessed based on radiological tumor evaluation by contrast-
enhanced computed tomography (CT) or contrast-enhanced magnetic resonance imaging 
(MRI) of chest/abdomen/pelvis. During treatment as well as active follow-up, tumor imaging 
will be performed with the same modality to the extent possible, every 6 weeks during the 
first 6 months after the start of study treatment, every 9 weeks until the end of year 2, and 
every 12 weeks thereafter until RECIST confirmed radiological disease progression or end of 
study.   
Safety evaluations will be done at full screening, at each clinic visit during the treatment 
period, and at the safety follow-up visit. The National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 will be used to grade 
severity of adverse events (AEs).  
Patients will be contacted to assess survival status every 3 months during long-term follow-
up.  In addition, extra survival sweep contacts will be conducted at the time of PFS final 
analysis and prior to OS final analysis to ensure that long-term follow-up data is current.  
5.2  
Primary variable  
The primary variable of this study is response rate as measured per RECIST 1.1 criteria.  
6.  
Study population  
6.1  
Inclusion criteria  
Patients eligible for inclusion into the study must meet the following inclusion criteria.  
6.1.1  
Eligibility criteria for prescreening  
Prescreening can be performed without evidence of disease progression after the initial 
treatment at the investigator’s discretion.  
  
1. 
Written informed consent for prescreening.  


  
   
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2. 
Unresectable locally advanced or metastatic pancreatic cancer, confirmed by histology.   
3. 
At least one but not more than two prior chemotherapy regimens with progression or 
documented intolerance (neoadjuvant or adjuvant chemotherapy would not be counted as a 
line of therapy. If prior radiation, measurable lesion outside radiation portal).  
4. 
Availability of archival or fresh tissue for testing of mesothelin expression level.  
Note: Archival tissue is preferred and fresh biopsy should only be obtained if no 
archival tissue is available and if in the investigator’s judgement, there is no additional 
risk for the patient’s safety. Patients with a sarcomatoid histology are not expected to 
have mesothelin overexpression and should not enter prescreening.  
5. 
Age ≥ 18 years.  
6. 
Life expectancy of at least 3 months.  
7. 
No prior treatment with anetumab ravtansine (or any other mesothelin-based therapy)   
Besides these basic criteria, any criterion as outlined below under inclusion eligibility 
criteria for the full study and exclusion criteria already known to prohibiting the patient’s 
participation in the study should be considered. No study-related procedures should be 
performed which are not covered by the prescreening ICF.  
6.1.2  
Eligibility criteria for full study  
The following inclusion criteria must be met at the time of screening, prior to the start of 
study drug, unless otherwise specified.  
1. 
Written informed consent for full study.  
2. 
Histological documentation of overexpressing mesothelin at the moderate (2+) or stronger 
(3+) level in at least 30% of tumor cells as determined by IHC.  
3. 
Unresectable locally advanced or metastatic pancreatic cancer   
4. 
At least one but not more than two prior chemotherapy regimens with progression or 
documented intolerance (neoadjuvant or adjuvant chemotherapy would not be counted as a 
line of therapy. If prior radiation, measurable lesion outside radiation portal).    
5. 
Patients must have at least 1 measurable lesion according to RECIST v 1.1 (specified in 
Section 9.4.1).  
6. 
ECOG PS of 0 or 1 (specified in Appendix 16.1).  
7. 
Life expectancy of at least 3 months.  
8. 
Adequate bone marrow, liver and renal function as assessed by the following laboratory 
requirements conducted within 7 days before starting study treatment:  
• 
Total bilirubin ≤ 1.5 x the upper limit of normal (ULN). Documented Gilbert 
syndrome is allowed if total bilirubin is mildly elevated (< 6 mg/dL).  
• 
ALT and AST ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement of their 
cancer).  
• 
ALP limit ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement of their 
cancer).  


  
   
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• 
Extent of baseline tumor burden will not interfere with causal assessment of 
treatment-emergent hepatotoxicity, at the investigator’s discretion.  
• 
Amylase and lipase ≤ 1.5 x ULN.  
• 
Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 according to the Modification 
of Diet in Renal Disease (MDRD) abbreviated formula (see Appendix 16.6).  
• 
Adequate coagulation, as assessed by the following laboratory test results:  
o International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN 
(CTCAE Grade ≤ 1).  
o Partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN 
(CTCAE Grade ≤ 1).  
Note: Patients on stable dose of anti-coagulation therapy will be allowed to 
participate if they have no sign of bleeding or clotting and INR / PT and PTT / 
aPTT test results are compatible with the acceptable benefit-risk ratio at the 
investigator’s discretion (see Section 8.1).  
• 
Platelet count ≥ 75,000/mm3 , without platelet transfusion within 3 weeks before the 
start of study treatment (see Section 8.1).  
• 
Hemoglobin (Hb) ≥ 8 g/dL,  
Note: Patients receiving chronic low-dose erythropoietin for chronic renal 
failure are allowed provided no dose adjustment is undertaken within 6 weeks 
before signing consent for full study and until safety follow-up visit and 
provided that they fulfill conditions of eligibility criteria (see also exclusion 
criterion number 18).  
• 
Absolute neutrophil count (ANC) ≥ 1000/mm3 
9. 
Left ventricular ejection fraction (LVEF) ≥ 50% or the lower limit of normal (LLN) 
according to local institution ranges of normality.  
6.2  
Exclusion criteria  
Patients who meet the following criteria at the time of full screening and on C1D1 will be 
excluded:  
1. 
Previous assignment to treatment during this study. Patients permanently withdrawn from 
study participation will not be allowed to re-enter the study.  
2. 
Previous (within 5 drug half-lives – if drug half-life in subjects is known – or 28 days, 
whichever is shorter, before the start of study treatment) or concomitant participation in 
another clinical study with investigational medicinal product(s) (IMP[s]).  
3. 
Patients with corneal epitheliopathy or any eye disorder that may predispose the patients to 
this condition at the discretion of the investigator.  
4. 
Previous or concurrent cancer that is distinct in primary site or histology within 5 years.  
Exceptions: curatively treated   
• 
Cervical cancer in situ. 


  
   
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• 
Non-melanoma skin cancer.  
• 
Superficial bladder tumors (Non-invasive tumor [Ta], Carcinoma in situ [Tis] and 
Tumor invades lamina propria [T1]).  
5. 
Major surgery, open biopsy or significant traumatic injury within 28 days before the start 
of study treatment.  
6. 
Pregnant or breast-feeding patients. WOCBP must have a serum pregnancy test performed 
a maximum of 7 days before the start of study treatment, and a negative result must be 
documented before the start of study treatment.  
7. 
Pre-existing cardiac conditions as outlined below:  
• 
Congestive heart failure ≥ New York Heart Association (NYHA) class 2 (specified in 
Appendix 16.2).  
• 
Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 
months). Myocardial infarction less than 6 months before the start of study treatment.  
• 
Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are 
permitted).  
8. 
Clinically significant uncontrolled hypertension (systolic blood pressure > 150 mmHg or 
diastolic pressure > 90 mmHg despite optimal medical management).  
9. 
Arterial thrombotic or embolic events such as cerebrovascular accident (including transient 
ischemic attacks), or venous pulmonary embolism within 6 months before the start of 
study treatment; venous thrombotic events such as deep vein thrombosis within 3 months 
before the start of study treatment.  
10. 
Ongoing or active infection (bacterial, fungal, or viral) of NCI-CTCAE version 4.03 Grade 
> 2.  
11. 
Known history of human immunodeficiency virus (HIV) infection.  
12. 
Known history of chronic hepatitis B or C.  
13. 
Patients with seizure disorder requiring medication.  
14. 
Symptomatic brain metastases or meningeal tumors or other uncontrolled metastases in the 
central nervous system (CNS) unless the patient  
• 
Is > 6 months from definitive therapy,  
• 
Has a negative imaging study within 4 weeks before study entry (ICF signature for 
full study) and  
• 
Is clinically stable with respect to the tumor at the time of study entry.  
15. 
History of organ allograft, stem cells or bone marrow transplant.  
16. 
Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event 
≥ CTCAE Grade 3 within 4 weeks before the start of study treatment.  
17. 
Non-healing wound, ulcer, or bone fracture.  
18. 
Renal failure requiring peritoneal dialysis or hemodialysis.  


  
   
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19. 
Known hypersensitivity to anetumab ravtansine, study drug classes or excipients in the 
formulation.  
20. 
Any illness or medical conditions that are unstable or could jeopardize the safety of the 
patient and his/her compliance in the study.  
21. 
Unresolved toxicity higher than NCI-CTCAE version 4.03 Grade 1 attributed to any prior 
therapy/procedure excluding anemia or neuropathy Grade 2 (see Section 6.1.2, inclusion 
criterion 8) and alopecia of any Grade.  
22. 
Any prohibited prior or concomitant therapy (see Table 2-8 in Section 8.1).  
6.3  
Withdrawal of patients from study  
6.3.1 Screening failure  
6.3.1.1  
Prescreening failure  
A patient whose tumor tissue is tested by IHC for mesothelin overexpression and whose result 
is not moderate (2+) and stronger (3+) mesothelin overexpression in at least 30% of the tumor 
cells, or who fails to meet any of the other eligibility criteria for prescreening, is regarded as a 
“prescreening failure”. These patients should not undergo any further screening procedures.  
6.3.1.2  
Full screening failure  
A patient who passes the prescreening, including the mesothelin overexpression testing, 
but for any other reason (e.g., failure to satisfy the remaining selection criteria) terminates 
the study before enrollment is regarded as a “full screening failure”. See Section 11.1 for 
data to be collected for screening failures.  
Re-starting the defined set of screening procedures to enable the “screening failure” patient’s 
participation at a later time point is not allowed – with the following exceptions:  
• 
The patient had successfully passed the screening procedures, but could not start 
subsequent treatment on schedule.  
• 
Initial screening occurred too early to complete the required washout period after prior 
therapy.  
• 
The in- / exclusion criteria preventing the patient’s initial attempt to participate have been 
changed (via protocol amendment).  
• 
Equivocal screening results require further testing for clarification even if, for logistical 
reasons, the further testing cannot be performed within the allocated time window (e.g. 
equivocal laboratory creatinine clearance requiring formal creatinine clearance 
measurement).  
• 
Resolution of toxicity, now meeting all criteria  
In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the patient to an unjustifiable health risk. Also, for re-screening, the patient has to 
resign the main consent document (for the full study), even if it was not changed after the 
patient’s previous screening.  
 


  
   
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6.3.2  Withdrawal criteria  
All patients who enter the study should complete all phases of the study unless they are screen 
failures or meet the criteria for withdrawal. Phases of the study include:  
1. Prescreening  
2. Full screening  
3. Registration  
4. Treatment  
5. Safety follow-up  
6. Active follow-up  
7. Long-term follow-up  
Study treatment discontinuation (i.e., discontinuation during the treatment period) does not 
constitute withdrawal from the study.  
Every effort should be made to retain patients who discontinue the treatment period for any 
reason. These patients are to be encouraged to remain on the study for follow-up of primary, 
secondary and other objectives (i.e., continue in the safety follow-up, active follow-up and/or 
long-term follow-up periods).  
Patients are expected to participate in the follow-up unless they explicitly object. Withdrawal 
of consent to treatment should be documented in the patient’s medical record. If the patient 
does not wish to be followed up further, this additional consent withdrawal for follow up 
would have to be documented, too.  
Withdrawal from study treatment, active follow-up and long-term follow-up  
Patients withdrawn from the study treatment phase of the study should be followed for 
primary, secondary and other objectives (i.e. continue in the safety follow-up, active followup 
and/or long-term follow-up periods) (see Figure 2-1 for withdrawal criteria).  
  
  


  
   
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Figure 2-1  
Withdrawal criteria  
PATIENTS MUST BE WITHDRAWN FROM THE STUDY TREATMENT IF ANY OF THE FOLLOWING 
OCCURS:  
• 
At their own request or at the request of their legally acceptable representative. At any time during the study and 
without giving reasons, a patient may decline to participate further. The patient will not suffer any disadvantage as 
a result.  
• 
If, in the investigator's opinion, continuation of the study treatment would be harmful to the patient's well-being.  
• 
At the specific request of the sponsor and in liaison with the investigator (e.g. obvious non-compliance, safety 
concerns).  
• 
Confirmed radiological PD as per RECIST criteria.  
• 
Clinical progression as assessed by investigator. Occurrence of unacceptable toxicity to anetumab ravtansine (see 
also Section 7.3.2).  
• 
CTCAE Grade 4 hypersensitivity and acute infusion reaction.  
• 
An adverse reaction deemed sufficiently serious to warrant discontinuation of treatment by the investigator or his 
designated associate(s).   
• 
Development of a secondary malignancy.  
• 
Patient starts treatment with any other anti-cancer therapy or any other prohibited medication as per Section 8.1.  
• 
Positive serum β-HCG test consistent with pregnancy. Pregnancy should be reported along the same timelines as 
an SAE.   
• 
Use of illicit drugs or other substances that may, in the opinion of the investigator or his designated associate(s), 
have a reasonable chance of contributing to toxicity or otherwise confound the results.   
• 
Development of any intercurrent illness or situation which may, in the judgment of the investigator, affect 
assessments of clinical status and study endpoints to a relevant degree.   
• 
Lost to follow-up.  
• 
Death.  
Patients must be withdrawn from treatment with anetumab ravtansine if any of the following occurs:  
• 
CTCAE Grade 4 non-hematological AE and Bayer Grade 4 corneal toxicity (see Table 2-6) (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 ≥ 8 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.  
  
  
 
 
SAFETY FOLLOW-UP VISIT  
All patients who discontinue study treatment must perform this visit, 30+7 days after the last administration of study treatment. 
  
Patients without confirmed radiological PD ending 
treatment as per RECIST criteria  
 
Patients ending treatment with confirmed radiological  
PD as per RECIST criteria  
  
 
 
ACTIVE FOLLOW-UP  
Imaging assessment will continue until confirmed PD is 
observed or they withdraw consent to active follow- 
up, are lost to follow-up or due to death.  
 
LONG-TERM FOLLOW-UP  
Patients who have confirmed PD will have information on 
survival and new anti-cancer treatment collected.   
Patients must be withdrawn if they withdraw consent to 
long term follow-up, are lost to follow-up or due to death  
AE = Adverse event; β-HCG = β subunit of human chorionic gonadotropin; CTCAE = Common Terminology Criteria for 
Adverse Events; Hb = Hemoglobin; RECIST =  Response Evaluation Criteria in Solid Tumors;  
PD = Progressive disease; Q3W = Every 3 weeks; SAE = Serious adverse event; TEAE = Treatment-emergent 
adverse event  
 


  
   
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6.3.3.  Lost to follow-up patients  
When a patient is lost to follow-up at any stage of the study, the site should try to contact the 
patient, the patient’s relatives, or another doctor treating the patient, unless prohibited by local 
regulations. All attempts to contact the patient or relatives should be documented.  
6.3.4  General withdrawal procedures  
In all cases, the reason for withdrawal must be recorded in the CRF and in the patient's 
medical records.  
The patient may object to the generation and processing of post-withdrawal data as specified 
below.  
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12.  
6.3.5  Replacement  
No replacement of patients will be allowed during this study.  
6.4  
Patient identification  
After a patient has signed the prescreening consent form, the coordinating center will provide 
a patient identification number to be entered into OnCore (Clinical Trials Management 
System).  
7.  
Treatment(s)  
7.1  
Treatments to be administered  
All patients who meet the entry criteria will receive the test drug anetumab ravtansine, 
considered to be an IMP: anetumab ravtansine 6.5 mg/kg IV Q3W  
7.2  
Identity of study treatment  
All study drugs will be labeled according to the requirements of local law and legislation.   
Anetumab ravtansine will receive study-specific labeling and will be provided by the sponsor.  
For all study drugs, a system of numbering in accordance with all requirements of GMP will 
be used, ensuring that each dose of study drug can be traced back to the respective bulk batch 
of the ingredients. Lists linking all numbering levels will be maintained by Bayer’s clinical 
supplies quality assurance (QA) group.  
A complete record of batch numbers and expiry dates of all study treatment as well as the 
labels will be maintained in the sponsor’s study file.  
  
7.2.1  
Test drug - anetumab ravtansine  
Anetumab ravtansine is an ADC consisting of a fully human IgG1 antibody (MF T, BAY 
861903) directed at the mesothelin antigen and conjugated to a synthetic maytansine 
derivative as toxophore (DM4, BAY 100-6640) through a reducible disulfide linker (SPDB 
linker).  


  
   
Cli nical St u d y Pr ot oc ol  
B A Y 9 4 - 9 3 4 3 ( A net u ma b i n Pa ncreatic Ca ncer)  
1 9 -Se pte m ber -2 0 1 8   
Versi o n 4 . 0  
Pa ge:  2 4  of 7 7   
  
 
T he details of t he i n vesti gati o nal dr u g are gi ve n i n T a bl e 2 - 1.  
 
T a bl e 2 -1  
I d e ntit y of a n et u m a b r a vt a n si n e  
C h e mi c al n a m e  
M e s ot h eli n a nti b o d y -dr u g c o nj u g at e:  
I m m u n o gl o b uli n G 1, a nti-( h u m a n m e s ot h eli n) h u m a n 
m o n o cl o n al M F - T-I g G 1 h e a v y c h ai n, di s ulfi d e wit h 
h u m a n m o n o cl o n al M F - T-I g G 1 -c h ai n, di m er, tri a mi d e 
wit h N 2´ -[ 4-[( 3-c ar b o x y pr o p yl) dit hi o] - 4-m et h yl -
1 o x o p e nt yl] -N 2´ -d e a c e t yl m a yt a si n e  
S u b st a n c e c o d e n u m b er( s)  
B A Y 9 4 -9 3 4 3  
A p p e ar a n c e   
  
Fr e e z e -dri e d dr u g pr o d u ct  
  
W hit e t o off -w hit e l y o p hili z e d c a k e or p o w d er  
  
R e c o n stit ut e d s ol uti o n  
Cl e ar or sli g htl y o p al e s c e nt s ol uti o n  
F or m ul ati o n  
Fr e e z e -dri e d pr o d u ct i n a 3 0 m L i nj e cti o n vi al, 
c o nt ai ni n g 5 m g/ m L of a cti v e i n gr e di e nt aft er 
r e c o n stit uti o n  
C o m p o siti o n  
A n et u m a b r a vt a n si n e / B A Y 9 4 -9 3 4 3 / L -hi sti di n e / 
gl y ci n e / s u cr o s e / p ol y s or b at e 8 0 / 1 N H Cl  
T y p e of p a c k a gi n g a n d c o nt e nt  
3 0 m L i nj e cti o n vi al  
I g G 1 = I m m u n o gl o b uli n G s u b cl a s s 1; N H Cl = N or m al h y dr o c hl ori c a ci d  
  
T he dr u g pr o d uct is a vaila ble as a l y o p hilizate. Eac h vial c o ntai ns 6 2. 5 m g of a net u ma b 
ra vta nsi ne; t he a m o u nt a vaila ble f or a d mi nistrati o n, base d o n retracta ble v ol u me of 
rec o nstit ute d s ol uti o n, is 6 0 m g of a net u ma b ra vta nsi ne. It s h o ul d be rec o nstit ute d i n water f or 
i njecti o n a n d dil ute d i n 0. 9 % s o di u m c hl ori de s ol uti o n ( n or mal sali ne) pri or t o a d mi nistrati o n 
as I V i nf usi o n.  
T he dr u g pr o d uct is t o be st ore d at 2° C t o 8° C ( 3 6° F t o 4 6° F).  
7. 2. 1. 1 Rec o nstit uti o n  
T he dr u g pr o d uct s h o ul d be rec o nstit ute d a n d pr ocesse d u n der ase ptic c o n diti o ns (i.e. 
q ualifie d la mi nar fl o w u nit a n d trai ne d pers o n nel) t o precl u de micr o bial c o nta mi nati o n.  
Usi n g a sterile s yri n ge, ge ntl y a d d 1 1. 9 m L of water f or i njecti o n t hr o u g h t he mi d dle of t he 
st o p per t o t he freeze-drie d pr o d uct i nt o t he 3 0 m L i njecti o n vial t o o btai n a s ol uti o n 
(a p pr o xi mate rec o nstit ute d v ol u me is 1 2. 5 m L). D uri n g rec o nstit uti o n, ma ke s ure t hat t he 
nee dle d oes n ot c o me i nt o c o ntact wit h t he ca ke or res ulti n g s ol uti o n; a v oi d s ha ki n g. T he 
l y o p hilizate s h o ul d diss ol ve c o m pletel y.  
T he rec o nstit ute d l y o p hilizate ma y be dil ute d o nl y after t he s ol uti o n is clear.  
Dil uti o n of t he rec o nstit ute d s ol uti o n  
Dil uti o n of t he rec o nstit ute d s ol uti o n wit h 0. 9 % s o di u m c hl ori de s ol uti o n ( n or mal sali ne) 
s h o ul d be d o ne u n der ase ptic c o n diti o ns (i.e. q ualifie d la mi nar fl o w u nit a n d trai ne d 
pers o n nel) t o precl u de micr o bial c o nta mi nati o n. A sli g ht t ur bi dit y ma y occ ur d uri n g t he 
dil uti o n w hic h d oes n ot affect t he q ualit y of t he dr u g pr o d uct.  P har mac y will c o nsi der t he use 
of i nli ne filters f or s u bse q ue nt a d mi nistrati o ns.   


  
   
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19-September-2018  
Version 4.0  
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Stability of the reconstituted solution  
Exposure to bright light should be avoided; standard room illumination does not necessitate 
any precautions.  
The reconstituted solution is physically and chemically stable for 24 h at room 
temperature and between 2°C and 8°C. However, unless administered immediately, for 
microbiologic consideration, the reconstituted solution should be stored between 2°C and 
8°C and used within 6 h according to USP 797 “Pharmaceutical Compounding – Sterile 
preparations”. If not reconstituted under aseptic conditions, the solution should be used 
immediately or stored at 2°C to 8°C and used within 1 h, according to USP 797.  
If frozen or stored above 25°C (77°F), the solution should be discarded.  
Stability of the diluted solution  
Exposure to bright light should be avoided; standard room illumination does not necessitate 
any precautions.  
Stability investigations have shown that if diluted under aseptic conditions, concentrations 
between 0.1 and 3.0 mg/mL are stable for the period of use (24 h) at room temperature and 
between 2°C and 8°C. However, unless administered immediately, for microbiologic 
consideration, diluted solution should be stored between 2°C and 8°C and used within 6 h 
according to USP 797 “Pharmaceutical Compounding – Sterile preparations”.  
If not diluted under aseptic conditions, the solution should be used immediately or stored at 
2°C to 8°C and used within 1 h, according to USP 797.  
If frozen or stored above 25°C, the solution should be discarded.  
Refer to IB for anetumab ravtansine for details regarding drug properties and formulation.  
7.3  
Dosage and administration  
7.3.1  Administration of anetumab ravtansine  
After reconstitution and dilution (as described in Section 7.2.1), anetumab ravtansine will be 
administered as a 1-hour IV infusion every 3 weeks on Day 1 of each 21-day cycle until 
confirmed radiological PD by RECIST 1.1, clinical progression as assessed by investigator, or 
any other criteria for withdrawal of treatment.  
The individual dose will be 6.5 mg/kg per infusion from Cycle 1 onwards. In obese patients, 
anetumab ravtansine dose should be calculated considering a maximum weight of 100 kg.  
Strict IV administration has to be ensured to avoid local intolerance reactions. After 
completion of the 1-hour anetumab ravtansine infusion, the infusion line will be rinsed with 
≥ 100 mL of 0.9% saline solution to be administered as a short infusion.  
See Section 9.1 for details on scheduled administrations. 
 
7.3.2  Dose modification  
The NCI-CTCAE v4.03 will be used to assess toxicities; in addition, a Bayer grading system 
(see Table 2-6 and Table 2-7) will be used to assess corneal toxicity.  


  
   
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19-September-2018  
Version 4.0  
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TEAE requiring dose modification (temporary treatment interruption, dose reduction, or 
permanent discontinuation of treatment) will be defined as any of the events described below 
that is possibly, probably, or definitely related to anetumab ravtansine and occurs anytime 
during the study (not only in Cycle 1).  
The dose reduction levels of anetumab ravtansine will follow pre-defined dose levels shown 
in Table 2-2.  
 
Table 2-2  
Dose levels of anetumab ravtansine  
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  
Q3W = Every 3 weeks  
  
7.3.2.1  
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 2-3 and Table 2-4 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 CSF (26) 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 Table 2-8).  
• 
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.  


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Clinical Study Protocol  
BAY 94-9343 (Anetumab in Pancreatic Cancer)  
19-September-2018  
Version 4.0  
Page:  30 of 77  
  
 
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, there could be no intra-patient dose escalation irrespective of the type of 
TEAE that has led to dose reduction in this patient.  
 
7.3.2.3  
Miscellaneous toxicities  
IV infusion reaction and other hypersensitivity events  
If a patient experiences a CTCAE Grade 2 or Grade 3 anetumab ravtansine infusion reaction 
or other CTCAE Grade 2 or Grade 3 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 or Grade 3 anetumab ravtansine 
infusion reaction or other CTCAE Grade 2 or Grade 3 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.  
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 
toxicity 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 consultation between the investigator and the sponsor.  


  
   
Clinical Study Protocol  
BAY 94-9343 (Anetumab in Pancreatic Cancer)  
19-September-2018  
Version 4.0  
Page:  31 of 77  
  
 
Dose modifications for corneal toxicity  
For the TEAE of corneal morphology changes and the best corrected visual acuity (BCVA) 
changes (blurred vision), the Bayer severity grading system (see Table 2-6 and Table 2-7) will 
be used to assess the severity of TEAEs requiring modification of anetumab ravtansine 
treatment.  
TEAE of corneal morphology changes 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 2-6).  


 
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18-December-2017  
Version 2.0  
Page:  32 of 77  
  
 
Table 2-6: Bayer classification and management of corneal epitheliopathies 
 
Grade 0 
 
Grade 1 
Grade 2 
 
Grade 3 
 
Grade 4 
Corneal  
Morphology 
No  
pathologic  
changes 
Any stage 
of  
superficial  
punctate  
keratitis a 
Epithelial  
opacities  
Micro- 
Cysts 
Micro- 
deposits 
Corneal  
ulcer  
without  
risk of  
acute  
rupture 
Corneal  
ulcer  
more  
severe  
than  
Grade 3 
 
 
 
Corneal  
erosion  
Corneal  
erosion  
Stromal  
opacity:  
non- 
central  
 
Stromal  
opacity:  
central 
 
 
Grade  
0  
Grade 1  
Grade  
2  
Grade  
3  
Grade 4  
Eye   
Treatment b  
Ocular  
lubricants  at 
the  
discretion   
of  
investiga- 
tor, in  
consult 
with 
ophthalmo-  
logist  
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   
consult 
with  
ophthalmo-  
logist  
Intensive  
therapy  
with  
ointments;  
topical  
steroids;  
therapeutic  
contact  
lens or  
occlusion  
recomme- 
nded at  the  
discretion 
of  
investigator  
in consult 
with  
ophthalmo-  
logist  
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 consult  
with   
ophthalmo-  
logist  


 
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18-December-2017  
Version 2.0  
Page:  33 of 77  
  
 
 
 
  
Grade  
0  
Grade 1  
Grade  
2  
Grade  
3  
Grade 4  
Anetumab  
ravtansinec 
No  change 
No  change 
Keep  
treatment  
dose level  and  
schedule if  the  
ophthalmol-  
ogical  exam 
can   
be  
performed  
as needed;  
otherwise  
consider  
dose  
reduction  
by  -1 dose  
level  
without  
dose  
schedule  
change at   
the  discretion   
of  investigator  
in   
consult with 
ophthalmologist 
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  
-2 dose level (or -3  
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 morphology changes only, not on visual acuity changes.  
  
  
  


APPROVED BY THE YALE UNIVERSITY IRB 7/5/2017 VALID THROUGH 10/20/2017 
   
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Table 2-7: 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  
Sympto 
matic  
visual  
acuity  
loss < 3  
lines   
(ETDRS  
Equivale  
nt a)  
Visual  
acuity  
loss ≥ 3  
lines, but  
< 6 lines   
(ETDRS   
equivalent   
a)  
Visual  
acuity 
loss  ≥ 
6 lines   
(ETDRS   
equivalent   
a  
Visual 
acuity  
loss   
≥ 6 lines  
(ETDRS   
equivalent a)  
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.  
  
Recommended measures in case of eye dryness and ocular hypertension  
Changes in tear production as evaluated by the Schirmer test and in intraocular pressure (IOP) 
are not expected to occur as a direct consequence of anetumab ravtansine therapy. However, 
IOP may increase in some patients as a consequence of the therapy with topical steroid 
eyedrops. Since these drugs may be required to manage the corneal epitheliopathy syndrome, 
IOP will be monitored during this study for patients receiving topical steroid eyedrops.  
Changes in IOP should be managed by the investigator following exam by an 
ophthalmologist. The remedial therapy should be chosen at investigator’s discretion or 
according to the institutional standards; therapeutic measures can include modification of the 
type or posology of topical steroid eye drop, initiation of topical IOP lowering drugs and any 
other therapeutic options according to the local SoC. 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 the investigator following exam by an ophthalmologist 
to provide adequate protection to the corneal epithelium. The remedial therapy for the 
treatment-emergent changes in the Schirmer’s test (dry eye) should be chosen at 
investigator’s discretion or according to the institutional standards. These measures may 
include topical lubricants such as eye drops and ointments, punctual occlusion, use of 
therapeutic contact lenses and any other treatment approaches according to the local SoC.  


  
   
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7.3.2.4  
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.  
 
7.3.2.5  
Permanent discontinuation of anetumab ravtansine due to TEAEs  
See Section 6.3.1.2 for withdrawal criteria.  
7.4  
Drug logistics and accountability  
All study drugs will be stored at the investigational site in accordance with GCP and GMP 
requirements and the instructions given by the clinical supplies department of the sponsor, 
and will be inaccessible to unauthorized personnel. Special storage conditions and a complete 
record of batch numbers and expiry dates can be found in the sponsor’s study file; the site-
relevant elements of this information will be available in the investigator site file. The 
personnel will use the study drug only within the framework of this clinical study and in 
accordance with this protocol. Receipt, distribution, return and destruction (if any) of the 
study drug must be properly documented according to the sponsor’s agreed and specified 
procedures.  
The Yale Cancer Center (YCC) will be the coordinating center for the distribution of drugs or 
supplies to the participating institution(s). The Investigational Drug Service (IDS) at Yale-
New Haven Hospital will be employed to serve as the central pharmacy.  Distribution of 
drugs and supplies will be conducted in adherence with the established policies of Yale-New 
Haven Hospital and Medical Center  
The study drug will be provided by Bayer and shipped to the IDS at Yale-New Haven  
Hospital which will then distribute to the collaborating sites. Drug vials will be provided by 
Bayer with a generic non-study specific label on the cartons containing the vials. Any study 
specific labeling to the vials to meet local requirements will need to be done by the IDS.  The 
vials will be distributed to collaborating sites as required by IDS.  
The number of vials used will be recorded on the appropriate treatment dispensing form. 
Reasons for dose delay and reduction will be recorded in the source documents and on the 
CRF.  
Treatment accountability on patient level must be verified at every cycle, starting on C1D1. 
The monitor will review overall drug accountability and destruction per the site 
documentation only.  
Written instructions on medication destruction will be made available to affected parties as 
applicable.  


  
   
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7.5  
Treatment compliance  
The administration of anetumab ravtansine will be performed in the clinic on Day 1 of each 
21-day cycle for anetumab ravtansine. Each administration must be recorded on the CRF and 
Drug Dispensing / Accountability Form.  
Reasons for dose delay, reduction, or omission will also be recorded in the source documents 
and on the CRF.  
An adequate record of receipt, distribution, and return of all study drugs must be kept in the 
form of a Drug Accountability Form.  
The preparation and administration of anetumab ravtansine will be performed by members of 
the investigator team during hospitalization and site visits. These persons will ascertain and 
document that the patient receives all treatments as planned.  
Patient compliance with the treatment and protocol includes willingness to comply with all 
aspects of the protocol, and to have blood collected for all safety evaluations. At the 
discretion of the principal investigator or sponsor, a patient may be discontinued from the 
study treatment for non-compliance with visits or study drug.  
8.  
Non-study therapy  
8.1  
Prior and concomitant therapy  
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, 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. From signing of consent for full study to safety follow-up visit, all 
concomitant medications (including start/stop dates, dose, frequency, route of administration 
and indication) must be recorded in the patient’s source documentation, as well as on the 
appropriate pages of the CRF. At prescreening and during active follow-up period, only 
concomitant medications that are administered to treat AEs related to study-specific 
procedures are mandatory to be reported. Administration of contrast media for protocol-
specified radiological procedures (CT scan or MRI) does not need to be reported on the 
concomitant medication CRF page, unless there is an AE related to the contrast medium 
injection (e.g. allergic reaction).  
Prohibited prior and concomitant therapies and permitted concomitant therapies are listed in 
Table 2-8 and Table 2-9, respectively.  
 
 
 
 


  
   
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 Table 2-8  
Prohibited prior and concomitant therapies  
Prohibited prior and 
concomitant therapy  
(see also Section 6.2)  
Time period when  
Comments prohibited  
Prohibited for all patients  
Anetumab ravtansine (or 
any other mesothelin-based  
therapy)  
Prior to study treatment  
 
Other systemic anticancer 
treatment (except study 
treatment) (cytotoxic therapy, 
targeted therapies, 
immunotherapy, hormonal 
therapy, or any other 
experimental or approved 
therapy)   
Prior to study treatment 
until safety follow-up visit   
Use of biologic response 
modifiers, such as G-CSF 
Within 6 weeks before the 
start of study treatment 
G-CSF and other hematopoietic growth factors may 
be used during the study in the management of 
acute toxicity such as febrile neutropenia when 
clinically indicated per ASCO Recommendations for 
Therapeutic Use of CSF (26) or at the discretion of 
the investigator or according to local label guidance 
(if medically necessary, growth factors may be 
administered at recommended doses no earlier 
than 24 h after and not in the 24 h before anetumab 
ravtansine administration; see also (27); however 
they may not be substituted for a required dose 
reduction). 
Blood transfusions and 
chronic therapy with IV or 
subcutaneous erythropoietin-
stimulating agents (epoetin 
alpha, darbepoetin alpha) 
Within 6 weeks before the 
start of study treatment. 
Thereafter, they are 
allowed per institution 
guidelines but may not be 
used as substitute for a 
required dose reduction. 
Patients receiving chronic low-dose erythropoietin 
for chronic renal failure are allowed provided no 
dose adjustment is undertaken within 6 weeks 
before signing consent for full study and until safety 
follow-up visit and provided that they fulfill 
conditions of inclusion criterion number 7 and 
exclusion criterion number 18. 
Platelet transfusions 
Within 3 weeks before the 
start of study treatment. 
Thereafter, they may not 
be used as substitute for a 
required dose reduction. 
Anti-arrhythmic therapy other 
than beta blockers or digoxin 
Acute steroid therapy or taper 
Chronic steroid therapy is acceptable, provided that 
the dose is stable for 1 month before the start of 
study treatment and thereafter. 
Radiotherapy 
Within 4 weeks before 
the start of screening for  
full study 
Except for pain control, see below in Table 2-9. 
Patients must have recovered from all therapy-
related toxicities. The site of previous radiotherapy 
should have evidence of PD if this is the only site of 
disease: measurable pleural disease should be 
assessed on a contrast enhanced CT/MRI done at 


  
   
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Prohibited prior and 
concomitant therapy  
(see also Section 6.2)  
Time period when  
Comments prohibited  
the minimum 4 weeks after the end of RT and 
compared with previous imaging; unequivocal 
progression should be judged by the investigator as 
per mRECIST per MPM. 
Drugs with known bone 
marrow toxicity 
Strong inhibitors and 
strong inducers of CYP3A4 
(listed in Appendix 16.5), 
including: - Herbal 
preparations containing 
CYP3A4 inducers  
(e.g. St John’s Wort) - 
Grapefruit and grapefruit juice 
(CYP3A4 inhibitor) 
Within 2 weeks before 
the start of study 
treatment until the safety 
follow-up visit 
DM4 is a substrate of CYP3A4.  
 
During study treatment, moderate and weak 
CYP3A4 inducers should be used with caution as 
decrease in plasma concentrations of DM4 cannot 
be ruled out.  
ASCO = American Society of Clinical Oncology; CSF = Colony stimulating factor; CT = Computed tomography; 
CYP3A4 = Cytochrome P450, family 3, subfamily A, polypeptide 4; DM4 = Derivatives of maytansine 4; GCSF = 
Granulocyte-colony stimulating factor; IV = Intravenous; MPM = Malignant pleural mesothelioma; mRECIST = 
Modified Response Evaluation Criteria in Solid Tumors; MRI = Magnetic resonance imaging; PD = Progressive 
disease; RT = Radiotherapy  
 
  
 Table 2-9  
Permitted concomitant therapies  
 
Permitted concomitant therapies  
                                  Comments  
Permitted for all patients 
Oral and parenteral anti-coagulant agents, e.g.  
heparin, enoxaparin, warfarin, 
rivaroxaban, dabigatran, apixaban or 
aspirin at a dose ≤ 100 mg  
Allowed if continued maintenance therapy is necessary at the 
investigator’s discretion and provided that they fulfill conditions 
of inclusion criterion number 8 (Section 6.1.2).  
Institutional standards for the management of 
infusion reactions   
May be utilized at the discretion of the investigator. Pre-
treatment with anti-nausea medication is allowed at the 
investigators discretion.  See anti-emetic note below.   
 
Palliative radiotherapy for pain control  
Allowed provided that:  
- In the opinion of the investigator, the patient does not have 
PD,  
- No more than 10% of the patient’s bone marrow is irradiated, 
- The radiation field does not encompass a non-pleural target 
lesion or a pleural measurable lesion,  
- The radiation field does not encompass a lung field (to 
reduce the risk for interstitial lung disease [ILD] caused by 
irradiation pneumonitis), and  
- Anetumab ravtansine administration is interrupted during 
radiotherapy. Study treatment can be restarted after end of 
radiotherapy, provided all requirements outlined in Section 7.3 
of this protocol are taken into account. The maximum 
interruption period for both drugs should not be exceeded.  


  
   
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Permitted concomitant therapies  
                                  Comments  
Standard therapies for concurrent medical 
conditions 
Prophylactic standard anti-emetics  
May be administered according to standard practice: 
dexamethasone plus 5-HT3 blockers, such as granisetron, 
ondansetron, or an equivalent agent, are allowed on “as 
needed” basis.  
Treatment with non-conventional therapies 
(for example herbs, except St John’s Wort, 
or endpoints, in the opinion of the 
investigator. acupuncture), and 
vitamin/mineral supplements 
Acceptable provided that they do not interfere 
with the study  
Bisphosphonates or denosumab, with supplement 
of calcium and vitamin D  
Palliative (e.g. analgesics) and supportive care 
(e.g. nutritional therapy) for other disease-related 
symptoms and for toxicity associated with 
treatment  
 
Strong P-gp inhibitors (e.g. amiodarone, 
azithromycin, captopril, carvedilol, 
clarithromycin, conivaptan, cyclosporine, 
diltiazem, dronedarone, erythromycin, 
felodipine, itraconazole, ketoconazole, 
lopinavir and ritonavir, quercetin, quinidine, 
ranolazine, ticagrelor, verapamil)  
DM4-Me (metabolite of DM4) is a P-gp substrate.   
Caution should be exercised with concomitant administration of 
strong P-gp inhibitors. If anetumab ravtansine must be co-
administered with a strong P-gp inhibitor, then the patient 
should be carefully monitored or the strong P-gp inhibitor 
replaced at investigator’s discretion.  
 
Narrow therapeutic index medications   
Patients taking narrow therapeutic index medications should be  
monitored proactively, if these medications cannot be avoided.  
 
Beta blockers or digoxin   
Permitted for patients with cardiac arrhythmias requiring therapy  
5-HT3 = 5-hydroxytryptamine (serotonin); DM4 = Derivatives of maytansine 4; DM4-Me = Methyl-DM4; ILD 
= Interstitial lung disease; PD = Progressive disease; P-gp = Permeability glycoprotein  
  
All prior anti-cancer therapies, and all concomitant therapies including ophthalmological 
therapies as of full screening will be recorded on the CRF. At prescreening and during active 
follow-up period, only concomitant medications that are administered to treat AEs related to 
study-specific procedures are mandatory to be reported.  
8.2  
Post-study therapy  
At the end of study treatment, further therapy is at the discretion of the investigator.  
No results are available from human interaction studies between anetumab ravtansine and 
other chemotherapies. No data are available to evaluate the potential interaction between 
anetumab ravtansine and radiation treatment. Therefore, when administering these agents 
after study treatment is withdrawn, it should be taken into consideration that anetumab 
ravtansine, DM4 or DM4-Me levels may be detectable for several weeks and could interact 
with chemotherapy and radiotherapy including palliative radiotherapy as outlined in Table 2-9 
following discontinuation of anetumab ravtansine.  


  
   
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Once the expected final number of events is reached and results are available, the remaining 
patients on anetumab ravtansine treatment, who are considered by the investigator to benefit 
from continued anetumab ravtansine treatment, can be continued in the trial until disease 
progression.  
9.  
Procedures and variables  
9.1  
Tabular schedule of evaluations  
Schedule of procedures is presented in Table 2-10 below  
  
  
Table 2-10:  EVALUATION SCHEDULE  
  
Day  
Pre- 
Screening 
Screeningc  
1  
8  
15  
1  
8  
15  
EOTd  
Active 
FUo  
LTFU (every 
3 months)  
Cycle  
1  
1  
2+  
2 
and 
3 
only 
 2 
and 
3 
only 
Anetumab  
ravtansine IVd  
  
  
x  
  
  
x  
  
  
  
  
  
Informed Consent 
x  
x  
  
  
  
  
  
  
  
  
  
Confirm  
Eligibility  
Criteria  
x  
x  
xn  
  
  
  
  
  
  
  
  
Demographics  
x  
 
  
  
  
  
  
  
  
  
  
Medical Historyf  
 
x  
  
  
  
  
  
  
  
  
  
Concomitant  
Medicationsj  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
  
Complete 
physical exam  
  
x  
  
  
  
  
  
  
  
  
  
Brief physical 
exam  
  
  
x  
x  
x  
x  
x  
x  
x  
  
  
ECOG  
Performance 
Status  
 
x  
x  
  
  
x  
  
  
x  
  
  
Vital signse  
  
x  
x  
x  
x  
x  
x  
x  
x  
  
  
Height  
  
xe  
xe  
  
  
  
  
  
  
  
  
12-lead ECGl  
  
x  
x  
  
  
x  
  
  
x  
  
  
Complete Blood 
Counta  
  
x  
x  
x  
x  
x  
x  
x  
x  
  
  


  
   
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Day  
Pre- 
Screening 
Screeningc  
1  
8  
15  
1  
8  
15  
EOTd  
Active 
FUo  
LTFU (every 
3 months)  
Cycle  
1  
1  
2+  
2 
and 
3 
only 
 2 
and 
3 
only 
Electrolyte and  
Chemistry Panela  
  
x  
x  
x  
x  
x  
x  
x  
x  
  
  
Coagulation 
Panela  
  
x  
  
  
  
x  
  
  
  
  
  
Serum 
pregnancy test 
(WOCBP only)  
  
x  
Every 6 weeks until EOT  
x  
  
  
Dipstick 
Urinalysis  
  
x  
x  
  
  
x  
  
  
  
  
  
Serum CEA, 
CA19-9g  
  
  
x  
  
  
x  
  
  
  
  
  
AE Evaluation  
xm  
x  
x  
x  
x  
x  
x  
x  
x  
x  
  
Radiologic 
Evaluationb  
  
x  
xb  
xb  
  
Echocardiogram/  
MUGAh  
  
x  
  
  
  
xh  
  
  
  
  
  
Ophthalmologic 
Exami  
  
x  
x  
  
  
x  
  
  
x  
  
  
Archival or  
Fresh Tumor 
Tissue for 
mesothelin 
expression 
testingk  
x  
  
  
  
  
  
  
  
  
  
  
Research 
specimens for 
mesothelin and 
exploratory 
analysis 
(biomarkers)  
  
  
x  
  
  
xp  
  
  
x  
  
  
Survival Follow-
Up   
  
  
  
  
  
  
  
  
  
  
x  
  
ALL VISITS AND PROCEDURES WILL BE PERFORMED WITHIN 48 HOURS (+/- 1 day) WINDOW 
UNLESS OTHERWISE SPECIFIED.  


  
   
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a Complete blood count with differential. Electrolyte and Chemistry panel includes amylase, albumin, 
alkaline phosphatase (ALP), bicarbonate, total bilirubin, direct bilirubin, urea or BUN, calcium, 
chloride, creatinine, eGFR, gamma-glutamyl transferase (GGT), glucose, lactic dehydrogenase 
(LDH), lipase, phosphorus, potassium, total protein, AST, ALT, sodium, and uric acid. Specific 
assessments to be run per visit are detailed below. Coagulation tests including PTT and INR or PT.   
b Contrast-enhanced CT or MRI of chest/abdomen/pelvis or PET/CT will be done every 6 weeks for 
the first 6 months after the start of treatment, or more frequently if clinically indicated, every 9 weeks 
until the end of year 2 and every 12 weeks thereafter until disease progression or end of study, 
whichever comes first. To be done in +/- 7 days.    
c Screening procedures are to be completed within 7 days of treatment initiation unless otherwise 
specified below. CT or MRI c/a/p scans will be done within 28 days of treatment. An ophthalmologic 
examination will be done within 3 weeks before the start of study treatment.  
d Treatment will be continued until disease progression, intolerable toxicities or withdrawal. End of 
treatment (EOT) visit will occur 30 days (+/- 7 days) after treatment discontinuation.  
e Vital signs will include measurement of weight, blood pressure, heart rate, temperature, and 
respiratory rate.  Height to be done at baseline only or at Cycle 1 Day 1 prior to the first dose of study 
drug.  
f Includes medical, surgical and prior cancer treatment history.  
g CEA and CA 19-9 will be checked every 3 weeks during the treatment period including on day 1 of 
cycle 1 and in follow up until progression  
h Echocardiogram or MUGA to be done at baseline, C2D1, C4D1 (+/- 7 days) and as clinically 
indicated thereafter.  
i Ophthalmology exam as below every cycle.   
j All prior anti-cancer therapies and all concomitant therapies including ophthalmological therapies. At 
prescreening and during active follow-up period, only concomitant medications that are administered 
to treat adverse events related to study-specific procedures are mandatory to be reported.    
k Archival tissue is preferred and fresh biopsy should only be obtained if no archival tissue is available 
and if in the investigator’s judgement, there is no additional risk for the patient’s safety.  
l 12-lead ECG to be done at screening, C1D1, C2D1, C3D1, C4D1, C5D1, C6D1, and EOT.  
m At prescreening, only adverse events that are related to study-specific procedures are mandatory to be 
reported.   
n Prior to first dose of study drug.  
o Patients who discontinue study treatment due to any other reason than confirmed radiological PD will 
continue clinic visits during active follow-up for efficacy assessments including tumor response. These 
assessments will continue until disease progression, consent withdrawal, lost to follow-up or end of 
study.  
P  Biomarker plasma for exploratory analysis will be done at C6D1 (+/- 1 cycle).      
9.2  
Visit description  
Unless stated otherwise, the measurements listed in the following sections will be performed 
by or under the supervision of an investigator or a delegate.  
9.2.1  Prescreening  
A prescreening step, including mesothelin expression level testing, can be performed without 
evidence of disease progression after the initial treatment at the investigator’s discretion. 
Written patient informed consent for prescreening must be obtained before any prescreening 


  
   
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or study-specific procedures. Enrollment in the study is defined as the signing of the consent 
form.  
Written informed consent for prescreening.  
Enroll patient in OnCore.  
Demographics (see Section 9.3.1).  
Study disease characteristics and prior therapies for the study indication (see 
Section 9.3.3).  
Check eligibility criteria for prescreening (see Section 6.1.1).  
Toxicity/AE assessment (see Section 9.5.1). At prescreening, only AEs and SAEs that are 
related to study-specific procedures are mandatory to be reported.  
Concomitant medication review (see Section 8.1). At prescreening, only concomitant 
medications that are administered to treat AEs related to study-specific procedures are 
mandatory to be reported.  
Mandatory biomarker archival or fresh biopsy tissue (see Section 9.6.1).  
All patients enrolled into the study will be listed on a patient enrollment log maintained in 
OnCore.  
9.2.2  
Full screening period  
Written patient informed consent for full study must be obtained before any study-specific 
procedures. The maximum interval allowed between signature of informed consent and the 
start of study treatment is 30 days. Certain results from diagnostic testing prior to the 
informed consent date may be used to fulfill screening criteria.  
Within 28 days before the start of study treatment:   
  
Written informed consent for full study.  
Updates of study disease characteristics and prior therapies for the study indication (see 
Section 9.3.3).  
Medical history (see Section 9.3.2) and non-study-indication-related medications (see 
Section 9.3.3).  
Check eligibility criteria for full study, and exclusion criteria (see Section 6.1.2 and 6.2, 
respectively).  
Radiological tumor evaluation with contrast-enhanced CT/MRI of chest/abdomen/pelvis 
(see Section 9.4.1). Pre-study CT/MRI may be acceptable as a baseline scan if done 
within 28 days, if evaluable for RECIST 1.1.  
Concomitant medication review (see Section 8.1).  
Complete physical examination (see Section 9.5.3.2.1).  
Weight and height.  


  
   
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12-lead electrocardiogram (ECG) (see Section 9.5.3.5).  
ECOG PS assessment (see Section 9.5.3.3).  
Echocardiogram (EchoCG) or multiple gated acquisition (MUGA) scan (see 
Section 9.5.3.6).  
A detailed ophthalmologic examination (visual acuity, IOP, Schirmer test and slit lamp) 
(see Section 9.5.3.7) will be done within 3 weeks before the start of study treatment.  
Within 7 days before the start of study treatment:  
• 
Toxicity/AE assessment (see Section 9.5.1).  
• 
Vital signs (see Section 9.5.3.4).  
• 
Laboratory (see Section 9.5.3.1).  
o Complete blood count with differential.  
o Electrolyte and chemistry panel.   
o Measurement of estimated GFR (eGFR) (see Appendix 16.6).  o Coagulation 
panel.   
o Urine dipstick. During the study, complete urinalysis should be done when 
dipstick results are indicative or clinically indicated.   
o Serum pregnancy test. Test should be repeated at least every 6 weeks until end 
of treatment visit; only for WOCBP.  
9.2.3  
Treatment period  
After all screening assessments have been completed and the patient’s eligibility has been 
confirmed and documented (confirmation of mesothelin overexpression moderate [2+] and 
stronger [3+] in at least 30% of tumor cells will be obtained from central lab and confirmation 
of at least 1 measurable lesion present will be obtained from radiological review), the patient 
may begin treatment.  
9.2.3.1  
Treatment – Cycle 1  
Cycle 1 Day 1  
The following procedures should be performed on C1D1 before receiving study treatment 
unless otherwise specified in the protocol:  
Check eligibility criteria for full study, and exclusion criteria (see Section 6.1.2 and 6.2, 
respectively).  
Enroll patient on treatment in OnCore.  
Toxicity/AE assessment (see Section 9.5.1).  
Concomitant medication review (see Section 8.1).  
Brief physical examination (see Section 9.5.3.2.2).  


  
   
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Vital signs (see Section 9.5.3.4).  
Weight.  
Height will be measured if it was not measured during the screening period.  
ECOG PS assessment (see Section 9.5.3.3).  
Laboratory (see Section 9.5.3.1):  
o Complete blood count with differential. 
o Electrolyte and chemistry panel (CMP).  
o Urine dipstick.   
o Serum CEA and CA19-9.  
Biomarker plasma collection for soluble mesothelin (see Section 9.6.1).  
Biomarker plasma collection for exploratory analysis (see Section 9.6.1).  
Study treatment administration (IV infusion [see Section 7.3]).  
12-lead ECG (see Section 9.5.3.5).   
Ophthalmologic examination (Schirmer test only) (see Section 9.5.3.7).  If the screening 
period Schirmer test is conducted within 7 days of starting study treatment, the test does 
not need to be repeated at C1D1. 
Cycle 1 Day 8  
For assessments of this visit, time windows of -1 day and +1 day are acceptable unless 
otherwise specified in the protocol.  
The following procedures should be performed on C1D8 before receiving study treatment 
unless otherwise specified in the protocol:   
Toxicity/AE assessment (see Section 9.5.1).  
Concomitant medication review (see Section 8.1).  
Brief physical examination (see Section 9.5.3.2.2).  
Vital signs (see Section 9.5.3.4).  
Weight.  
Laboratory (see Section 9.5.3.1):  
o Complete blood count with differential. 
o Electrolyte and chemistry panel (CMP).  
 
Cycle 1 Day 15  


  
   
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For assessments of this visit, time windows of -1 day and +1 day are acceptable unless 
otherwise specified in the protocol.  
The following procedures should be performed on C1D15 before receiving study treatment 
unless otherwise specified in the protocol:   
Toxicity/AE assessment (see Section 9.5.1).  
Concomitant medication review (see Section 8.1).  
Brief physical examination (see Section 9.5.3.2.2).  
Vital signs (see Section 9.5.3.4).  
Weight.  
Laboratory (see Section 9.5.3.1):  
o Complete blood count with differential. 
o Electrolyte and chemistry panel (CMP).  
9.2.3.2  
Treatment – Cycle 2 and higher  
Cycle 2 and higher Day 1  
For assessments of this visit, time windows of -2 day and +2 day are acceptable unless 
otherwise specified in the protocol.  
The following procedures should be performed on Cycle 2 and higher, Day 1 before 
receiving study treatment unless otherwise specified in the protocol.  
Toxicity/AE assessment (see Section 9.5.1).  
 
Concomitant medication review (see Section 8.1).  
  
Brief physical examination (see Section 9.5.3.2.2).  
Vital signs (see Section 9.5.3.4).  
Weight.  
12-lead ECG (see Section 9.5.3.5) on C2D1, C3D1, C4D1, C5D1 and C6D1.  
ECOG PS assessment (see Section 9.5.3.3).  
EchoCG or MUGA scan (see Section 9.5.3.6) on C2D1, C4D1, and afterwards at the 
investigator’s discretion based on clinical need.  
Ophthalmologic examinations (visual acuity and slit lamp mandatory; Schirmer test 
mandatory at Cycle 4 Day 1 and Cycle 7 Day 1 only; IOP and additional Schirmer 
tests optional) (see Section 9.5.3.7) every cycle from C2D1 onwards, or more 
frequently at investigator’s discretion (important to refer to Table 2-6 and Table 2-
7). To be performed within 7 days before anetumab ravtansine infusion.  
Laboratory (see Section 9.5.3.1).  
o Complete blood count.   


  
   
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o Electrolyte and chemistry panel.   
o Measurement of eGFR (see Appendix 16.6).   
o Coagulation panel.   
o Urine dipstick.  
Serum Pregnancy testing; only for WOCBP (every odd cycle, every 6 weeks) Biomarker 
plasma for exploratory analysis (see Section 9.6.1) will be collected on C6D1. Study 
treatment administration (IV infusion).  
Cycle 2 and higher Day 8  
Site visits and below-described procedures on D8 will be performed on C1, C2 and C3 only. 
From Cycle 4 onwards, visits on D8 are no longer required.   
For assessments of this visit, time windows of -1 day and +1 day are acceptable unless 
otherwise specified in the protocol.  
The following procedures should be performed on Cycle 2 and higher, Day 8 before 
receiving study treatment unless otherwise specified in the protocol:  
Toxicity/AE assessment (see Section 9.5.1).  
Concomitant medication review (see Section 8.1).  
Brief physical examination (optional as per local practice and/or at investigator’s 
discretion, see Section 9.5.3.2.2).  
Vital signs (see Section 9.5.3.4).  
Weight.  
Laboratory (see Section 9.5.3.1):  
o Complete blood count with differential. 
o Electrolyte and chemistry panel (CMP).  
Cycle 2 and higher Day 15  
Site visits and below-described procedures on D15 will be performed on C1, C2 and C3 only. 
From Cycle 4 onwards, visits on D15 are no longer required.  
For assessments of this visit, time windows of -1 day and +1 day are acceptable unless 
otherwise specified in the protocol.  
The following procedures should be performed on Cycle 2 and higher, Day 15 before 
receiving study treatment unless otherwise specified in the protocol:  
Toxicity/AE assessment (see Section 9.5.1).  
Concomitant medication review (see Section 8.1).  


  
   
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Brief physical examination (optional as per local practice and/or at investigator’s 
discretion, see Section 9.5.3.2.2).  
Vital signs (see Section 9.5.3.4).  
Weight.  
Laboratory (see Section 9.5.3.1):  
o Complete blood count with differential. 
o Electrolyte and chemistry panel (CMP).  
9.2.4  
Efficacy assessments  
9.2.4.1  
Radiological tumor evaluations and forced vital capacity 
measurements  
Radiological tumor evaluation with contrast-enhanced CT or MRI of chest/abdomen/pelvis 
will be performed at the following intervals (for further details, see Sections 9.4.1).  
Full screening (baseline):  
Within 28 days before the start of study treatment.  
Treatment and active follow-up:  
Every 6 weeks during the first 6 months after the start of study treatment.  
Every 9 weeks until the end of year 2.  
Every 12 weeks thereafter until confirmed radiological disease progression or end of study 
per Investigator’s assessment.  
Visit window of +/- 7 days is allowed.  
9.2.5  
Follow-up periods  
9.2.5.1  
Safety follow-up (End of Treatment visit)  
When a patient discontinues the study treatment for any reason (except death, consent 
withdrawal or lost to follow-up) a safety follow-up visit will be performed 30 (+7) days after 
the last administration of study treatment.  
The following assessments should be performed at the safety follow-up (End of Treatment) 
visit:  
Toxicity/AE assessment (see Section 9.5.1).  
Concomitant medication review (see Section 8.1).  
Brief physical examination (see Section 9.5.3.2.2).  
Vital signs (see Section 9.5.3.4).  
Weight.  


  
   
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12-lead ECG (see Section 9.5.3.5).  
ECOG PS assessment (see Section 9.5.3.3).  
Ophthalmologic examinations (visual acuity and slit lamp mandatory; IOP and 
Schirmer test optional) (see Section 9.5.3.7) 
Laboratory (see Section 9.5.3.1).  
o 
Complete blood count.  
o 
Electrolyte and chemistry panel.  
o 
Measurement of eGFR (see Appendix 16.6).  
o 
Serum pregnancy test; only for WOCBP.  
Biomarker plasma collection for soluble mesothelin (see Section 9.6.1).  
Biomarker plasma collection for exploratory analysis (see Section 9.6.1).  
  
9.2.5.2  
Active follow-up  
Patients who discontinue study treatment due to any other reason than confirmed radiological 
PD will continue clinic visits during active follow-up for efficacy assessments including 
tumor response. These assessments will continue until disease progression, consent 
withdrawal, lost to follow-up or end of study.  
Radiological tumor evaluation with contrast-enhanced CT/MRI of chest/abdomen/pelvis. 
During active follow-up, tumor scans will be performed with the same modality every 
6 weeks during the first 6 months after the start of study treatment, every 9 weeks until 
the end of year 2, and every 12 weeks thereafter until confirmed radiological disease 
progression or end of study (see Section 9.4.1). Visit window of +/- 7 days is allowed.  
Toxicity/AE assessment (see Section 9.5.1), in parallel with CT/MRI. During active 
follow-up period, only AEs and SAEs that are related to study-specific procedures are 
mandatory to be reported. However, at the investigator’s discretion, SAEs may be 
reported if considered potentially relevant. In such cases, the SAEs will be processed 
by the sponsor according to all applicable regulations.  
Concomitant medication review (see Section 8.1), in parallel with CT/MRI. During active 
follow-up period, only concomitant medications that are administered to treat AEs 
related to study-specific procedures are mandatory to be reported.  
New anti-cancer treatment, in parallel with CT/MRI.  
9.2.5.3  
Long-term follow-up  
Patients enter the long-term follow-up period following confirmed radiological progression, 
or withdrawal of consent to active follow-up. Patients with confirmed PD during the 
treatment period enter long-term follow-up immediately after the safety follow-up visit.   


  
   
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All patients in the long-term follow-up period will be contacted every 3 months (±14 days) 
until data maturation for the OS final analysis is reached, death, withdrawal of consent, lost to 
follow-up or end of study, whichever occurs first. Patients or their health care providers will 
be contacted either in person or by telephone. In addition, extra survival sweep contacts will 
be conducted at the time of PFS final analysis and prior to OS final analysis to ensure that 
long-term follow-up data is current.  
The information to be recorded at these contacts:  
Survival status.  
Date of death.  
Date of locally confirmed progression.  
New anti-cancer treatment.  
9.3  
Population characteristics  
Population characteristics including patient demographics, medical history, and other baseline 
characteristics listed in this section must be documented on the CRF by the investigator 
before the start of study treatment.  
9.3.1  
Demographic  
Baseline patient data pertaining to demographic information will be collected at prescreening, 
including:  
• 
Date of birth and age.  
• 
Sex.  
• 
Race (where legally allowed).  
• 
Ethnicity (where legally allowed).  
• 
Region.  
9.3.2  
Medical history  
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected after consent for full study is signed as available to the 
investigator:  
• 
Start before signing of the informed consent for full study.  
• 
Considered relevant for the patient’s study eligibility.  
Detailed instructions on the differentiation between (i) medical history and (ii) AEs can be 
found in Section 9.5.1.1.  
9.3.3  
Other baseline characteristics  
The following study disease characteristics will be collected as of prescreening and will be 
updated if applicable during screening for full study:  


  
   
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Date of diagnosis.  
Stage of at diagnosis.  
Treatment of pancreatic cancer before enrollment (e.g. surgery, radiation and systemic 
therapy).  
All non-study-indication-related medications and significant non-drug therapies taken 
within 30 days before ICF signature for full study will be documented, including:  
• 
Trade name of medication.  
• 
Reason for medication (indication).  
• 
Dose of medication.  
• 
Start date and end date or if continuing at patient's last visit.  
9.4  
Efficacy  
The primary efficacy variable is progression-free survival (PFS) based on assessment of the 
investigator’s review. For definition and analysis of the primary variable and for description 
of secondary and other variables, please refer to Section 10.2.  
9.4.1  
Radiological tumor assessments  
The first radiological (contrast-enhanced CT/MRI of chest/abdomen/pelvis) tumor evaluation 
will be conducted during full screening within 28 days before the start of study treatment (see 
flow chart in Section 9.1). Pre-study CT/MRI may be acceptable as a baseline scan if done 
within 28 days, if evaluable for RECIST measurement in TIMC. Baseline CT/MRI should be 
obtained prior to start of treatment. A sole positron emission tomography (PET) scan without 
a diagnostic CT/MRI is not acceptable for radiological evaluation of target lesions; findings 
must be confirmed by CT or MRI. Although PET scan findings may be used as supportive 
evidence of tumor assessment, the CT or MRI results will be the definitive and documented 
data for the study. All subsequent scans should be done with the identical method and 
technique (e.g. slice thickness, field of view) to those obtained at baseline. These screening 
images will be reviewed to confirm there are measurable lesions in TIMC.  If focal 
neurological symptoms are present at screening, a CT scan or MRI of the brain is required to 
rule out brain metastasis by the investigator. All additional suspected sites of disease should 
be imaged (e.g. cervical lymph nodes, bone etc.).  
During treatment as well as active follow-up, tumor imaging and local assessments will be 
performed for the following time points: every 6 weeks for the first 6 months after the start of 
study treatment, every 9 weeks until the end of year 2, and every 12 weeks thereafter until 
confirmed radiological disease progression or end of study. Visit window of +/- 7 days is 
allowed. MRI shall be performed instead of CT when local regulations do not permit the use 
of CT as requested per protocol schedule.  
All images need to be sent to the Yale Diagnostic Radiology (YDR) Precision Metrics service 
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Investigators will determine treatment response locally at each investigational site according 
to RECIST 1.1 criteria. Preferably all scans should be interpreted by the same 
radiologist/investigator during the study.  
In the event of locally suspected progression, the imaging will be reviewed by radiology and 
investigator.  Radiological confirmation by independent blinded evaluation is required before 
a final decision to stop the treatment is made. The site should also wait for the review results 
before administering the next dose of treatment. In case of uncertain radiological disease 
progression, the patient may stay on treatment at the investigator’s discretion until 
progression is definitely confirmed by review on the subsequent tumor assessment.  
When the review assessment confirms progression, study treatment should be stopped 
permanently and patient will enter safety follow-up (safety follow-up visit to be scheduled 30 
(+/-7) days after the last administration of study treatment) and long-term follow-up period.  
In the event the review assessment does not find progression, the severity and clinical 
significance of local PD finding should be assessed. If patient has not significantly clinically 
deteriorated and has no toxicity requiring withdrawal, the patient should continue on 
treatment and further imaging should be conducted as per protocol required timelines. If 
patient has clinically deteriorated or has toxicity such that keeping patient on treatment would 
be against patient’s interest, the study treatment should be stopped permanently. The patient 
will enter the safety follow-up (safety follow-up visit to be scheduled 30 (+/-7) days after the 
last administration of study treatment) and active follow-up period.  
The PD events for the primary endpoint of this study, and the time point and best response 
values for the secondary response endpoints, will be determined by independent blinded 
reviewers according to RECIST criteria.  
The final evaluation of treatment response will be done by Yale Diagnostic Radiology  
Precision Metrics review retrospectively. The reviewer will determine the response per 
RECIST 1.1 criteria of each patient as of each time point. Responses of CR and PR will be 
confirmed by repeated observation per mRECIST criteria. Confirmed responses of CR and 
PR will be dated per mRECIST criteria.  
In case a patient discontinues study for reasons other than confirmed disease progression and 
does not want to enter or stay in the active-follow-up, information on locally confirmed date 
of progression should be collected during long-term follow-up. Progression results not 
documented by collected imaging will be classified as clinical progression and used in 
sensitivity analysis.  
9.4.2  
Survival  
Patients will be contacted for survival every 3 months (±14 days) during long-term follow-up 
until data maturation for the OS final analysis is reached, death, withdrawal of consent, lost to 
follow-up or the end of study, whichever occurs first (see flow chart in Section 9.1). In 
addition, extra survival sweep contacts will be conducted at the time of PFS final analysis and 
prior to OS final analysis to ensure that long-term follow-up data is current.  
  


  
   
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9.5  
Safety  
9.5.1  
Adverse events  
9.5.1.1. Definition of adverse event (AE)  
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of 
a medicinal (investigational) product.  
A surgical procedure that was planned prior to the start of the study by any physician treating 
the patient should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE).  
New lesions or disease progression per se should not be regarded as AEs. Instead, the 
associated signs and symptoms should be recorded as AEs.  
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal e.g. physical examination findings, symptoms, diseases, laboratory, ECG.  
• Conditions that started before signing of informed consent for full study and for 
which no symptoms or treatment are present until signing of informed consent for 
full study are recorded as medical history (e.g. seasonal allergy without acute 
complaints).  
• Conditions that started before signing of informed consent for full study and for 
which symptoms or treatment are present after signing of informed consent for full 
study, at unchanged intensity, are recorded as medical history (e.g. allergic 
pollinosis).  
• Conditions that started or deteriorated after signing of informed consent for full study 
will be documented as AEs. This includes intercurrent illnesses.  
9.5.1.2 Definition of serious adverse event (SAE)  
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f):  
a. Results in death.  
b. Is life-threatening. The term ‘life-threatening’ in the definition refers to an event in 
which the patient was at risk of death at the time of the event, it does not refer to an 
event which hypothetically might have caused death if it were more severe.  
c. Requires inpatient hospitalization or prolongation of existing hospitalization.  
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met:  
–The admission results in a hospital stay of less than 12 hours.  
–The admission is pre-planned.   


  
   
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(e. g. electi ve or sc he d ule d s ur ger y arra n ge d pri or t o t he start of t he st u d y; 
a d missi o n is part of t he st u d y pr oce d ures as descri be d i n Secti o n 9. 2).  
– T he a d missi o n is n ot ass ociate d wit h a n A E   
(e. g. s ocial h os pitalizati o n f or p ur p oses of res pite care).  
H o we ver, it s h o ul d be n ote d t hat i n vasi ve treat me nt d uri n g a n y h os pitalizati o n ma y 
f ulfill t he criteri o n of ‘ me dicall y i m p orta nt’ a n d as s uc h ma y be re p orta ble as a n S A E 
de pe n de nt o n cli nical j u d g me nt. I n a d diti o n, w here l ocal re g ulat or y a ut h orities 
s pecificall y re q uire a m ore stri n ge nt defi niti o n, t he l ocal re g ulati o n ta kes prece de nce.  
d.  Res ults i n persiste nt or si g nifica nt disa bilit y / i nca pacit y. Disa bilit y mea ns a 
s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life’s f u ncti o ns.  
e. Is a c o n ge nital a n o mal y / birt h defect.  
f. Is a n ot her seri o us or i m p orta nt me dical e ve nt as j u d ge d b y t he i n vesti gat or.  
9. 5. 1. 3   
Cl assific ati o ns f or a d verse e ve nt assess me nt  
All A Es will be assesse d a n d d oc u me nte d b y t he i n vesti gat or acc or di n g t o t he cate g ories 
detaile d bel o w.  
Seri o us ness  
F or eac h A E, t he seri o us ness m ust be deter mi ne d acc or di n g t o t he criteria gi ve n i n 
Secti o n 9. 5. 1. 1.  
  
I nte nsit y  
T he i nte nsit y of a n A E s h o ul d be d oc u me nte d usi n g t he N CI- C T C A E v 4. 0 3. F or e ve nts n ot 
liste d i n t he N CI- C T C A E, t he f oll o wi n g scale will be use d:  
• 
Gra de 1: Mil d  
• 
Gra de 2: M o derate  
• 
Gra de 3: Se vere  
• 
Gra de 4: Life -t hreate ni n g  Gra d e 5: Fatal  
C a u s al rel ati o ns hi p   
T he assess me nt of t he ca usal relati o ns hi p bet wee n a n A E a n d t he a d mi nistrati o n of treat me nt 
is a decisi o n t o be ma de b y t he i n vesti gat or, w h o is a q ualifie d p h ysicia n, base d o n all 
i nf or mati o n a vaila ble at t he ti me of t he c o m pleti o n of t he C R F.  
T he  assess me nt is base d o n t he q uesti o n w het her t here was a “reas o na ble ca usal relati o ns hi p” 
t o t he st u d y treat me nt i n q uesti o n.  
P ossi ble a ns wers are “ yes” or “ n o”  
A n assess me nt of “ n o” w o ul d i ncl u de:  


  
   
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1. The existence of a highly likely alternative explanation, e.g. mechanical bleeding at 
surgical site.  
or  
2. Non-plausibility, e.g. the patient is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; cancer 
developing a few days after the first drug administration.  
An assessment of “yes” indicates that that the AE is reasonably associated with the use of the 
study treatment.  
Important factors to be considered in assessing the relationship of the AE to study treatment 
include:  
• 
The temporal sequence from drug administration: The event should occur after the 
drug is given. The length of time from drug exposure to event should be evaluated in 
the clinical context of the event.   
• 
Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction  
(re-challenge): Patient’s response after de-challenge or re-challenge should be 
considered in view of the usual clinical course of the event in question.   
• 
Underlying, concomitant, intercurrent diseases:   
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the patient may have.   
• 
Concomitant medication or treatment:   
The other drugs the patient is taking or the treatment the patient receives should be 
examined to determine whether any of them might have caused the event in question.   
• 
Known response pattern for this class of drug: Clinical/preclinical.   
• 
Exposure to physical and/or mental stresses: The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event.   
• 
The pharmacology and pharmacokinetics of the study treatment:   
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) 
of the study treatment, coupled with the individual patient’s pharmacodynamics 
should be considered.   
• 
The assessment is not possible.   
Causal relationship to protocol-required procedure(s)  
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s).  
Possible answers are “yes” or “no”.  


  
   
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Action taken with study treatment   
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.  
• 
Drug withdrawn  
• 
Drug interrupted  
• 
Dose reduced  
• 
Dose not changed  
• 
Not applicable  
• 
Unknown  
Other specific treatment(s) of adverse events  
• 
None  
• 
Remedial drug therapy  
• 
Other  
Outcome  
The outcome of the AE is to be documented as follows:   
• 
Recovered/resolved  
• 
Recovering/resolving  
• 
Recovered/resolved with sequelae  
• 
Not recovered/not resolved  
• 
Fatal  
• 
Unknown  
9.5.1.4  
Assessments and documentation of adverse events  
AEs observed, mentioned upon open questioning by a member of the investigator team or 
spontaneously reported by the patient will be documented in the patient’s records and on the 
appropriate CRF. AEs will be documented in an event-based manner, using NCI-CTCAE 
version 4.03 guidelines. In addition, since the NCI-CTCAE may not adequately capture the 
severity of new corneal epitheliopathy, an alternative severity grading system for ocular 
adverse drug reactions will be used (see Table 2-6 and Table 2-7).  
9.5.1.5  
Reporting of serious adverse events  
The definition of SAEs is given in Section 9.5.1.1. Each SAE must be followed up until 
resolution or stabilization by submission of updated reports to the designated recipient.  
It is not mandatory to report new SAEs occurring after the protocol-defined observation 
period, however, at the investigator’s discretion these may be reported if considered 
potentially relevant. In such cases, the SAEs will be processed by the sponsor according to all 
applicable regulations.  


  
   
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Investigator’s notification of the sponsor  
The Investigator/ Sponsor shall report to Bayer within 24 hours of the investigator’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).  
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  
  


  
   
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Reports for all Bayer products can also be phoned in via our Medical Communications 
Department  
  
Phone:                   
1-888-842-2937  
  
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs. This information, including all relevant contact 
details, is summarized in the investigator site file. This information will be updated as 
needed.  
The investigator must report immediately (within 24 hours of the investigator’s awareness) all 
SAEs occurring during the observation period defined in Section 9.5.1.3 to the Yale Center 
for Clinical Investigation (YCCI) Project Manager as detailed in the instructions for SAE 
reporting included in the Investigator File. For this, an AE page in the CRF as well as the 
complementary pages provided in the Investigator File must be completed for each SAE.   
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.  
If disease progression leads to signs and symptoms that meet the criteria for seriousness (see 
Section 9.5.1.1), the associated signs and symptoms should be reported as SAE, not the 
underlying cause (i.e. “progressive disease” should not be recorded as SAE). In this case, 
disease progression should be mentioned on the SAE form as “alternative explanation”. 
If a new primary malignancy is noted at any time before end of active follow-up, it must be 
reported as an SAE, whether or not it is assessed as related to study treatment.  
For documentation of laboratory findings as SAE, please refer to Section 9.5.3.1.  
Notification of the IECs / IRBs  
Notification of the IECs / IRBs and Bayer Health Care about all relevant events (e.g. SAEs, 
suspected, unexpected, serious adverse reactions [SUSARs]) will be performed by the 
sponsor and/or by the investigator according to all applicable regulations and local policies.  
All SAEs, whether originating at Yale or at collaborating sites, meeting the criteria for prompt 
reporting will be reported to the Yale University Human Investigation Committee (HIC) as 
per IRB Policy 710.  
The Yale University HIC prompt reporting criteria are: Unexpected (in terms of nature, 
specificity, severity, or frequency) AND related or possibly related to participation in the 
research AND the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, legal, or social harm) than was previously known or 
recognized. Collaborating sites should report adverse events to their local IRB per 
institutional policy.   


  
   
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Notification of the authorities  
The processing and reporting of all relevant events (e.g. SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations.  
Sponsor’s notification of the investigational site  
The sponsor will inform all investigational sites about reported relevant events (e.g. SUSARs) 
according to all applicable regulations.  
9.5.1.5  
Expected adverse events  
For this study, the applicable reference document for anetumab ravtansine is the most current 
version of the IB.  
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current IB. If relevant new safety information is identified, the information will 
be integrated into an update of the IB and distributed to all participating sites.  
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.  
9.5.1.6  
Adverse events of special safety interest  
Anetumab ravtansine is an investigational drug and current knowledge of the AEs associated 
with this compound is limited.  
As with any new chemical entity, there is always potential for unexpected AEs, including 
hypersensitivity reactions.  
Corneal disorders are considered as AEs of special interest. Specific dose modification 
schemes are defined in Section 7.3.2.1. An alternative severity grading system for ocular 
adverse drug reactions will be used in addition to NCI-CTCAE version 4.03 criteria, since the 
NCI-CTCAE may not adequately capture the severity of these novel adverse reactions (see 
Table 2-6 and Table 2-7).  
There is no need to report corneal toxicities as SAEs unless they meet the criteria for an SAE 
as defined in Section 9.5.1.1; however these events will need to be closely monitored and 
reviewed, and documented timely and accurately both in source data and on the CRF. Details 
of ophthalmologic examination will be documented on the “ophthalmologic examination” 
CRF page and in case AEs occur, also on “AE” CRF page, ensuring the reporting 
terminology used on those pages matches and reflects the source.  
9.5.2  Pregnancies  
The investigator must report to the sponsor any pregnancy occurring in a female study patient 
during her participation in this study. The outcome of the pregnancy should be followed up 
carefully, and any outcome of the mother and the child at delivery should be reported.  
The child’s health should be followed up until 4 weeks after birth.  


  
   
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For a pregnancy in the partner of a male study patient, all efforts will be made to obtain 
similar information on course and outcome, subject to the partner’s consent.  
For all reports, the forms provided are to be used. The investigator should submit them within 
the same timelines as an SAE.  
9.5.3  
Further safety  
9.5.3.1  
Laboratory evaluations  
Safety laboratory analyses will be performed locally according to the schedule summarized in 
the flow chart of Section 9.1.  
Complete blood count: Hemoglobin, hematocrit, platelet count, white blood cell count 
(WBC). WBC must include differential including neutrophil, lymphocyte, monocyte, 
basophil, and eosinophil counts.  
Electrolyte and chemistry panel: sodium, potassium, chloride, bicarbonate, calcium, 
phosphorus, glucose (fasting or random/unspecified), AST, ALT, gamma-glutamyl 
transferase (GGT), bilirubin (total and direct), ALP, uric acid, total protein, albumin, 
lipase, amylase, lactic dehydrogenase (LDH), blood urea nitrogen (BUN) or urea, and 
creatinine.  
Coagulation panel: PTT, and PT or PT-INR.  
Urinalysis: Only dipstick test will be done, and complete urinalysis (e.g. microscopic 
analysis of the urine sediment) will only be done if the dipstick results are indicative 
or clinically indicated.  
Serum pregnancy test in WOCBP. Test should be repeated at least every 6 weeks until 
safety follow-up visit. Postmenopausal women who have not had periods for more 
than 1 year without an alternative medical cause or surgically sterilized women will 
not be required to undergo a serum pregnancy test (this information should be 
recorded under medical history on the CRF).  
eGFR according to the MDRD abbreviated formula (see Appendix 16.6).  
An isolated laboratory abnormality that meets the criteria for a CTCAE Grade 4 classification 
is not reportable as an SAE, unless the investigator assesses that the event meets standard 
International Conference on Harmonization (ICH) criteria for an SAE (see SAE definition in 
Section 9.5.1.1). All laboratory abnormalities, including CTCAE Grade 4 abnormalities, will 
be documented on the laboratory CRF.  
9.5.3.2  
Physical examination   
Physical examinations will be performed according to the schedule summarized in the flow 
chart of Section 9.1. Clinically significant abnormal physical examination findings are 
recorded either as medical history or as AEs (see Section 9.5.1.1).  
Complete physical examination  
Complete physical examination of all organ systems per usual standards.  


  
   
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Brief physical examination  
Brief physical examination includes, but is not limited to, review of organ systems and 
physical areas of symptomatic concern or investigator’s degree of suspicion for any 
abnormality. After Cycle 1, brief physical examinations are only mandatory on Day 1 of each 
cycle and are optional as per local practice at Day 8 and Day 15 visits.  
9.5.3.3  
ECOG Performance Status  
Change of ECOG PS will be measured for safety reason; grading definitions are given in 
Appendix 16.1. ECOG PS will be assessed at prescreening, full screening, on Day 1 of each 
cycle and at safety follow-up visit (see flow chart in Section 9.1).  
9.5.3.4  
Vital signs  
Body weight, height, heart rate, blood pressure, body temperature, and respiratory rate will be 
assessed according to the schedule summarized in the flow chart of Section 9.1. Any 
clinically relevant measurements or changes are to be reported as AEs (e.g. weight gain or 
loss, hypertension, tachycardia, bradycardia, etc.).  
9.5.3.5  
12-lead ECG  
12-lead ECGs will be performed according to the schedule summarized in the flow chart of 
Section 9.1. The overall interpretation of the ECG (normal/abnormal, clinical relevance) and 
the ECG diagnosis will be documented in the source documents and on the CRF. This review 
should be completed by a qualified physician and signed and dated at the time of review.  
9.5.3.6  
Cardiac function  
Cardiac function test is mandatory. It will be measured by EchoCG or MUGA scan at full 
screening and on C2D1, C4D1, and afterwards at the investigator’s discretion based on 
clinical need (see flow chart in Section 9.1). EchoCG shall be performed instead of MUGA 
when local regulations do not permit the use of MUGA as requested per protocol schedule.  
9.5.3.7  
Ophthalmologic examinations  
Corneal toxicity has been identified as a TEAE of special interest for which a causal 
relationship with anetumab ravtansine has been deemed probable by the investigators in 
Phase I trial. A detailed ophthalmologic examination (visual acuity [BCVA according to 
ETDRS, or Snellen, or Landolt C or other charts], IOP, dry eye test [Schirmer test] and slit 
lamp) will be done for all patients during full screening within 3 weeks before the start of 
study treatment (see flow chart in Section 9.1). Visual acuity test and slit lamp examination 
will be repeated before infusion in every cycle except C1D1, and at safety follow-up visit, or 
more frequently at investigator’s discretion (important to refer to Table 2-6 and Table 2-
7).   
IOP measurement is to be repeated during anetumab ravtansine therapy if the patient receives 
steroid eye drops as treatment for eye toxicity. IOP measurements should be repeated at two 
weeks and six weeks after starting topical corticosteroids for any subjects who are treated 
with topical corticosteroids for more than ten days. If neither the two week nor the six week 
IOP evaluation reveal elevated IOP (i.e., IOP increase by ≥ 7 mmHg), the frequency of IOP 


  
   
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evaluations can be reduced to every 4 months.  If IOP evaluation reveals an elevated IOP, 
appropriate medical management should be initiated with follow-up appropriate for the 
elevation in IOP. Changes in IOP should be managed by the investigator. The remedial 
therapy should be chosen at investigator’s discretion or according to the institutional 
standards; therapeutic measures can include modification of the type or posology of topical 
steroid eye drop, initiation of topical IOP lowering drugs and any other therapeutic options 
according to the local SoC. Ophthalmological monitoring should be maintained until the IOP 
has returned to normal values.  
Dry eye (Schirmer) tests will be repeated at C1D1 (if screening period Schirmer test is 
conducted within 7 days of starting study treatment, the test does not need to be repeated at 
C1D1), and on treatment prior to C4D1 and C7D1. Schirmer tests may be repeated more 
frequently during treatment at investigator’s discretion (e.g. in case of eye dryness during 
anetumab ravtansine therapy).   
During treatment, ophthalmologic examination can be done up to 7 days before anetumab 
ravtansine infusion.  
9.6  
Other procedures and variables  
9.6.1  Biomarkers  
Preclinical and Phase I evidence suggests that mesothelin expression (or expression level 
above a certain threshold) in human tumors may be required for binding, internalization, and 
anti-tumor activity of anetumab ravtansine. All patients will have formalin-fixed, paraffin-
embedded (FFPE) tumor samples available for IHC determination of mesothelin expression 
at prescreening as a potential predictive biomarker (see also flow chart in Section 9.1). In the 
absence of archival tissue, fresh biopsies may be used if deemed safe by the investigator and 
there is no additional risk for the patient in the investigator’s judgement. Only patients whose 
tumors express mesothelin at staining intensity of moderate (2+) or stronger (3+) in at least 
30% of tumor cells will participate further in this study. Mesothelin levels will be determined 
using an IHC assay (clone SP74).  
In addition to obligatory measurement of mesothelin expression levels, biomarker plasma 
(from whole blood) will be collected on C1D1 pre-dose, C6D1 (+/- 1 cycle), and at end of 
treatment if possible, to be banked for future correlative research.  
Exploratory biomarker analysis may also be performed using additional tumor tissue for 
future studies of scientific interest; these might include alterations in tumor-associated genes 
and to perform gene expression analysis.   
The exploratory biomarkers may include, but are not limited to, DNA sequencing of tumor-
associated genes and gene expression profiling. Next generation sequencing (NGS), and 
RNA, protein or miRNA expression analysis may be performed.  
In addition to the biomarkers listed above, other biomarkers deemed relevant to gain further 
knowledge about the pathomechanism of the disease or about the drug (i.e. mode of action-


  
   
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related effect or safety of the drug) and/or the pathomechanism of the disease may be 
measured, based on newly emerging data from other ongoing studies and/or literature data.  
Details on the collection, processing, storage and shipment of biomarker samples will be 
provided in separate documents (e.g. sample handling sheets or lab manual).  
9.7  
Appropriateness of procedures / measurements  
The efficacy assessments used in the study include those considered SoC to evaluate 
antitumor activity in patients with advanced or metastatic pancreatic cancer.   
The safety assessments are appropriate and standard to monitor safety and assess toxicity.  
Appropriateness of RECIST criteria. RECIST 1.1 criteria, designed to assess response of 
solid tumors is highly appropriate for determination of the primary endpoint of RR.  
10.  
Statistical methods and determination of sample size  
10.1  
General considerations  
Statistical analysis will be performed using SAS version 9.2 or later; the version used will be 
specified in the SAP.  
In general, continuous variables will be summarized using number of non-missing values (n), 
number of missing values, means, standard deviations, medians, maximum, minimum, and 
interquartile range.  
Ordinal variables will be summarized using n, number of missing values, medians, maximum, 
minimum, and interquartile range.  
Categorical variables will be summarized using n, number of missing values, and 
percentages.  
Time-to-event variables will be summarized using Kaplan-Meier estimates.  
Further details on the statistical analyses will be provided in the SAP.  
10.2  
Variables and planned statistical analyses  
10.2.1  
Population characteristics  
Population characteristics (see Section 9.3) will be reported by summary statistics and 
listings. Further details will be described in the SAP.  
10.2.2  
Primary efficacy variable  
Response rate is defined as time from start of treatment until disease progression (according 
to RECIST, per blinded radiology review) or death. Patients not experiencing death or 
progression will be censored at the last tumor assessment.  
Additional details, including additional censoring rules, will be described in the SAP.  


  
   
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10.2.2.1 Primary efficacy analysis  
The primary efficacy analysis tests the following hypotheses:  
H0: In patients with advanced or metastatic pancreatic cancer overexpressing mesothelin and 
pretreated with prior chemotherapy, a response per RECIST under treatment with anetumab 
ravtansine at 6.5 mg/kg Q3W would not be seen.  
versus   
HA: In patients with advanced or metastatic pancreatic cancer overexpressing mesothelin and 
pretreated with prior chemotherapy, a response per RECIST under treatment with anetumab 
ravtansine at 6.5 mg/kg Q3W would be seen.  
The minimax, Simon 2-stage design testing 5% null hypothesis versus a 21% alternative 
requires a maximum of 30 patients.  If there are no patients exhibiting any response among 
the first 20 then the trial will terminate early.  If there is at least one response among the first 
20 then the trial will accrue an additional 10 patients for a maximum of 30. Four or more 
responses out of 30 will reject the null hypothesis in favor of the 21% response alternative.  
These criteria have significance level (alpha) 0.1 and power 90%.  The probability of 
stopping early is 36% if the response rate is 5% or lower.  The expected sample size is 26.4.  
Sensitivity analyses will be performed, including analyses to assess the impact of missing 
data and the possibility of survivorship and selection biases. Further details will be described 
in the SAP.  
10.2.2.2  
Safety variables  
Safety variables will include AEs, laboratory changes (hematology, clinical chemistry and 
clinical urinalysis), abnormal findings in physical examination, changes in ECOG PS, 
changes in vital signs (weight, blood pressure, heart rate, respiratory rate, and body 
temperature), changes in ECG, changes in cardiac function test (EchoCG or MUGA scan) and 
changes in ophthalmologic examinations (visual acuity and slit lamp examination, IOP and 
Schirmer test if repeated). All AEs whether considered drug-related or not, will be reported 
on the CRF with a diagnosis, start/stop dates, action taken, whether treatment was 
discontinued, any corrective measures taken, outcome and other possible causes. For all 
events, the relationship to treatment and the intensity of the event according to CTCAE v4.03 
will be determined by the investigator, using the terms and definitions given in Section 
9.5.1.2.  
Definition of treatment-emergent safety events  
The treatment period for safety purposes is defined as the start of study treatment until 
30 days after the last day of study treatment.  
Treatment-emergent safety events (e.g. TEAEs) are safety events which arise or worsen 
during the treatment period.  
Additional details will be described in the SAP.  


  
   
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Safety analysis  
The final safety analysis will be performed at the time of the final primary endpoint analysis..  
All enrolled patients who receive at least 1 dose of treatment will be valid for safety analysis.  
All observations pertinent to the safety of treatment will be recorded on the CRF and included 
in the Clinical Study Report (CSR).  
Descriptive summary tables will be presented for all safety parameters. All TEAEs, 
treatment-emergent and hematological/biochemical toxicities based on laboratory 
measurements, as well as drug-related AEs and SAEs, will be graded by CTCAE v4.03 and 
categorized by MedDRA.  
Results of physical examination, vital signs, ECG, and other safety variables as described in 
the SAP will be summarized. The number (%) of patients who discontinue study drug due to 
AE or for whom a dose reduction or interruption is needed due to AE will also be 
summarized.  
10.2.3  
Other variables  
  
10.2.3.1  
Biomarker variables  
An analysis of mesothelin expression levels in all patients evaluated for mesothelin 
expression will be performed.  Biomarker parameters that may predict response, e.g. 
mesothelin expression levels in tumors and in plasma, may be analyzed by patient, and 
associated with tumor response using descriptive statistics, if appropriate. The association 
between biomarker and selected safety, efficacy, or PK parameters may be graphically 
displayed. Further exploratory statistical analyses may be performed. Biomarker variables 
and analyses will be further described in the SAP.  
10.3  Planned interim analyses  
An interim analysis for RR at the time 20 patients are evaluable will be performed.  
11.  
Data handling and quality assurance  
11.1  
Data recording  
The data collection tool for this study will be via the Yale OnCore system.  Data forms will 
be available within the trial webpage and all data will be entered remotely via web access.  
Non-Yale sites will have access to OnCore for this purpose.  
11.1.1  Source documentation  
The site must implement processes to ensure availability of all required source 
documentation. A source document checklist (not part of this protocol) will be used at the site 
to identify the source data for key data points collected and the monitor will work with the 
site to complete this.  


  
   
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It is the expectation of the sponsor that all data entered into the CRF has source 
documentation available at the site.  
11.1.2  Data recorded from prescreening and full screening failures  
At minimum, the following data should be recorded in the CRF:  
• 
Demographic information (patient number; year of birth / age; sex; if applicable race / 
ethnicity)  
• 
Date of all informed consent(s)that were signed  
• 
Relevant inclusion/exclusion criteria for prescreening and for full study (if available)  
• 
Reason for premature discontinuation  
• 
Result of mesothelin overexpression level testing (if available)  
• 
Date of last visit.  
These data will be transferred to the respective database.  
For prescreening failures who experienced an SAE related to prescreening procedures, and 
for full screening failures who had signed consent for full study and who experienced an 
SAE, the following data should be collected in the CRF in addition to the data specified 
above:  
• 
All information related to the SAE such as:   
o The SAE itself  
o Concomitant medication 
o Medical history 
o Other information needed for SAE complementary page.  
11.2  
Monitoring  
The study principal investigator and YCCI are responsible for monitoring the performance of 
all of the participating sites.  This will be performed by conducting a study site initiation visit, 
as well as regularly scheduled monitoring visits and/or remote monitoring throughout the life 
of the protocol. At the end of the trial, the monitor will then perform a study site close-out 
visit at all participating sites.   
YCCI will utilize their institution’s initiation, monitoring and close-out visit reports. 
Following each site visit, a visit report will be generated containing information on site 
activities, and a summary of pertinent points and action items together with a copy of the 
follow-up letter will be sent to each investigative site.   
During these monitoring visits, some of the items that will be reviewed are the following:   
• 
Training of the sites   
• 
Site personnel qualifications to participate in the trial   


  
   
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• 
That study related documents are current   
• 
That regulatory compliance is accomplished   
• 
That each subject has signed the informed consent   
• 
That the current and approved protocol is complied with (including reporting and 
logging of all protocol deviations)   
• 
That all SAEs and AEs have been reported to the local regulatory and Ethics/IRB 
Committees, YCCI, and Bayer as appropriate   
• 
That source documentation matches CRFs   
• 
That required procedures for study drug accountability, distribution, and storage are 
followed.   
YCCI will document the required study monitoring activities in a Study Monitoring Plan.  
11.3  
Audit and inspection  
To ensure compliance with GCP and regulatory requirements, the YCCI Office of Quality  
Assurance and Training will audit the trial at least annually or as determined by the Yale 
Cancer Center DSMC. The overall principal investigator, study coordinator and/or data 
manager may request access to all source documents and other study documentation for 
onsite or remote monitoring, audit or inspection.  
Involvement in this study as a participating investigator implies acceptance of potential audits 
or inspections, including source data verification, by representatives designated by the 
Principal Investigator or Yale. The purpose of these audits or inspections is to examine study-
related activities and documents to determine whether these activities were conducted and 
data were recorded, analyzed, and accurately reported in accordance with the protocol, 
institutional policy, and any applicable regulatory requirements.  
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible. The investigator should notify the sponsor immediately of any such inspection.  
The Sponsor-Investigator/institution and participating site investigators/institutions agree to 
allow the auditor or inspector direct access to all relevant documents and allocate their time 
and the time of their staff to the auditor/inspector to discuss findings and any issues. Audits 
and inspections may occur at any time during or after completion of the study.  
11.4  
Archiving  
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.  
Patient (hospital) files including tumor images will be archived according to local regulations 
and in accordance with the maximum period of time permitted by the hospital, institution or 
private practice. Where the archiving procedures do not meet the minimum timelines required 
by the sponsor, alternative arrangements must be made to ensure the availability of the source 
documents for the required period.  
The reading institution will archive the data for at least 15 years.  


  
   
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The investigator/institution notifies the sponsor if the archival arrangements change (e.g. 
relocation or transfer of ownership).  
The investigator site file is not to be destroyed without the sponsor’s approval.  
The contract with the investigator/institution will contain all regulations relevant for the study 
center.  
12.  
Premature termination of the study  
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g. treatment arms; dose steps; centers]) at any time, which may be due but not limited to 
the following reasons:   
• If risk-benefit ratio becomes unacceptable owing to, for example, 
o Safety findings from this study (e.g. SAEs)  
o Results of parallel clinical studies 
o Results of parallel animal studies  
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity).  
• 
If the study conduct (e.g. recruitment rate; dropout rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame.  
The investigator has the right to close his/her center at any time.  
For any of the above closures, the following applies:  
• 
Closures should occur only after consultation between involved parties. Final decision 
on the closure must be in writing.  
• 
All affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study center; 
head of study center) must be informed as applicable according to local law.  
• 
All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor. The investigator will retain all other documents until 
notification is given by the sponsor for destruction.  
• 
In the event of a partial study closure, ongoing patients, including those in post-study 
follow-up, must be taken care of in an ethical manner.  
Details for individual patient's withdrawal can be found in Section 6.3.1.  
13.  
Ethical and legal aspects  
13.1  
Investigator(s) and other study personnel  
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate. This list will be updated as needed; an 


  
   
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abbreviated version with personnel relevant for the centers will be available in each center’s 
investigator site file.  
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site.  
The principal investigator of each center must sign the protocol signature page and must 
receive all required external approvals (e.g. health authority, ethics committee, sponsor) 
before patient recruitment may start at the respective center. Likewise, all amendments to the 
protocol must be signed by the principal investigator and must have received all required 
external approvals before coming into effect at the respective center.  
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor’s study file.  
The global sponsor of this study is identified on the title page of this protocol. If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature pages.  
13.2  External data evaluation bodies Data Safety Monitoring Committee 
(DSMC)  
The Yale Cancer Center DSMC will serve at the DSMC of record.  The Yale DSMC will 
review and monitor compliance, toxicity and deviations from this study. The committee is 
composed of clinical specialists with experience in oncology and who have no direct 
relationship with the study. Information that raises any questions about participant safety will 
be addressed with the Principal Investigator.  
The DSMC will review this protocol at a minimum of once every six months. Information to 
be provided to the committee includes: a study narrative by the PI, a summary DSMC report 
produced by OnCore (which includes participant accrual, response, trial status history, SAEs, 
Adverse Events, Deviations and survival); audit results, and monitoring reports as applicable. 
Other information (e.g. scans, laboratory values) will be provided upon request.  
13.3  
Funding and financial disclosure  
13.3.1 Funding  
This study will be funded by Bayer Health Care via grant to the sponsor.  
13.3.2 Financial disclosure   
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research patients has to provide a financial disclosure 
according to all applicable legal requirements. All relevant documentation will be filed in the 
TMF.  


  
   
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13.4  
Ethical and legal conduct of the study  
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
GCP guidelines and the guiding principles detailed in the Declaration of Helsinki. The study 
will also be carried out in keeping with applicable local law(s) and regulation(s).  
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations. When necessary, an extension, amendment or renewal of the IEC/IRB 
approval must be obtained and also forwarded to the sponsor. The responsible unit (e.g. 
IEC/IRB, head of the study center/medical institution) must supply to the sponsor, upon 
request, a list of the IEC/IRB members involved in the vote and a statement to confirm that 
the IEC/IRB is organized and operates according to GCP and applicable laws and regulations.  
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.  
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial patients without prior IEC/IRB/sponsor approval/favorable opinion. As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/sponsor. Any deviations from the protocol must be explained and documented by 
the investigator.  
Details on discontinuation of the entire study or parts thereof can be found in Section 12.  
 
13.5  
Patient information and consent  
13.5.1 Patient information and informed consent form for prescreening  
An ICF for prescreening with brief information on the study will be provided to patients with 
unresectable locally advanced or metastatic pancreatic cancer who would like to participate in 
this study.  
The ICF for prescreening includes the general aspects of the study conduct, details on the 
tissue samples required to perform the mesothelin overexpression test, and information on 
risks in case a fresh biopsy is needed.   
The patient has the right to ask the investigator to explain the study in detail and the right to 
withdraw from the study at any time without any disadvantage and without having to provide 
reasons for this decision.  
13.5.2 Patient information and informed consent form for full study  
An ICF for screening of study treatment eligibility (ICF for full study) will be provided no 
longer than 28 days prior to start of study treatment to the patient who passes the 


  
   
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prescreening, including mesothelin overexpression level test, and who still has interest to 
participate in this study. The ICF for full study should be provided prior to activities related 
to the screening for full study.  
All relevant information on the study will be summarized in the ICF for full study provided 
by the sponsor or the study center.   
The investigator or designee will explain all relevant aspects of the study to each patient / 
legal representative or proxy consenter (if the patient is under legal protection), prior to 
his/her entry into the full study (i.e. before any examinations and procedures associated with 
the selection for the full study are performed excluding the prescreening procedures or further 
study-specific data is recorded on study-specific forms).  
The patient has the right to ask the investigator to explain the study in detail and the right to 
withdraw from the study at any time without any disadvantage and without having to provide 
reasons for this decision.  
The investigator and research team will follow all YCC CTO SOPs at Yale and local SOPs on 
consent elsewhere.  
13.6  
Publication policy and use of data  
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov.   
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.  
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations. The sponsor is interested in the publication of the 
results of every study it performs.   
13.7  
Confidentiality  
All records identifying the patient will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.  
Patient names will not be supplied to the sponsor. Only the patient number will be recorded in 
the CRF, and if the patient name appears on any other document (e.g. pathologist report), it 
must be obliterated before a copy of the document is supplied to the sponsor. Study findings 
stored on a computer will be stored in accordance with local data protection laws. As part of 
the informed consent process, the patients will be informed in writing that representatives of 
the sponsor, IEC/IRB, or regulatory authorities may inspect their medical records to verify 
the information collected, and that all personal information made available for inspection will 
be handled in strictest confidence and in accordance with local data protection laws.  
If the results of the study are published, the patient’s identity will remain confidential.  
The investigator will maintain a list to enable patients to be identified.  
 


  
   
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14.  
Reference list  
  
1. 
Golfier, S., et al., Anetumab ravtansine: a novel mesothelin-targeting antibody-drug 
conjugate cures tumors with heterogeneous target expression favored by bystander 
effect. Mol Cancer Ther, 2014. 13(6): p. 1537-48.  
2. 
Bera, T.K. and I. Pastan, Mesothelin is not required for normal mouse development or 
reproduction. Mol Cell Biol, 2000. 20(8): p. 2902-6.  
3. 
Argani, P., et al., Mesothelin is overexpressed in the vast majority of ductal 
adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker 
by serial analysis of gene expression (SAGE). Clin Cancer Res, 2001. 7(12): p. 38628.  
4. 
Hassan, R., T. Bera, and I. Pastan, Mesothelin: a new target for immunotherapy. Clin 
Cancer Res, 2004. 10(12 Pt 1): p. 3937-42.  
5. 
Hassan, R. and M. Ho, Mesothelin targeted cancer immunotherapy. Eur J Cancer, 
2008. 44(1): p. 46-53.  
6. 
Bharadwaj, U., et al., Mesothelin confers pancreatic cancer cell resistance to 
TNFalpha-induced apoptosis through Akt/PI3K/NF-kappaB activation and IL-6/Mcl-1 
overexpression. Mol Cancer, 2011. 10: p. 106.  
7. 
Bharadwaj, U., et al., Mesothelin overexpression promotes autocrine IL-6/sIL-6R 
trans-signaling to stimulate pancreatic cancer cell proliferation. Carcinogenesis, 
2011. 32(7): p. 1013-24.  
 


  
   
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15.  
Protocol amendments  
Protocol Version 4.0, 19-September-2018  
 
 
Page # 
Section  
Change & Rationale 
- 
Header 
Version date changed to 19-September-2018 
- 
Version number 
Updated from 3.0 to 4.0 
Page 1 
Title Page 
Updated version date 
Page 3 
2. Synopsis—
Duration of 
Treatment 
Language was updated to clarify that scans will be read by 
precision metrics or an equivalent system  
Page 3 
2. Synopsis— 
Diagnosis and 
main criteria for 
inclusion 
/exclusion 
The eligibility criterion was updated to be consistent with language 
in eligibility criteria in body of the protocol. Neoadjuvant or 
adjuvant chemotherapy would not be counted as a line of therapy.   
 
Page 6 
Table of Contents 
Updated 
Page 15 
5.1 Design 
Overview 
Language “by the Bayer designated vendor with the companion 
diagnostic” was removed. 
Page 21 
6.3.1.2 Full 
screening failure 
“Re-testing for mesothelin expression after obtaining an initial 
negative result is not allowed” was removed from the protocol as 
retesting has been allowed.  
Page 23 
Figure 2-1 
Minor grammatical and formatting updates 
Page 29 
7.3.2.2 Non-
hematological 
toxicities 
• Minor formatting updates were made 
• The following sentence was clarified; “If treatment 
modification is required due to Grade ≥3 non-hematological 
TEAE” to “If treatment modification is required due to a 
non-hematological TEAE as listed above”  
• Table 2-5 was updated to clarify that dose adjustments for 
Grade 1–2 toxicities can be made at investigator’s discretion 
Page 35 
7.4  
Sentence “On the day of receipt, the responsible site personnel will 
confirm receipt of study drug via OnCore.” was removed. This 
procedure is occurring via fax confirmation. 
Page 38 
Table 2-9 
Permitted 
Information on infusion reaction management was clarified to state 
that “Pre-treatment with anti-nausea medication is allowed at the 
investigators discretion.  See anti-emetic note below. “ 


  
   
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Page # 
Section  
Change & Rationale 
Concomitant 
therapies 
Page 45 
9.2.3.1 
Treatment—Cycle 
1 Day 1 
The following language was added to clarify C1D1 Schirmer 
testing:  
“If the screening period Schirmer test is conducted within 7 days 
of starting study treatment, the test does not need to be repeated at 
C1D1.” 
Page 45 
9.2.3.1 
Treatment—Cycle 
1 Day 8, Cycle 1 
Day 15, Cycle 2 
and higher Day 8, 
& Cycle 2 and 
higher Day 15 
Laboratory testing was clarified:  
• “Complete Blood Count” was updated to “Complete blood 
count with differential” 
• “Electrolyte and chemistry panel (only AST, ALT, and 
bilirubin)” was updated to “Electrolyte and chemistry panel 
(CMP) 
 
Page 62 
9.5.3.7 
Ophthalmologic 
examinations 
The following language was added to clarify C1D1 Schirmer 
testing:  
“If the screening period Schirmer test is conducted within 7 days 
of starting study treatment, the test does not need to be repeated at 
C1D1.” 
Page 73 
15. Protocol 
amendments 
Updated protocol amendment summary 
  
16.  
Appendices  
16.1  
ECOG Performance Status  
Grade  
Description  
0  
Fully active, able to carry on all pre-diseases performance without 
restriction.  
(Karnofsky 90-100)  
1  
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature (e.g. light 
housework, office work).  
(Karnofsky 70-80)  
2  
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking 
hours.   
(Karnofsky 50-60)  
3  
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours.  
(Karnofsky 30-40)  


  
   
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4  
Completely disabled. Cannot carry on any self-care. Totally confined 
to bed or chair. (Karnofsky 10-20)  
  
16.2  
New York Heart Association (NYHA) functional classification  
NYHA Class  Symptoms  
I  
No symptoms and no limitation in ordinary physical activity, e.g. shortness of 
breath when walking, climbing stairs etc.  
II  
Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity.  
III  
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g. walking short distances (20–100 m).  
Comfortable only at rest.  
IV  
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients.  
Source (43)  
16.3  
Response assessment  
Tumor response will be evaluated in this study using the RECIST 1.1 criteria.  
Response Criteria  
Complete response (CR): Disappearance of all target lesions. Disappearance of all 
nontarget lesions and normalization of tumor marker level, if applicable. Any pathological 
lymph nodes (whether target or non-target) must have decreased in size to have a short axis 
of < 10 mm.  
Partial response (PR): At least a 30% decrease in the sum of diameters of target lesions 
taking as reference the baseline sum diameters. No appearance of new lesions. Non-target 
lesions must be stable or can be not evaluable.  
Progressive disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study = nadir (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. For non-target lesions, unequivocal 
progression of existing lesions represents PD.  
Note: the appearance of one or more new lesions is also considered progression.  
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.  
Table below provides an overview how the overall response is assessed.  
  
Overall Response Assessment  
Target  
lesions  
Non-target  
lesions  
New  
lesions  
Overall  
response  


  
   
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CR  
CR  
No  
CR  
Non-CR/Non-PD  
No  PR  
PR  
Non-PD or not all evaluated  
SD  
Non-PD or not all evaluated  
No  
SD  
NE  
Non-PD  
No  
NE  
PD  
CR = Complete response; NE = Not evaluated; PD = Progressive disease; PR = Partial response;  
SD = Stable disease   
Adapted from (44)  
  
16.4  
National Cancer Institute’s Common Terminology Criteria for Adverse 
Events, version 4.03  
This study will utilize the NCI-CTCAE v4.03 for toxicity and SAE reporting by sites. A copy 
of the CTCAE v4.03 can be downloaded from the website (45).  
16.5  
CYP3A4 inhibitors and inducers  
Table below provides an overview of strong CYP3A4 inhibitors and inducers.  
 
 
  
Strong CYP3A4 inhibitors  
Strong CYP3A4 inducers  
Boceprevir  
Clarithromycin  
Conivaptan  
Grapefruit juice  
Indinavir  
Itraconazole  
Ketoconazole  
Lopinavir / Ritonavir  
Mibefradil (withdrawn in US)  
Nefazodone  
Nelfinavir  
Posaconazole  
Ritonavir  
Saquinavir  
Telaprevir  
Telithromycin  
Voriconazole  
Avasimibe  
Carbamazepine  
Phenytoin Rifampin  
St. John’s wort  
CYP3A4 = Cytochrome P450, family 3, subfamily A, polypeptide 4 Source 
(46)  
CR   
CR   
NE   
PD   
Any  
Yes or No   
Any   
PD   
Yes or No   
Any   
Any  
Yes  


  
   
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16.6  
Calculation of glomerular filtration rate by the Modification of Diet in 
Renal Disease formula  
In accordance with established nephrology practice and guidelines, renal function at baseline 
and throughout the study will be assessed by means of the estimated GFR, calculated using 
the abbreviated MDRD study formula.  
This equation of 4 variables (serum creatinine level, age, sex, and ethnicity) is recommended 
by the National Kidney Foundation for use in individuals 18 years or older. The formula can 
be found at the following website (47).  
Patients with a baseline GFR < 30 mL/min/1.73 m2 calculated by this method will not be 
allowed to participate in the study.  
  
16.7  
Mosteller Equation for calculation of body surface area (BSA)  
BSA (m2) = SQR RT ([Height(cm) x Weight(kg) ]/ 3600 ) 
Where SQR RT is square root (√).