Phase I/II Study of the Human Anti-Mesothelin Antibody Drug Conjugate Anetumab Ravtansine (AR), Combined With the PD-L1 Inhibitor Atezolizumab in Non-Small Cell Lung Cancer
Phase: PHASE1
Conditions: Mesothelin Positive, Stage III Non-Small Cell Lung Cancer AJCC v7, Stage IIIA Non-Small Cell Lung Cancer AJCC v7, Stage IIIB Non-Small Cell Lung Cancer AJCC v7, Stage IV Non-Small Cell Lung Cancer AJCC v7
Sponsor: Mayo Clinic



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Table of Contents 
Phase I/II Study of the Human Anti-Mesothelin Antibody Drug Conjugate Anetumab Ravtansine 
(AR), Combined with the PD-L1 Inhibitor Atezolizumab in Non-Small Cell Lung Cancer ............... 1 
Protocol Resources ...................................................................................................................................... 2 
Table of Contents ........................................................................................................................................ 3 
Schema ......................................................................................................................................................... 4 
Protocol Synopsis ........................................................................................................................................ 5 
1.0 
Background ............................................................................................................................... 9 
2.0  
Goals ........................................................................................................................................ 18 
3.0 
Patient Eligibility .................................................................................................................... 19 
4.0 
Test Schedule ........................................................................................................................... 24 
5.0 
Grouping Factor ..................................................................................................................... 27 
6.0  
Registration Procedures ......................................................................................................... 27 
7.0 
Protocol Treatment ................................................................................................................. 30 
8.0 
Dosage Modification Based on Adverse Events ................................................................... 31 
9.0 
Ancillary Treatment/Supportive Care .................................................................................. 47 
10.0 
Adverse Event (AE) Monitoring and Reporting .................................................................. 50 
11.0 
Treatment Evaluation Using RECIST Guideline ................................................................ 61 
12.0 
Descriptive Factors ................................................................................................................. 67 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient .................................................... 68 
14.0 
Body Fluid Biospecimens ....................................................................................................... 69 
15.0 
Drug Information.................................................................................................................... 70 
16.0 
Statistical Considerations and Methodology ........................................................................ 75 
17.0 
Tissue Biospecimens/Pathology Considerations .................................................................. 82 
18.0  
Records and Data Collection Procedures ............................................................................. 84 
19.0 
Budget ...................................................................................................................................... 85 
20.0 
References ................................................................................................................................ 86 
APPENDIX A: ECOG PERFORMANCE STATUS SCORES ............................................................ 88 
APPENDIX B: APPENDIX C: NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL 
CLASSIFICATION ................................................................................................................................ 893 
 
 
 

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Protocol Synopsis 
Title / Phase 
A Phase I/II Study of the human anti-mesothelin antibody drug conjugate 
anetumab ravtansine (AR), combined with the PD-L1 inhibitor Atezolizumab in 
non-small cell lung cancer 
Mayo Clinic Study 
Number 
MC1711 
Mayo Clinic Cancer 
Center Investigator 
Alex A Adjei MD, PhD 
Study Drug(s) 
Anetumab ravtansine (AR, BAY 94-9343), Atezolizumab 
Objectives 
Primary Goals(s) 
Phase I 
To identify the recommended  phase II dose of anetumab ravtansine combined 
with atezolizumab in advanced MSLN+  NSCLC. 
Phase II 
To determine the confirmed response rate for the combination of anetumab 
ravtansine and atezolizumab in MSLN+  2nd line NSCLC  
 
Secondary Goals 
Phase I 
1. To describe  adverse events and toxicities of the combination treatment of  
anetumab ravtansine and Atezolizumab; 
2. To identify preliminary evidence of clinical activity (i.e. response, timed 
endpoints, etc.) 
Phase II 
1. To determine the progression-free survival (PFS) and the 1-year PFS rate for 
the combination of anetumab ravtansine and atezolizumab in 2nd-line NSCLC 
2. To determine the overall survival of anetumab ravtansine combined with 
atezolizumab in second-line therapy of NSCLC 
3. Adverse events will also be summarized as well. 
Correlative  
1. To determine using flow cytometry the levels of Bcl-2 interacting mediator of 
cell death (BIM) in circulating CD8+  CD11a+ PD-1+ T-cells, in peripheral 
blood samples collected from patients prior to initiation of therapy (baseline) and 
correlating these with confirmed response rate  during and following treatment 
with the combination regimen. 
2. To determine tissue MSLN and PD-L1 expression and correlate with response 
to combination therapy with atezolizumab and anetumab ravtansine 
3. To correlate baseline serum soluble PDL-1 (sPDL-1) with response to therapy.   

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Target Accrual and 
Study Duration 
Duration:  
Phase I: 3 months (maximum 6 months). 
In the phase I portion, there will be 3-6 patients per dose level for a total of 6-12 
patients.   
Phase II stage 1: 6 months; stage II: 6 months.  
Total duration: 15-18 months 
In this part of the trial, 17 patients will be accrued (this will include the patients 
treated at the MTD from the phase I component). If 3 responses or less are 
observed in the first 17 patients, then the trial will be terminated and the 
treatment deemed not worthy of further study. If at least 4 responses are observed 
among these 17 patients, then an additional 20 patients will be accrued to the 
second stage. If 11 or more responses are observed at the end of the trial the 
treatment will be considered promising. This design yields at least 90% 
probability of a positive result if the true response rate is at least 40%. A 
maximum of 12 patients will be accrued to the phase I portion leading to a 
maximum of 49 patients for this study. 

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Study Procedures 
Disease Evaluation:  Tumors will be measured using the Full Analysis Set via 
imaging (CT scan) at baseline and after every 2 doses of  anetumab ravtansine 
and atezolizumab (i.e. q 6 weeks). ORR will be defined as the total number of 
patients with confirmed responses of either CR or PR divided by the total number 
of patients who are evaluable for response prior to or on Cycle 3 Day 1 and prior 
to or on Day 1 of every other cycle thereafter. 
Adverse Events: Drug safety will be monitored and evaluated continuously 
throughout the study by obtaining, reviewing and analyzing data on adverse 
events (AEs), changes in laboratory values, vital signs, electrocardiograms 
(ECGs), and physical examination findings. Using the Common Terminology 
Criteria for Adverse Events (CTCAE) V.4.0, the frequency of AEs will be 
tabulated by grade across all dose levels and cycles. 
Eye examination (slit lamp) every 3 weeks (since anetumab ravtansine and 
atezolizumab have eye AE)   
Hematology: Baseline, Cycle 1 Day 1, and on Day 1 of each subsequent cycle 
and end of treatment. 
Chemistry: Baseline, Cycle 1 Day 1, and on Day 1 of each subsequent cycle and 
end of treatment. 
Urinalysis: Baseline, Day 1 of each cycle, and end of treatment.  
Performance Status: Baseline, Cycle 1 Day 1, and on Day 1 of each subsequent 
cycle and end of treatment. 
Physical Examination (including neurological examination, vital signs, and 
body weight): Baseline, Cycle 1 Day 1, and on Day 1 of each subsequent cycle 
and end of treatment. 
12-Lead Electrocardiogram: Baseline, and  as clinically indicated during  the 
study.  
Biomarker Assessment/Correlative Studies: Tissue PD-L1 expression, Treg 
accumulation and IFN-gamma expression in response to atezolizumab plus 
anetumab ravtansine will be determined. The correlation in expression of Bim 
levels in CD8+ CD11a+ PD-1+ T-cells to response rate and also the percentage 
change of Bim levels at baseline, during and after treatment will be assessed. 
Hence, Bim expression at baseline, followed by every 6 weeks of atezolizumab 
therapy and upon completion of therapy will be assessed. 

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Statistical Analysis 
Sample Size Assumptions / Target Number of Valid Cases 
A Simon two-stage design will be used in which a 20% response rate is 
considered not promising, a 40% response rate is considered promising, and the 
probabilities of a type I error (falsely accepting a nonpromising therapy) and type 
II error (falsely rejecting a promising therapy) are set at 0.10 and 0.10, 
respectively. In this scenario, the maximum trial size would be 37 patients. In the 
first stage of this design, 17 patients will be accrued (this will include the patients 
treated at the MTD from the phase I component). If 3 responses or less are 
observed in the first 17 patients, then the trial will be terminated and the 
treatment deemed not worthy of further study. If at least 4 responses are observed 
among these 17 patients, then an additional 20 patients will be accrued to the 
second stage. If 11 or more responses are observed at the end of the trial the 
treatment will be considered promising. This design yields at least 90% 
probability of a positive result if the true response rate is at least 40%. A 
maximum of 12 patients will be accrued to the phase I portion leading to a 
maximum of 49 patients for this study. 
 
Interim Analyses  
After 17 patients accrued on the phase II portion including patients treated at 
RP2D 
 
1.0 
Background 
1.1  
Non- small cell lung cancers (NSCLC) 
Lung cancer is the leading cause of cancer-related mortality worldwide, accounting for 
more than one million deaths every year. NSCLC comprises of 85% of lung cancers, and 
approximately 40% of patients with newly diagnosed NSCLC have advanced stage 
disease.(1) The outcomes of advanced NSCLC remain dismal, with overall survival of 
about 1 year. Platinum-based chemotherapy, which is considered the standard of care and 
better than best supportive care, can be associated with significant morbidity.(2) More 
recently, advances in identifying actionable molecular targets like EGFR mutations and 
ALK translocations have demonstrated significantly improved survival in the patients 
who harbor these alterations. However, the proportion of NSCLC patients with any 
targetable alterations is less than 25%.(3) There is a need for effective and safe therapies 
for optimizing outcomes in patients with advanced NSCLC. 
1.2  
Anetumab ravtansine (BAY 94-9343) 
Anetumab ravtansine (BAY 94-9343) is an antibody-drug conjugate (ADC) targeting 
mesothelin, a protein normally present on mesothelial cells and overexpressed in the 
majority of mesotheliomas. Mesothelin expression is seen in approximately 40-60% 
patients with NSCLC (4, 5) The expression profile as well as the fact that mesothelin is 
an internalizing antigen highlights mesothelin as an adequate target for antibody-
mediated delivery of cytotoxics. The biological function of mesothelin is unknown; 
mesothelin-deficient mice do not display a specific phenotype (6). 
 
Anetumab ravtansine is a fully human IgG1 antibody (MF-T, BAY 86-1903) directed at 
the mesothelin antigen and conjugated to a synthetic maytansine derivative as toxophore 
(DM4, BAY 100-6640) by a disulfide linker moiety to its lysine residues. DM4 is a 

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spindle poison, and its mechanism of action (MoA) is inhibition of microtubule assembly 
(similar to that of vinca alkaloids). 
 
1.21   Non clinical experience 
 
In vivo, AR showed potent inhibition of the growth of the tumor xenograft 
models (7). Anetumab ravtansine eradicated tumors in 5 out of 6 animals in the 
MIA PaCa-2/meso pancreatic cancer model at a dose of 0.05 mg/kg, while it 
demonstrated tumor regression in 25% of the animals in the HT-29/meso colon 
cancer model (P<0.001). In the OVCAR-3 ovarian cancer model treated with 
anetumab ravtansine at a dose of 0.05 mg/kg (Q3Dx3), 100% of mice responded 
to the treatment, and 4 out of 6 mice had complete tumor eradication lasting for 
at least 12 weeks after last dose. In the mesothelioma model (NCI-H226), 2 
cycles of triple IV inoculations of 0.2 mg/kg AR (related to the concentration of 
DM4) significantly reduced tumor growth compared with the vehicle control 
(94%, P < 0.001) and achieved a 63% response rate (partial response [PR] in 5 
out of 8 mice). In contrast, treatment with free active methyl-DM4 (DM4-Me) 
did not affect tumor growth significantly. In the same study, cisplatin alone and 
in combination with pemetrexed resulted in 70% reduction of tumor growth (P < 
0.01), with anetumab ravtansine therapy demonstrating 14-fold lower tumor 
weight as compared with the combination of cisplatin and pemetrexed (P < 0.05).  
 
The efficacy of anetumab ravtansine monotherapy was also demonstrated in 
preclinical patient-derived xenograft (PDX) MPM tumor models.(7) Anetumab 
ravtansine administered at a dose of 0.2 mg/kg resulted in transient regression in 
6 out of 8 tumors in the pancreatic tumor model PAXF736 (P < 0.001), and a 
complete eradication of all tumors in the ovarian tumor model OVCAR6719 (P < 
0.001). It also demonstrated at least a partial tumor regression in all the mice in 
the mesothelioma model Meso7212 (P < 0.001). This was compared to the 
standard of care therapies and revealed that therapy was anetumab ravtansine was 
more efficacious than gemcitabine in the pancreatic model (P < 0.01), cisplatin in 
the ovarian model (P < 0.01), and cisplatin (P < 0.05) and pemetrexed (P < 
0.001) in the mesothelioma model. The difference between the effects of a 
microtubule-targeting drug vinorelbine and anetumab ravtansine was not 
significant. 
 
Further details can be found in the latest available version of the investigator's 
brochure (IB), which contains comprehensive information on the study drug. 
 
1.22 
Clinical experience 
 
As of 13 July 2015, a total of 148 patients with advanced refractory solid tumors 
expressing mesothelin have been treated with anetumab ravtansine given as a 
single agent by 1-hour IV infusion in the Phase I First in Human (FiH) 15051 
study. The dose-escalation part of the FiH study 15051 was completed in FEB 
2013 with 45 patients evaluated in 10 cohorts spanning the dose range from 0.15 
mg/kg to 7.5 mg/kg given by 1-hour IV infusion Q3W. The maximum tolerated 
dose (MTD) was defined as 6.5 mg/kg Q3W. Subsequently 2 expansion cohorts 
(n=32) were treated at 6.5 mg/kg Q3W. Two further randomized expansion 
cohorts of anetumab ravtansine (n=71) given QW in mesothelioma and ovarian 
cancer were initiated on 16 Jan 2014. Of these 71 patients, 19 with ovarian 

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cancer received 1.8 mg/kg QW and 21 received 2.2 mg/kg QW; 16 with 
mesothelioma received 1.8 mg/kg QW and 15 received 2.2 mg/kg QW. Data 
from one of the subjects in 1.8 mg/kg QW was not available in the listings.  
 
Using the data cut on 13 JUL 2015, mesothelin protein expression levels at the 
membrane of tumor cells have been determined using the SP74 MSLN IHC assay 
under development by Ventana Roche. Although mesothelin expression has 
determined retrospectively in the Q3W dosing schedule, only patients with 
tumors exhibiting ≥ 30% positive tumor cells with moderate or stronger 
membrane staining have been enrolled in the QW expansion cohort. 
 
A total of 53 males and 94 females were treated, with a mean age of 60.5 years. 
Within the escalation cohorts (total 45 patients) the most common cancers were 
mesothelioma (n=21), pancreatic (n=9), breast (n=5), and ovarian cancer (n=4) 
while in the three expansion cohorts (n=32 receiving 6.5 mg/kg Q3W and n=70 
receiving either 1.8 mg/kg QW or 2.2 mg/kg QW) subjects had ovarian cancer 
(n=59) or mesothelioma (n=43). 
 
Information on secondary pharmacologic effects of the ADC was available on 38 
patients among both the dose escalation and expansion cohort combined. The 
formation of anti- anetumab ravtansine antibodies with titer of ≥32 occurred in 6 
out of 38 subjects (16%) treated at the MTD of 6.5 mg/kg Q3W. The formation 
of anti- anetumab ravtansine antibodies seemed to have no discernible correlation 
to the incidence of adverse effects.  
 
Clinical pharmacokinetic information on anetumab ravtansine has been 
characterized in the dose-escalation study 15051. Following IV administration, 
maximum ADC concentrations were typically observed within 1 hour of the end 
of infusion, and declined with a mean terminal phase half-life values of 
approximately 5 to 6 days. The maximum concentration of drug (Cmax) and area 
under the curve (AUC) increased in a dose-proportional manner in the 0.15 
mg/kg to 7.5 mg/kg Q3W dose range studied. Cmax of DM4 and DM4 Me were 
observed within a median duration of 5 hours and 8-24 hours, respectively, after 
anetumab ravtansine infusion. At MTD, the average terminal half-lives of DM4 
and DM4-Me were approximately 3 days and 5.5 days, respectively. This is 
generally consistent with the range of half-life values reported for biologics and 
with no accumulation expected after Q3W dosing. 
 
In the dose-escalation part of the study 15051, the MRD for anetumab ravtansine 
was 6.5 mg/kg and lower, with 7.5mg/kg being the non-tolerated dose. 58 of 147 
subjects (39.5%) had at least one treatment-emergent adverse event (TEAE), of 
which 11 (7.5%) were deemed possibly related to anetumab ravtansine itself. In 
the Q3W dose escalation cohorts, 2 subjects (4.4%) experienced TEAEs likely 
related to anetumab ravtansine (hyponatremia and cardiac chest pain). In the 
Expansion 6.5 mg/kg Q3W cohort in subjects with ovarian cancer and 
mesothelioma, 5 subjects (15.6%) experienced TEAEs deemed secondary to AR 
(sinus tachycardia and hypotension in first subject, infusion related reaction, 
dyspnea, hypoxia, flushing and noncardiac chest pain in the second subject, 
fatigue in the third subject, hyponatremia and decreased appetite in the fourth 
subject, and esophagitis in the fifth subject). In the Exp 1.8 mg/kg QW cohort, 3 
subjects (8.8%) experienced TEAEs considered at least possibly related to the 

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study drug (pericardial effusion and noncardiac chest pain in the first subject, 
amylase increased in the second subject, and maculopapular rash in the third 
subject). In the Exp 2.2 mg/kg QW cohort, 1 subject experienced TEAEs from 
the drug (pericarditis, pleural effusion, and hypoxia). All of these adverse events 
have resolved completely, except a subject with amylase rise in Exp 1.8 mg/kg 
QW cohort and another subject with pleural effusion in Exp 2.2 mg/kg cohort). 
 
In the dose escalation cohorts, 1 subject in 6.5 mg/kg dose cohort had a dose 
reduction due to grade 3 rise in AST (aspartate aminotransferase) on day 8 after 
first dose of anetumab ravtansine, and another subject in 7.5 mg/kg dose cohort 
had a dose reduction due to Grade 3 peripheral neuropathy after second dose of 
anetumab ravtansine. In the Exp 6.5 mg/kg cohort, 15 of 32 (46.9%) subjects had 
dose reduction to 5.5 mg/kg Q3W (10 subjects with corneal epitheliopathy and 6 
subjects with peripheral neuropathy). Four of the 15 patients above had further 
dose reductions to 4.5 mg/kg Q3W (3 due to corneal epitheliopathy and 1 due to 
peripheral neuropathy). In the Exp 1.8 mg/kg QW cohort, 1 out of 34 subjects 
had annular keratopathy leading to dose reduction to 1.5 mg/kg QW. In the Exp 
2.2 mg/kg QW cohort, 4 of 36 patients had TEAEs (one each of neutropenia, 
blurred vision, ocular hyperemia, corneal deposits, or neuropathy peripheral) 
leading to dose reduction to 1.8 mg/kg QW.  
 
In the Q3W dose escalation cohort, 6 subjects (13.3%) had TEAEs leading to 
drug discontinuation (Grade 2 diarrhea in a subject in Cohort 3, Grade 5 dyspnea 
leading to death in a subject in Cohort 5, Grade 2 flushing in a second subject in 
Cohort 5, Grade 2 pericardial effusion in a subject in Cohort 7, Grade 5 
neutropenic sepsis leading to death in a subject in Cohort 10, and Grade 3 corneal 
disorder in a second subject in Cohort 10). Two out of these adverse events were 
deemed likely secondary to the study drug itself (Grade 2 flushing in Cohort 5 
and Grade 3 corneal disorder in Cohort 10). In the Exp 6.5 mg/kg Q3W cohort, 3 
subjects had drug discontinuation due to TEAEs (1 subject with Grade 5 sepsis 
leading to death; 1 subject with Grade 2 performance status decreased; and 1 
subject with Grade 2 neuropathy peripheral, Grade 1 atrial tachycardia, and 
Grade 2 decrease in ejection fraction). One of these TEAEs was felt not to be 
causally related to the study drug (Grade 2 peripheral neuropathy). In the Exp 1.8 
mg/kg QW cohort, 1 of 34 subjects had drug discontinuation due to Grade 4 
amylase increase which was deemed likely secondary to anetumab ravtansine 
itself. In the Exp 2.2 mg/kg QW cohort, 3 of 36 subjects had drug discontinuation 
due to TEAEs (Grade 2 pleural effusion, Grade 2 pneumothorax and Grade 2 
failure to thrive), of which the pleural effusion was likely secondary to the drug. 
 
A significantly higher incidence of dose modifications due to drug-related 
TEAEs at the MTD of 6.5 mg/kg Q3W could be at least in part explained by the 
much longer drug exposure (duration of time on treatment) in patients who start 
treatment at this dose. The ORR, as determined by the incidence of PR, was 
notably better in patients who started at 6.5 mg/kg Q3W. Among the 38 patients 
treated with AR at 6.5 mg/kg Q3W in the study 15051, 5 of 16 (31.3%) subjects 
with advanced, recurrent predominantly epithelial mesothelioma and 1 of 21 
(5%) subjects with advanced, recurrent predominantly epithelial ovarian cancer 
had a confirmed PR. 7 of 16 (44%) subjects with mesothelioma and 12 of 21 
(57%) subjects with ovarian cancer in this cohort had stable disease; 1 subject 
with mesothelioma and 3 with ovarian cancer had durable stable disease (≥6 

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months). Nine of 16 (56.2%) mesothelioma subjects in the Exp 6.5 mg/kg Q3W 
cohort have received only one regimen of systemic cytotoxic chemotherapy 
before entering the study 15051, with 5 of the 9 subjects (55.6%) showing a PR 
that lasted 174 days in 1 subject and ≥600 days in the other 4 subjects. AR 
showed less activity in mesothelioma subjects treated on QW schedule (1 subject 
each in Exp 1.8 mg/kg QW cohort nd Exp 2.2 mg/kg QW cohort). 
 
Objective tumor responses persisted in 6 of 7 patients with PR in whom the 
starting dose of 6.5 mg/kg Q3W had to be reduced to 5.5 mg/kg Q3W due to a 
drug-related TEAE, and even in 2 of 4 patients who required a second dose 
reduction to 4.5 mg/kg Q3W due to another related TEAE. In contrast, none of 
the 35 patients who started at doses < 6.5 mg/kg Q3W had a PR, and only 1 of 9 
patients who started at 5.5 mg/kg Q3W had an unconfirmed PR. If patients were 
to start treatment at doses < 6.5 mg/kg Q3W, the potential for clinical benefit 
could be reduced despite the lower risk of dose modification due to a drug-
related TEAE. 
 
Objective responses or prolonged SD occurred only in patients with strong 
mesothelin expression (e.g. MPM of epithelioid and mixed histology). 
The safety finding of particular interest at the 6.5 mg/kg Q3W dose has been the 
corneal epitheliopathy and keratitis with and without blurred vision probably 
related to anetumab ravtansine: 11 of 38 patients (29%) developed corneal 
adverse events (AEs). None of these events affected the deep corneal stroma or 
were considered serious or led to drug discontinuation and all events were 
reversible. 
 
Furthermore, population, physiologically-based pharmacokinetic (PopPBPK) 
modeling of preliminary data from the FiH study 15051, combined with a 
probabilistic regression analysis provided evidence that the area under the ADC 
plasma concentration-time curve at steady state, AUC (ADC), is a descriptor for 
the occurrence of corneal epitheliopathy, as shown in  
 
Figure 1. Based on the on average linear PK of AR (see above in this section), it 
can be assumed that dose reduction will lead to a reduced total drug exposure, i.e. 
AUC (ADC), and thus, also to a reduced probability of corneal epitheliopathy 
(see Figure 1 below)  
 

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1.3  
Atezolizumab  
Atezolizumab is a human monoclonal antibody directed against programmed death-
ligand 1 (PD-L1) with potential immune checkpoint inhibitory and antineoplastic 
activities. 
 
Atezolizumab targets immune cells or tumor cells and prevents interaction with either 
programmed death-1 (PD-1) receptor or B7.1 (CD80), both of which function as 
inhibitory receptors expressed on T cells. Interference of the PD-L1: PD-1 and PDL1: 
B7.1 interactions may enhance the magnitude and quality of the tumor-specific T-cell 
response through increased T-cell priming, expansion, and/or effector function (8, 9) . In 
May 2016, atezolizumab (Tecentriq™) was approved for the treatment of patients with 
locally advanced or metastatic urothelial carcinoma whose disease had worsened during 
or following platinum-containing chemotherapy, or within 12 months of receiving 
platinum-containing chemotherapy.  
 
Atezolizumab was engineered to eliminate Fc-effector function via a single amino acid 
substitution at position 298 on the heavy chain, which results in a non-glycosylated 
antibody that has minimal binding to Fc receptors and, consequently, eliminates 
detectable Fc-effector function. By eliminating Fc-effector function and antibody 
dependent cell-mediated cytotoxicity (ADCC), antibody-mediated clearance of activated 
effector T cells is also eliminated. 
 
PD-L1 expression is prevalent in many human tumors (e.g., lung, bladder, ovarian, 
melanoma, colon carcinoma), and its overexpression has been associated with poor 
prognosis in patients with several cancers (9-12). PD-L1 binds to two known receptors, 
PD-1 and B7.1 (CD80). PD-l is expressed on activated T cells, and receptor expression is 
sustained in states of chronic stimulation such as chronic infection or cancer (13, 14) . 
 
Ligation of PD-L1 with PD-1 inhibits T-cell proliferation, cytokine production, and 
cytolytic activity, leading to the functional inactivation or inhibition of T cells. Similarly, 
while the receptor B7.1 has been best defined as a costimulatory molecule expressed by 
B lymphocytes and other antigen-presenting cells (APCs), B7.1 expressed on the surface 
of T cells may provide an additional signaling mechanism through which PD-L1 can 
negatively regulate T cell responses (8). As a result, aberrant expression of PD-L1 on 
tumor cells and tumor-infiltrating immune cells, such as macrophages and dendritic cells, 
has been reported to impede anti-tumor immunity and contribute to immune evasion (15, 
16) 
Given the inhibitory effects of PD-L1 signaling on T cell proliferation and activity, 
targeted interruption of the PD-L1/PD-1 and PD-L1/B7.1 pathways represent an 
attractive strategy to reinvigorate tumor-specific T-cell immunity. The other known 
ligand of PD-1, programmed death-ligand 2 (PD-L2), is primarily expressed in normal 
tissues such as the lung. As a result, targeting tumor-overexpressed PD-L1 is a more 
promising strategy than targeting PD-1, as it preserves the immune homeostatic PD- 
L2:PD-1 interaction in normal tissues while dually inhibiting the PD-L1:PD-1 and PD- 
L1:B7.1 pathways to enhance anti-tumor T cell immunity. 
 
Blockade of PD-L1 or PD-1 with monoclonal antibodies has been reported to result in 
strong and often rapid antitumor effects in several mouse tumor models (17, 18). These 
data suggest that tumor-specific T cells may be present in the tumor microenvironment in 
an inactive or inhibited state, and blockade of the PD-L1/PD-1 pathway can reinvigorate 

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tumor-specific T-cell responses. 
Collectively, these data establish the PD-L1/PD-1 pathway as a promising new 
therapeutic target in patients with advanced tumors. Immune-related adverse events 
reported from the two recent studies were consistent with the role of the PD-L1/PD-1 
pathway in regulating peripheral tolerance. 
 
1.31 
Non clinical experience 
 
The safety, pharmacokinetics (PK), and toxicokinetics of atezolizumab were 
investigated in mice and cynomolgus monkeys to support intravenous (IV) 
administration and to aid in projecting the appropriate starting dose in humans. 
Given the similar binding of atezolizumab for cynomolgus monkey and human 
PD-L1, the cynomolgus monkey was selected as the primary and relevant 
nonclinical model for understanding the safety, PK, and toxicokinetics of 
atezolizumab. 
 
Overall, the nonclinical PK and toxicokinetics observed for atezolizumab 
supported entry into clinical studies, including providing adequate safety factors 
for the proposed phase 1 starting doses. The results of the toxicology program 
were consistent with the anticipated pharmacologic activity of down-modulating 
the PD-L1/PD-1 pathway and supported entry into clinical trials in patients. 
Please refer to the Investigator’s Brochure for details on the nonclinical studies. 
 
1.32 
Clinical Experience 
 
Current clinical studies of atezolizumab include one ongoing phase 1a 
monotherapy study, three ongoing combination studies, five phase 2 studies, and 
one phase 3 study. Details of all ongoing studies can be found in the 
Atezolizumab Investigator’s Brochure. 
1.4 
Rationale for combination of anetumab ravtansine  and atezolizumab in mesothelin-
expressing NSCLC 
Although the results with immunotherapy are encouraging as compared to the standard 
chemotherapy, a proportion of patients that have been treated with immunotherapy 
eventually experience disease relapse. This phenomenon has sometimes been attributed 
to tumor escape mechanisms or T-cell exhaustion. The patients who do not respond to 
these agents are noted to have an inability to mount an immune attack due to poor 
antigenicity. The use of AR could theoretically overcome this barrier to response. 
Mechanistically, AR binds to human mesothelin and internalizes the antigen, DM4 
binding then results in disruption of microtubule dynamics and cell death which could 
result in the release of neoantigens. This increased antigenic burden could synergize with 
the restored T-cell function due to PD-L1 blockade and result in increased cell death. 
Preliminary data in ovarian cancer mice models have confirmed a synergistic effect 
between ADCs and PD1 inhibitors. In addition, trastuzumab emtansine (T-DM1) renders 
HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade (19). 
 
1.5 
Rationale for Correlative Studies 
The Mayo Clinic group led by Dr Haidong Dong was the first to describe soluble PDL-1 
(sPDL-1) as a potential predictive biomarker of efficacy of PD1/PDL1 inhibitors. His 
data indicate that high levels of circulating sPDL-1 are associated with poor clinical 

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outcomes in melanoma patients. His group went on to demonstrate in a cohort of 80 
melanoma patients that none of those patients with detectable sPDL-1in their blood 
responded to treatment with pembrolizumab. (Dronca R, Harrington SM, Enninga EAL, 
et al.).  Thus, sPD-L1 may represent a blood-based biomarker of resistance to PD-1/PDL-
1 inhibition.  In addition, this group has demonstrated that Bim is overexpressed in a 
tumor-reactive T cell subset (TTR) that engages with PD-L1 expressing tumors. Not only 
was upregulation of Bim in circulating TTR a negative prognostic factor in a historic 
group of patients with metastatic melanoma who did not receive immunotherapy, but 
upregulation of Bim in circulating TTR was also predictive of responses to the PD-1 
inhibitor pembrolizumab in a more recent cohort of patients. Moreover, Bim levels in 
circulating TTR decreased in both responders and those with pseudo-progression. Based 
on these data, we will evaluate levels of sPD-L1 and upregulation of Bim in TTR as blood-
based biomarkers in this trial.

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2.0  
Goals 
2.1 
Primary Goals  
Phase I 
To identify the recommended phase II dose of anetumab ravtansine  combined with 
atezolizumab in advanced MSLN+ NSCLC. 
Phase II 
To determine the confirmed response rate for the combination of anetumab ravtansine 
and atezolizumab in MSLN+ 2nd line NSCLC 
 
2.2 
Secondary Goals 
 
  
Phase I 
2.21  
To describe adverse events and toxicities of the combination treatment of 
anetumab ravtansine and atezolizumab 
2.22  
To identify preliminary evidence of clinical activity (i.e. response, timed 
endpoints, etc.) 
 
  
Phase II 
2.23  
To determine the progression-free survival (PFS) and the 1-year PFS rate for the 
combination of anetumab ravtansine and atezolizumab in 2nd-line NSCLC 
2.24 
To determine the overall survival of anetumab ravtansine combined with 
atezolizumab in second-line therapy of NSCLC 
2.25 
Adverse events will also be summarized as well.   
 
2.3 
Correlative Goals 
2.31  
To determine using flow cytometry the levels of Bcl-2 interacting mediator of 
cell death (BIM) in circulating CD8+  CD11a+ PD-1+ T-cells, in peripheral 
blood samples collected from patients prior to initiation of therapy (baseline) and 
correlating these with confirmed response rate during and following treatment 
with the combination regimen. 
2.32  
To determine tissue MSLN and PD-L1 expression and correlate with response to 
combination therapy with atezolizumab and anetumab ravtansine 
2.33 
To correlate baseline serum soluble PDL-1 (sPDL-1) with response to therapy. 
 

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3.0 
Patient Eligibility  
Phase I only: Prior to discussing protocol entry with the patient, call the MCCC 
Registration Office at 
for dose level and to ensure that a place on the 
protocol is open to the patient. 
3.1 
Pre Registration - Inclusion Criteria  
3.11 
Ability to understand and the willingness to sign a written informed consent 
document. 
3.12 
Age ≥18 years. 
3.13 
Patient has disease amenable to biopsy if the archival tissue sample is 
unavailable.  Note: Archive sample must not be older than 36 months. 
3.2 
Registration - Inclusion Criteria 
3.21 
Phase I only: Diagnosis of advanced/metastatic NSCLC for which no standard 
treatment option. Phase II only: Advanced NSCLC patients who have received 
at least 1 platinum-based systemic chemotherapy regimen  
3.22 
Patients with tumors having actionable genomic alterations should  have received 
prior therapy with FDA approved agents targeting these aberations (ie EGFR, 
ALK, ROS1,BRAF V600E) 
3.23 
ECOG performance status 0 or 1. (See Appendix A) 
3.24 
Phase II only: Must have at least one measurable lesion as defined by RECIST 
criteria (see Section 11). 
3.25 
Ability to understand and the willingness to sign a written informed consent 
document. 
3.26 
Histological or cytologically confirmed NSCLC that shows moderate or stronger 
mesothelin expression in 30% of tumor cells by a companion assay.  MSLN 
expression score using Ventana IHC SP74 assay.  Phase I only: In addition 5-
30% tumor cells and 1, 2, or 3+ MSLN score. Phase II only: 30% tumor cells and 
either 2+/3+.  
3.27 
Life expectancy of ≥12 weeks. 
3.27 
Adequate bone marrow and organ function as defined by the following 
laboratory values ≤14 days prior to registration: 
• 
Absolute neutrophil count  ≥1.5 × 109/L 
• 
Platelets  ≥100 × 109/L 
• 
Hemoglobin  ≥9 g/dL 
• 
Chemistries as follows: 
o Potassium ≥lower limit of normal (LLN) range for the institution  
o Calcium ≥LLN (corrected for serum albumin, if albumin abnormal) 
o Magnesium ≥LLN 
o Sodium ≥LLN  
o Phosphorus ≥LLN.  
NOTE: Supplementation may be given before the first dose of study 
medication. 
• 
INR ≤1.5 

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• 
Serum creatinine ≤1.5mg/dL or creatinine clearance ≥50 mL/min (calculated 
by Cockcroft Gault equation) 
 
Cockcroft-Gault Equation: 
Creatinine clearance for males =  (140 - age)(weight in kg) 
 
(72)(serum creatinine in mg/dL) 
 
Creatinine clearance for females =  
(140 - age)(weight in kg)(0.85) 
 
(72)(serum creatinine in mg/dL) 
 
• 
ALT and AST ≤2.5 x ULN or ≤5 x ULN if liver metastases are present. 
• 
Total bilirubin ≤ 1. 5 x ULN 
3.28 
Standard 12-lead ECG with the following parameters at screening (defined as the 
mean of the triplicate ECGs):  
o QTcF interval at screening < 450msec (using Fridericia’ s correction)  
3.29a 
Negative pregnancy test performed ≤7 days prior to registration (women of 
childbearing potential only). 
3.29b Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study) 
3.29c 
Willing to provide blood samples for correlative research purposes 
3.3 
Registration - Exclusion Criteria  
3.31 
Prior treatment with anti-PD-1, or anti-PD-L1antibody which resulted in a patient 
having serious (grade 3-4) immune related adverse events.   
 
Note: 
• 
Patients who have received prior treatment with anti-CTLA-4 may be 
enrolled, provided the following requirements are met: 
o Minimum of 12 weeks from the first dose of anti-CTLA-4 and  >6 weeks 
from the last dose 
o No history of severe immune-related adverse effects from anti-CTLA-4 
(NCI CTCAE Grade 3 and 4) 
3.32 
More than one prior taxane regimen at any stage of the disease under study 
(“taxane” refers to paclitaxel, docetaxel, Abraxane® and cabazitaxel). Adjuvant 
and/or neoadjuvant treatments are considered together as one prior regimen. 
3.33 
Treatment with any other investigational agent or investigational device within 4 
weeks prior to registration (or within five half-lives of the investigational 
product, whichever is longer). Patients must be ≥ 2 weeks since any 
investigational agent administered as part of a Phase 0 study (also referred to as 
an “early Phase I study” or “pre-Phase I study” where a sub- therapeutic dose of 
drug is administered) at the Coordinating Center PI’s discretion, and should have 
recovered to eligibility levels from any toxicities. 
3.34 
Treatment with systemic immunostimulatory agents (including, but not limited 
to, interferon-α or interleukin-2) within 6 weeks or five half-lives of the drug 
(whichever is shorter) prior to registration. 

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3.35 
Received radiotherapy ≤4 weeks or limited field radiation for palliation ≤2 weeks 
prior to registration, and who has not recovered to Grade 1 or better from related 
side effects of such therapy (exceptions include alopecia) and/or in whom ≥25% 
of the bone marrow was irradiated. 
3.36 
Patients who have a previous or concurrent cancer that is distinct in primary site 
or histology from the cancer being evaluated in this study, except 
• 
Cervical carcinoma in situ, non-melanoma skin cancer, superficial non-
invasive bladder tumors, DCIS or any previous cancer curatively treated >3 
years before the start of anetumab ravtansine. 
3.37 
Treatment with systemic immunosuppressive medications (including, but not 
limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, 
thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) ≤ 2 weeks prior to 
registration. 
 
Note: 
• 
Patients who have received acute, low dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) may be 
enrolled. 
• 
The use of inhaled corticosteroids and mineralocorticoids (e.g., 
fludrocortisone) for patients with orthostatic hypotension or adrenocortical 
insufficiency is allowed. 
3.38  
Patients with known primary central nervous system (CNS) malignancy or 
symptomatic CNS metastases are excluded, with the following exceptions: 
• 
Patients with asymptomatic untreated CNS disease may be enrolled, 
provided all of the following criteria are met: 
o Evaluable or measurable disease outside the CNS 
o No metastases to brain stem, midbrain, pons, medulla, cerebellum, or 
within 10 mm of the optic apparatus (optic nerves and chiasm) 
o No history of intracranial hemorrhage or spinal cord hemorrhage 
o No ongoing requirement for dexamethasone for CNS disease; patients on 
a stable dose of anticonvulsants are permitted. 
o No neurosurgical resection or brain biopsy ≤28 days prior to registration 
• 
Patients with asymptomatic treated CNS metastases may be enrolled, 
provided all the criteria listed above are met as well as the following: 
o Radiographic demonstration of improvement upon the completion of 
CNS-directed therapy and no evidence of interim progression between 
the completion of CNS-directed therapy and the screening radiographic 
study 
o No stereotactic radiation or whole-brain radiation ≤28 days prior to 
registration 
o Screening CNS radiographic study ≥4 weeks from completion of 
radiotherapy and ≥ 2 weeks from discontinuation of corticosteroids 
3.39a  History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins 
3.39b  Patients who have a history or current evidence of bleeding disorder, i.e., any 
hemorrhage/bleeding event of CTCAE Grade ≥2, ≤28 days prior to registration. 

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3.39c  History or current evidence of uncontrolled cardiovascular disease including, but 
not limited to, the following conditions: 
• 
Congestive heart failure of New York Heart Association (NYHA, refer to 
appendix C) Class III or IV. 
• 
Unstable angina (symptoms of angina at rest) or new-onset angina ≤6 
months before the start of anetumab ravtansine. 
3.39d  Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
3.39e  Pregnant women are excluded from this study because atezolizumab is an 
investigational agent with the unknown potential for teratogenic or abortifacient 
effects. Note: Because there is an unknown but potential risk for adverse events 
in nursing infants secondary to treatment of the mother with atezolizumab, 
breastfeeding should be discontinued if the mother is treated with atezolizumab.  
3.39f  Patients on supraphysiologic doses of steroids or use of such ≤6weeks prior to 
registration. 
3.39g  Known clinically significant liver disease, including active viral, alcoholic, or 
other hepatitis; cirrhosis; fatty liver; and inherited liver disease. 
 
Note: 
• 
Patients with past or resolved hepatitis B infection (defined as having a 
negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc 
[antibody to hepatitis B core antigen] antibody test) are eligible. 
• 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction (PCR) is negative for HCV RNA 
3.39h  History or risk of autoimmune disease, including, but not limited to, systemic 
lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular 
thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Bell’s palsy, Guillain-Barré syndrome, 
multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis. 
 
Note: 
• 
Patients with a history of autoimmune hypothyroidism on a stable dose of 
thyroid replacement hormone are eligible. 
• 
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen 
are eligible. 
• 
Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis 
would be excluded) are permitted provided that they meet the following 
conditions: 
o Patients with psoriasis must have a baseline ophthalmologic exam to rule 
out ocular manifestations 
o Rash must cover less than 10% of body surface area (BSA) 
o Disease is well controlled at baseline and only requiring low potency 
topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 

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Protocol Version Date: 09Apr2019 
0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 
0.05%) 
o No acute exacerbations of underlying condition within the last 12 months 
(not requiring psoralen plus ultraviolet A radiation [PUVA], 
methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high 
potency or oral steroids) 
3.39i  History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing 
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed 
tomography (CT) scan. Note: History of radiation pneumonitis in the radiation 
field (fibrosis) is permitted. 
3.39j  Severe infections ≤4 weeks prior to registration, including, but not limited to, 
hospitalization for complications of infection, bacteremia, or severe pneumonia. 
3.39k  Signs or symptoms of infection ≤2 weeks prior to registration. 
3.39l  Major surgical procedure ≤28 days prior to registration or anticipation of need for 
a major surgical procedure during the course of the study. 
3.39m  Patients with corneal epitheliopathy or any eye disorder that may predispose the 
patients to this condition as judged by an ophthalmologist. 
• 
Note: Low grades of superficial punctate keratitis, within the range seen in 
the normal population, should not lead to the exclusion of the patient. 
3.39n  Non-healing serious wound, ulcer, or bone fracture unrelated to the primary 
tumor. 
3.39o  Previous assignment to treatment during this study. Patients permanently 
withdrawn from study participation will not be allowed to re-enter the study.  
3.39p  Substance abuse, psychological, or social conditions that may interfere with the 
patient's participation in the study or evaluation of the study results. 
 

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Protocol Version Date: 09Apr2019 
4.0 
Test Schedule 
4.1 
Study Calendar 
Tests and 
procedures 
Pre-
registration 
Screening 
≤14 days 
prior to 
registration 
Cycle 1 
Day 1 
Cycle 2 
Day 1  
Cycle 3 
Day 1 
Cycle 4 
Day 1 and 
subsequent 
cycles 
End of 
Treatment1 
Window 
 
 
 
(±5days) 
(±5days) 
(±5days) 
 
History and exam, 
Weight, PS 
 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
Hematology: CBC 
with differential 
 
X 
X2 
X 
X 
X 
X 
Serum chemistry3 
 
X 
X2 
X 
X 
X 
X 
Urinalysis 
 
X 
X2 
X 
X 
 
 
Serum pregnancy 
test (if applicable) 
 
X4 
 
 
 
 
 
Coagulation panel5 
 
X 
X 
 
 
 
 
12-lead EKG6 
 
X 
 
 
 
 
 
Echocardiogram  
 
X 
 
 
 
 
 
Ophthalmologic 
examination 7 
 
X 
 
X 
X 
X 
X 
                                                     
1 End of treatment visit should be at least 21 days from last dose of study drug. 
2 Need not be repeated if performed within 14 days of Cycle 1 Day 1  
3 Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium, magnesium. TSH (at baseline only) 
4 Pregnancy test must be performed ≤7 days prior to registration 
5 Coagulation panel: INR or PT and PTT or aPTT. 
6 Baseline and as clinically indicated 
7 A detailed ophthalmologic examination (visual acuity, IOP, Schirmer test and slit lamp) will be done for all patients during screening ≤ 28 days 
before the start of study treatment, as indicated during the study. During treatment, ophthalmologic examination (visual acuity and slit lamp only) 
can be performed ≤7 days before planned anetumab ravtansine infusion and at the safety follow-up exam. The IOP measurement is to be 
repeated during anetumab ravtansine therapy if the patient receives steroid eye drops for ≥10 days as treatment for corneal epitheliopathy. This 
measurement is performed at 2 weeks and 6 weeks after the initiation of steroid treatment. If IOP increases by <7 mmHg, the frequency of IOP 

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Protocol Version Date: 09Apr2019 
Tests and 
procedures 
Pre-
registration 
Screening 
≤14 days 
prior to 
registration 
Cycle 1 
Day 1 
Cycle 2 
Day 1  
Cycle 3 
Day 1 
Cycle 4 
Day 1 and 
subsequent 
cycles 
End of 
Treatment1 
Window 
 
 
 
(±5days) 
(±5days) 
(±5days) 
 
Adverse event 
evaluation 
 
X 
X2 
X 
X 
X 
X 
Tumor 
measurements8 
 
X 
 
 
X 
 
X 
Mandatory tissue 
(archival or fresh 
biopsy) for MSLN 
determination9 
X 
 
 
 
 
 
 
Mandatory Blood 
for Biomarker 
study10 
 
X 
 
 
X 
 
X11 
Anetumab 
Ravtansine 
administration 
followed by 
Atezolizumab 
Administration 
 
 
X 
X 
X 
X 
 
 
                                                                                                                                                                                                                                            
evaluation can be reduced to every 4 months. If IOP increases by ≥7 mmHg, a medical management plan with follow-up IOP evaluations will be 
initiated after consultation with an ophthalmologist and investigator. The Schirmer test is performed at C3D1 and C5D1. All these tests may be 
repeated during treatment at the investigator’s discretion. 
8 Contrast-enhanced CT/MRI is acceptable as a baseline scan if done within 28 days before C1D1.  Visit window of ≤7 days is allowed. Tumor 
measurements are repeated every odd cycle starting with Cycle 3. Documentation (radiologic) must be provided for patients removed from study 
for progressive disease. 
9 Mandatory biopsy will be collected before treatment if archival tissue (≤12 months of registration) not available.  See Section 17. 
10 Mandatory blood will be collected before treatment, every odd cycle starting with cycle C3D1 (in conjunction with imaging, for efficacy) and 
EOT.  See section 14.  
11 Optional blood sample collection at Disease Progression.  See section 14 for further details. 

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4.2 
Event Monitoring/Survival Follow-up 
 
 
Event Monitoring Phase* 
Every  
3 months 
until PD  
At PD 
After PD 
every  
6 months 
Death 
New 
Primary 
Event 
Monitoring 
X 
X 
X 
X 
At each 
occurrence 
*If a patient is still alive 2 years after registration, no further follow-up is required. 
 
 

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5.0 
Grouping Factor  
Phase: Phase I vs. Phase II 
 
6.0  
Pre-registration/Registration Procedures 
6.1 
Pre-Registration (Step 1)  
6.11 
Phase I:  Prior to discussing protocol entry with the patient, call the MCCC 
Registration Office at 
 for dose level and to ensure that a place on 
the protocol is open to the patient. 
 
6.12 
Phase II: To pre- register a patient, access the Mayo Clinic Cancer Center 
(MCCC) web page and enter the registration/randomization application. The 
registration/ randomization application is available 24 hours a day, 7 days a 
week. Back up and/or system support contact information is available on the 
website. If unable to access the website, call the MCCC Registration Office at 
 between the hours of 8 a.m. and 5:00 p.m. Central Time 
(Monday through Friday). 
The instructions for the registration/randomization application are available on 
the MCCC web page 
 detail the 
process for completing and confirming patient registration. Prior to initiation of 
protocol treatment, this process must be completed in its entirety and an MCCC 
subject ID number must be available as noted in the instructions. It is the 
responsibility of the individual and institution registering the patient to confirm 
the process has been successfully completed prior to release of the study agent. 
Patient registration via the registration/randomization application can be 
confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office 
. If the patient 
was fully registered, the MCCC Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
6.13 
Prior to accepting the pre-registration, the registration/randomization application 
will verify the following: 
• 
IRB approval at the registering institution 
• 
Patient pre-registration eligibility  
• 
Existence of a signed consent form   
• 
Existence of a signed authorization for use and disclosure of protected 
health information. 
6.14 
A mandatory correlative research component is part of this study, the patient will 
be automatically registered onto this component (see Sections 3.29c and 17.1). 
6.2 
Registration Requirements (Step 2):  
6.21 
Phase I: To register a patient, fax 
a completed eligibility 
checklist to the Mayo Clinic Cancer Center (MCCC) Registration Office between 
8 a.m. and 4:30 p.m. central time Monday through Friday.   
 
6.22 
Phase II: To register a patient, access the Mayo Clinic Cancer Center (MCCC) 
web page and enter the registration/randomization application.  The 

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registration/randomization application is available 24 hours a day, 7 days a week.  
Back up and/or system support contact information is available on the Web site.  
If unable to access the Web site, call the MCCC Registration Office at 
between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday through 
Friday). 
The instructions for the registration/randomization application are available on 
the MCCC web page 
 and detail the process 
for completing and confirming patient registration.  Prior to initiation of protocol 
treatment, this process must be completed in its entirety and a MCCC subject ID 
number must be available as noted in the instructions.  It is the responsibility of 
the individual and institution registering the patient to confirm the process has 
been successfully completed prior to release of the study agent.  Patient 
registration via the registration/randomization application can be confirmed in 
any of the following ways: 
• 
Contact the MCCC Registration Office 
.  If the patient 
was fully registered, the MCCC Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
6.23 
Phase I and II 
6.231 Documentation of IRB approval must be on file in the Registration 
Office before an investigator may register any patients. 
In addition to submitting initial IRB approval documents, ongoing IRB 
approval documentation must be on file (no less than annually) at the 
Registration Office 
 If the necessary documentation 
is not submitted in advance of attempting patient registration, the 
registration will not be accepted and the patient may not be enrolled in 
the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, 
submission of annual IRB approvals to the Registration Office is no 
longer necessary. 
6.232 At the time of registration, Registration/Randomization Application will 
verify the following: 
• 
IRB approval 
• 
Patient eligibility  
• 
Existence of a signed consent form 
6.233 At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her 
sample(s) for future research at Mayo. 
• 
Patient has/has not given permission to store and use his/her 
sample(s) for future research to learn, prevent, or treat other health 
problems. 
6.234 Corrlative Research 
A mandatory correlative research component is part of this study, the  
patient will automatically be registered onto this component (see Section 
14). 

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Protocol Version Date: 09Apr2019 
An optional correlative research component is part of this study, there 
will be an option to select if the patient is to be registered onto this 
component (see Section 17.0). 
• 
Patient has/has not given permission to give his/her recurrence tissue 
sample for research testing 
6.235 Consent and treatment on this protocol must commence at Mayo Clinic 
Rochester, Mayo Clinic Florida, or Mayo Clinic Arizona under the 
supervision of a medical oncologist. 
6.236 Treatment cannot begin prior to registration and must begin ≤ 28 days 
after registration.  
6.237 Screening tests/procedures (see Section 4.0) must be completed within 
the guidelines specified on the test schedule. 
6.238 All required baseline symptoms (see Section 10.6) must be documented 
and graded. 
6.239 Study drug is available on site 
 
 

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Protocol Version Date: 09Apr2019 
Investigators are to contact the Study Chair as soon as any dose-limiting toxicity (DLT) 
occurs. 
 
7.6 
Definition of DLT  
Dose-limiting toxicity (DLT) will be defined as an AE occurring in Cycle 1 of the study, 
attributed (definitely, probably, or possibly) to treatment and meeting the following 
criteria: 
• 
Grade 4 ANC ≥7 days or  ≥Grade 3 ANC of any duration with fever > 38.3ºC.  
• 
Grade 4 platelet count or Grade 3 platelet count associated with bleeding.  
• 
AST/ALT/ alkaline phosphatase ≥ Grade 3 if total bilirubin < 1.5 x UNL.  
• 
AST/ALT/alkaline phosphatase ≥ 2.5xUNL together with ≥ Grade 2 total 
bilirubin (> 1.5 x UNL).  
• 
Other ≥ Grade 3 non-hematologic toxicities (except transient asymptomatic 
electrolyte abnormality and nausea, vomiting or diarrhea untreated with anti-
emetic support or anti-diarrheal agents, respectively). 
Grade 3 laboratory abnormalities without clinically significant sequel (e.g., amylase 
elevation, etc) will NOT be considered DLT. 
   
7.7 
Dose Escalation Rule  
Please refer to Section 16 for specifics of dose-finding algorithm.  
 
7.8 
Phase II Treatment Schedule 
Agent 
Dose 
Schedule 
Anetumab ravtansine 
MTD from Phase I 
IV D1 every 3 weeks 
Atezolizumab 
1200 mg 
IV D1 every 3 weeks 
 
8.0 
Dosage Modification Based on Adverse Events  
Strictly follow the modifications in this table until individual treatment tolerance can be 
ascertained.  If multiple adverse events are seen, administer dose based on greatest reduction 
required for any single adverse event observed.  Dose modifications apply to the treatment given 
in the preceding cycle and are based on adverse events observed since the prior dose. 
In the event that individual patients experience Grade 3 or Grade 4 treatment related toxicity or 
intolerable Grade 2 toxicity despite optimal supportive care, treatment might be delayed and/or 
dose reduced as described below.  In the event of multiple toxicities, dose modification should be 
based on the worst toxicity observed.  Subjects are to be instructed to notify Investigators at the 
first occurrence of any adverse symptom.  Decisions on dose reduction and resumption of 
treatment determined according to the judgment of the investigator. 
The start of a new cycle may be delayed by up to 12 weeks due to study treatment-related 
toxicities. In the event that a cycle has to be delayed by more than 2 weeks due to toxicity, the 
patient will be taken off study treatment unless otherwise specified below. Note: Patients can 
coninue with Atezolizumab if removed from anetumab ravtansine and remain on study.   
8.1  
Dose Adjustment and Management Recommendation of anetumab ravtansine 

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For all TEAEs except for the corneal epitheliopathy and BCVA changes, CTCAE v.4.03 
will be used to assess severity. 
 
For TEAEs representing corneal epitheliopathy and BCVA changes, the Bayer Severity 
 
Grading system will be used to assess severity of TEAEs. 
TEAEs requiring anetumab ravtansine treatment modification (temporary treatment 
interruption, dose reduction, or permanent discontinuation of treatment) will be defined 
as any of the events described below that are possibly, probably, or definitely related to 
anetumab ravtansine. 
 
8.11 
Hematological TEAEs requiring treatment modification 
 
• 
ANC <500/mm3 (CTCAE Grade 4) for ≥7 days 
• 
Febrile neutropenia (ANC <1000/mm3 and a single body temperature reading 
of >38.3°C (≥101°F) or a sustained body temperature of ≥38.0°C (≥100.4°F) 
for more than 1 hour 
• 
Platelet count <25,000/mm3 (CTCAE Grade 4) for ≥7 days regardless of the 
presence of active bleeding or platelet count > 50,000/mm3 (CTCAE Grade 
≥3) with clinically significant bleeding (i.e., bleeding requiring platelet 
transfusion) 
 
8.12 
Nonhematological TEAEs requiring treatment modification of any or all agents 
of study treatment 
 
• 
CTCAE Grade 4 non-hematologic toxicity 
• 
CTCAE Grade 3 non-hematologic toxicity that, in the investigator’s 
opinion, warrants treatment modification excluding the following: 
• 
CTCAE Grade 3 nausea, vomiting, or diarrhea if manageable with 
antiemetic or antidiarrheal agents within 7 days would not require 
treatment modification 
• 
CTCAE Grade 3 fatigue lasting ≤72 hours would not require 
treatment modification 
• 
Certain asymptomatic CTCAE Grade 3 laboratory abnormalities 
without a clear clinical correlate, if the investigator determines that 
this TEAE would not require treatment modification. 
• 
Grade 3 corneal epitheliopathy according to the Bayer Severity 
Grading that, in the investigator’s opinion, warrant treatment 
modification. 
• 
Grade 2 corneal epitheliopathy according to the Bayer Severity Grading 
that, in the investigator’s opinion, warrants treatment modification. 
CTCAE Grade ≥ 2 neurotoxicity 
• 
AST and/or ALT increase > 3.0 x ULN (CTCAE Grade ≥ 2) with 
concomitant increase in total bilirubin > 1.5 x ULN (CTCAE Grade ≥ 2). 
For patients with liver metastases, AST/ALT increase > 5.0 x ULN with 
concomitant increase in total bilirubin > 2.0 x ULN 

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8.13 
IV infusion-related reaction and other hypersensitivity events 
 
If a subject experiences CTCAE Grade ≥2 anetumab ravtansine infusion reaction 
or other CTCAE Grade ≥2 hypersensitivity event deemed at least possibly related 
to anetumab ravtansine, the infusion of anetumab ravtansine will be held. In case 
of a CTCAE Grade 2 or 3 event, anetumab ravtansine treatment may be restarted 
at the time determined at the investigator’s discretion. In case of a CTCAE Grade 
4 event, anetumab ravtansine treatment should be permanently discontinued 
  
8.14 
Miscellaneous 
 
Any drug-related CTCAE Grade ≤ 2 TEAE thought to be at least possibly related 
to anetumab ravtansine that, in the investigator’s opinion, is thought to require 
treatment modification. Such TEAEs might be CTCAE Grade ≤ 2 toxicities, 
which interfere with daily life activities, such as long lasting fatigue, anorexia, or 
corneal toxicity. 
 
8.15 
Anetumab ravtansine treatment modification due to corneal epitheliopathy 
 
The Bayer Severity Grading system will be used to assess the severity of TEAEs 
of corneal epitheliopathy and BCVA changes (attached table). The worst Bayer 
severity grade in the worst eye will be considered as the overall grade of corneal 
epitheliopathy for the purpose of treatment modification decisions. 
 
TEAEs of corneal epitheliopathy (confirmed by slit lamp biomicroscopy 
examination that are deemed to be at least possibly related to anetumab 
ravtansine should be managed according to the principles for the modification of 
anetumab ravtansine treatment due to this type of TEAE (i.e., no change, 
temporary treatment interruption, dose reduction, or permanent discontinuation 
of treatment) outlined in the attached table below. Treatment modification 
decisions should be based only on the severity of corneal epitheliopathy and not 
the severity of BCVA changes (attached table). 
 
Bayer classification and management of corneal epitheliopathy 
Toxicity 
(worst 
grade, 
worst eye) 
Corneal 
morphology 
changes 
Anetumab ravtansine 
interruption and dose reduction 
Remedial eye treatment a 
Grade 0 
No pathologic 
changes 
No change/continue treatment 
Treatment with ophthalmic 
lubricants b 
Grade 1 
Treatment-emergent 
superficial punctate 
keratitis (SPK) (new 
or 
worsening by ≥2 
grades) 
no change/continue treatment 
Treatment with ophthalmic 
lubricants should be used. 
Topical steroids may be 
added. b 
 
Grade 2 
Epithelial opacities 
Corneal microcysts 
or 
microdeposits 
Treat on time at the same dose if 
ophthalmological exam can be 
performed as frequently as 
prescribed 
Intensive treatment with 
ophthalmic lubricants (may be 
enhanced with ointments b). 
Topical steroids should be 

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Corneal erosion 
Stromal opacity 
(non-central) 
by the investigator. 
If ophthalmological exam cannot 
be performed as frequently as 
prescribed 
by the investigator, treatment may 
be held until the event has 
resolved to the acceptable 
severity level. b 
The event must resolve to 
acceptable level within 6 weeks 
after the last dose. c, d 
Treatment may be restarted at the 
same dose or at the dose reduced 
by 1 level. b,e 
added. 
Therapeutic contact lenses 
may be used. b 
Grade 3 
Corneal ulcer 
without 
risk of acute rupture 
Stromal opacity 
(central) 
Treatment should be held until 
the event has resolved to the 
acceptable severity level. b 
The event must resolve to 
acceptable level within 6 weeks 
after the last dose. c, d 
Treatment should be restarted at 
the dose reduced by 1 level. e 
If Grade 3 corneal morphology 
change 
occurs again after dose reduction, 
the 
current dose should be reduced by 
1 level or permanently 
discontinued. b 
Intensive treatment with 
ophthalmic lubricants, 
enhanced with ointments. 
Topical steroids should be 
added. 
Therapeutic contact lenses or 
eye occlusion are 
recommended. b 
Grade 4 
Corneal ulcer more 
severe than Grade 3 
Permanently discontinue 
treatment. 
Intensive treatment with 
ophthalmic lubricants, 
enhanced with ointments, 
should be used. 
Topical steroids should be 
added. 
Topical antibiotics may be 
added. b 
Therapeutic contact lenses or 
eye occlusion are 
recommended. b 
Amniotic membrane 
transplant and other locally 
approved treatments may be 
used. b 
a Other remedial therapies for corneal epitheliopathy may be added or substituted at investigator's 
discretion or according to the institutional guidelines. 
b At the investigator’s (and / or the ophthalmologist’s) discretion. 
c Worsening or resolution of corneal epitheliopathy must be confirmed by slit lamp biomicroscopy. 
d Treatment may be restarted at the investigator’s discretion even if the epitheliopathy change has 
resolved 
to the acceptable severity level >6 weeks after the last dose, if the investigator in consultation with the 

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Protocol Version Date: 09Apr2019 
sponsor deems that continued treatment is appropriate based on the investigator’s assessment of the 
benefit-risk ratio. 
e Anetumab ravtansine dose reduction by 1 dose level translates to a change from 6.5 mg/kg Q21D to 
5.5 mg/kg Q21D or from 5.5 mg/kg Q21D to 4.5 mg/kg Q21D. Dose reductions of anetumab ravtansine 
are permitted for as long as the continuation of treatment is appropriate based on the investigator’s 
assessment of the benefit-risk ratio. 
 
Recommendations for changes in tear production and intraocular pressure (IOP) 
 
Reduced tear production is a risk factor for developing ocular surface disease, including corneal 
epitheliopathy. Therefore, tear production will be evaluated by Schirmer’s test in this study to 
determine if changes in this parameter may be helpful to identify subjects at higher risk of 
developing corneal epitheliopathy. 
 
Treatment-emergent abnormal values in the Schirmer test (dry eye) should be evaluated and 
managed by an ophthalmologist to provide adequate protection to the corneal epithelium. 
 
Remedial therapy for treatment-emergent changes in Schirmer test (dry eye) should be chosen at 
the investigator’s discretion or according to institutional standards. These measures may include 
topical lubricants such as eye drops and ointments, punctual occlusion, use of therapeutic contact 
lenses, and / or any other locally approved treatment chosen at the discretion of the investigator 
and the ophthalmologist. Ophthalmological monitoring should be maintained until changes in the 
Schirmer test (dry eye) have resolved. 
 
Increases in the intraocular pressure (IOP) may occur in some subjects with corneal 
epitheliopathy as a consequence of remedial therapy with topical steroid eye drops. Because this 
treatment may be required for adequate remedial treatment of corneal epitheliopathy, IOP will be 
monitored during this study. 
 
Treatment-emergent changes in IOP should be evaluated and managed by an ophthalmologist. 
 
Remedial therapy for IOP changes should be chosen at the investigator’s discretion or according 
to institutional standards. These measures can include modification of the type or posology of 
topical steroid eye drop, initiation of topical IOP lowering drugs, or any other locally approved 
treatment chosen at the discretion of the investigator and the ophthalmologist. Ophthalmological 
monitoring should be maintained until IOP changes have resolved. 
 
8.16 
Continuation of anetumab ravtansine after treatment modification 
 
Anetumab ravtansine treatment may be restarted at the appropriate dose if the TEAE 
requiring treatment modification has resolved to CTCAE Grade 1. Treatment 
modification epitheliopathy) within 42 days after the last dose of anetumab ravtansine 
(i.e., the next scheduled dose would be delayed by ≤21 days). 
 
If treatment modification of anetumab ravtansine is caused by a hematological TEAE, 
and the continuation of treatment is appropriate at investigator’s discretion, the anetumab 
ravtansine dose will be adjusted as described in table below. 
 
8.17 
Anetumab ravtansine dose adjustments in response to neutrophil and platelet nadir counts 
of the previous cycle: 
 

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Protocol Version Date: 09Apr2019 
CTCAE 
System/Organ/Class 
(SOC) 
GRADE 
ADVERSE EVENT 
AGENT 
ACTION** 
INVESTIGATIONS 
Grade 2  
Neutrophil count 
decrease >500 or <500 
for <7 days AND 
Platelet count decreased 
≥25,000  
Anetumab 
ravtansine 
No change 
INVESTIGATIONS 
Grade  
Neutrophil count 
decrease <500 for ≥7 
days  
AND  
Platelet count decreased 
<25,000 for ≥7 days 
with or 
without active bleeding, 
OR 
<50,000 for ≥7 days 
with 
clinically significant 
bleeding b 
Anetumab 
ravtansine 
Decrease 1 dose level 
BLOOD AND 
LYMPHATIC 
SYSTEM 
DISORDERS 
Grade 3 
Febrile neutropenia 
AND  
Platelet count  
<25,000 for ≥7 days 
with or 
without active bleeding, 
OR 
<50,000 for ≥7 days 
with 
clinically significant 
bleeding b 
 
Decrease 1 dose level 
a Anetumab ravtansine dose reduction by 1 dose level translates to a change from 6.5 mg/kg (BW) Q21D 
to 5.5 mg/kg Q21D, or from 5.5 mg/kg Q21D to 4.5 mg/kg Q21D. 
b Clinically significant bleeding is that which requires platelet transfusion. 
c Febrile neutropenia is defined as ANC < 500 with fever of  >38.3°C [101°F] or a sustained body 
temperature of ≥38.0°C [100.4°F] for more than one hour). 
 
If anetumab ravtansine treatment modification is required due to a nonhematological 
TEAE, and the continuation of anetumab ravtansine treatment is appropriate at the 
investigator’s discretion, then the anetumab ravtansine dose will be reduced after CTCAE 
Grade 4 nonhematologic TEAE and Bayer Grade 3 corneal epitheliopathy, or either 
reduced or maintained at the investigator’s discretion after CTCAE Grade 3 non-
hematologic TEAE or Bayer Grade 2 corneal epitheliopathy change (attached table). 
 
The anetumab ravtansine dose reduction due to nonhematological TEAEs will be 
performed by 1 mg/kg Q21D as appropriate, i.e., from 6.5 mg/kg Q21D to 5.5 mg/kg 
Q21D, or from 5.5 mg/kg Q21D to 4.5 mg/kg Q21D. 
 

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If treatment interruption is caused by a CTCAE Grade 2 or 3 anetumab ravtansine 
infusion related reaction or other CTCAE Grade 2 or 3 hypersensitivity events deemed at 
least possibly related to anetumab ravtansine, treatment may be restarted at the time 
determined at the investigator’s discretion. Retreatment should be started at the infusion 
rate reduced by 50%, along with anti-allergic prophylaxis (e.g., antihistamines, 
acetaminophen, and / or corticosteroids) chosen at the investigator’s discretion (but not to 
exceed 42 days since last dose) or according to institutional guidelines. 
 
Treatment with anetumab ravtansine should be withdrawn if a TEAE resolved to CTCAE 
Grade ≤ 1 (or Bayer severity Grade ≤ 2 for corneal epitheliopathy) in >42 days after the 
last dose of anetumab ravtansine. 
 
Dose re-escalation 
 
Dose re-escalation for anetumab ravtansine after dose reduction is not allowed, except 
reescalation after dose reduction for corneal epitheliopathy if the first Grade 3 event 
resolves to Grade ≤ 2 within 21 days and does not recur. 
 
8.2 
Treatment Delay and Dose Reduction of Atezolizumab 
8.21 
General AE Management and Dose Modification Guidelines 
There will be no dose reduction for atezolizumab in this study. Patients may 
temporarily suspend study treatment for up to 84 days (12 weeks) beyond the 
scheduled date of delayed infusion if study drug-related toxicity requiring dose 
suspension is experienced. If atezolizumab is held because of AEs for ≥84 days 
beyond the scheduled date of infusion, the patient will be discontinued from 
atezolizumab and will be followed for safety and efficacy as specified in this 
protocol. 
 
If a patient must be tapered off steroids used to treat AEs, atezolizumab may be 
held for additional time beyond 84 days (12 weeks) from the scheduled dose until 
steroids are discontinued or reduced to a prednisone dose (or dose equivalent) of 
10 mg/day. The acceptable length of interruption will be at the discretion of the 
investigator. 
 
Dose interruptions for reasons other than toxicity, such as surgical procedures, 
may be allowed.  
 
Any toxicity associated or possibly associated with atezolizumab treatment 
should be managed according to standard medical practice. Additional tests, such 
as autoimmune serology or biopsies, may be used to determine a possible 
immunogenic etiology. Although most immune- related adverse events (irAEs) 
observed with immunomodulatory agents have been mild and self-limiting, such 
events should be recognized early and treated promptly to avoid potential major 
complications (20) (Appendix C). Discontinuation of atezolizumab may not have 
an immediate therapeutic effect, and there is no available antidote for 
atezolizumab. In severe cases, immune-related toxicities may be acutely 
managed with topical corticosteroids, systemic corticosteroids, or other 
immunosuppressive agents. The investigator should consider the benefit-risk 
balance prior to further administration of atezolizumab. In patients who have met 

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the criteria for permanent discontinuation, resumption of atezolizumab may be 
considered if the patient is deriving clinical benefit and has fully recovered from 
the immune-related event. 
 
Patients can be re-challenged with atezolizumab ONLY after careful 
consideration of benefit- risk balance and medical judgment by the trial Principal 
Investigator. Atezolizumab may NOT be resumed if the patient experiences any 
of the following events, regardless of benefit: 
• 
Grade 3 or 4 pneumonitis 
• 
AST or ALT >5×ULN or total bilirubin >3×ULN 
• 
Grade 4 diarrhea or colitis 
• 
Grade 4 hypophysitis 
• 
Any grade myasthenic syndrome/myasthenia gravis, Guillain-Barré, or 
meningoencephalitis 
• 
Grade 3 or 4 ocular inflammatory toxicity 
• 
Grade 4 or any grade of recurrent pancreatitis 
• 
Grade 3 or 4 infusion-related reactions 
• 
Grade 4 rash 
Treatment may, under limited and compelling circumstances, be resumed in 
patients who have recovered from the following events after consultation with 
the trial Principal Investigator: 
• 
Grade 2 pneumonitis 
• 
Grade 2 ocular inflammatory toxicity 
• 
Grade 2 infusion-related reactions 
 
For detailed information regarding management of adverse events associated 
with atezolizumab, please refer to the most current version of the Atezolizumab 
Package Insert and the FDA product label. 
 
The primary approach to grade 1 to 2 irAEs is supportive and symptomatic care 
with continued treatment with atezolizumab; for higher-grade irAEs, 
atezolizumab should be withheld and oral and/or parenteral steroids 
administered. Recurrent grade 2 irAEs may also mandate withholding 
atezolizumab or the use of steroids. Assessment of the benefit-risk balance 
should be made by the investigator, with consideration of the totality of 
information as it pertains to the nature of the toxicity and the degree of clinical 
benefit a given patient may be experiencing prior to further administration of 
atezolizumab. Atezolizumab should be permanently discontinued in patients with 
life-threatening irAEs. 
 
Patients should be assessed clinically (including review of laboratory values) for 
toxicity prior to, during, and after each infusion. If unmanageable toxicity due to 
atezolizumab occurs at any time during the study, treatment with atezolizumab 
should be discontinued. 
8.22 
Management of Specific AEs 
Management of certain AEs of concern are presented in the table below as they 
have been observed with this agent and are potentially immune related.  
8.221 Pleural and pericardial effusion: Patients experiencing dyspnea, chest 
pain, or unexplained tachycardia should be evaluated for the presence of 

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a pericardial effusion. Patients with pre- existing pericardial effusion 
should be followed closely for pericardial fluid volume measurements 
and impact on cardiac function. When intervention is required for 
pericardial or pleural effusions, atezolizumab should be held, and 
appropriate workup includes cytology, lactate dehydrogenase (LDH), 
glucose, cholesterol, protein concentrations (with pleural effusions), and 
cell count. 
 
8.222 Pulmonary events: Dyspnea, cough, fatigue, hypoxia, pneumonitis, and 
pulmonary infiltrates have been associated with the administration of 
atezolizumab. Patients will be assessed for pulmonary signs and 
symptoms throughout the study and will also have CT scans of the chest 
performed at every tumor assessment. 
 
All pulmonary events should be thoroughly evaluated for other 
commonly reported etiologies such as pneumonia or other infection, 
lymphangitic carcinomatosis, pulmonary embolism, heart failure, chronic 
obstructive pulmonary disease, or pulmonary hypertension. Management 
guidelines for pulmonary events are provided in the table below. 
 
8.223 Endocrine disorders: Patients experiencing one or more unexplained AEs 
possibly indicative of endocrine dysfunction (including fatigue, 
myalgias, impotence, mental status changes, and constipation) should be 
investigated for the presence of thyroid, pituitary, or adrenal 
endocrinopathies. The patient should be referred to an endocrinologist if 
an endocrinopathy is suspected. Thyroid-stimulating hormone (TSH) and 
free T3 and T4 levels should be obtained to determine whether thyroid 
abnormalities are present. TSH, prolactin, and a morning cortisol level 
will help to differentiate primary adrenal insufficiency from primary 
pituitary insufficiency. The table below describes dose management 
guidelines for hyperthyroidism, hypothyroidism, symptomatic adrenal 
insufficiency, and hyperglycemia. 
 
8.224 Meningoencephalitis: Immune-related meningoencephalitis is an 
identified risk associated with the administration of atezolizumab. 
Immune-related meningoencephalitis should be suspected in any patient 
presenting with signs or symptoms suggestive of meningitis or 
encephalitis, including, but not limited to, headache, neck pain, 
confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness. Encephalopathy from metabolic or 
electrolyte imbalances needs to be distinguished from potential 
meningoencephalitis resulting from infection (bacterial, viral, or fungal) 
or progression of malignancy, or secondary to a paraneoplastic process. 
 
All patients being considered for meningoencephalitis should be urgently 
evaluated with a CT scan and/or MRI scan of the brain to evaluate for 
metastasis, inflammation, or edema. If deemed safe by the treating 
physician, a lumbar puncture should be performed and a neurologist 
should be consulted. 
 

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Patients should receive full supportive care while on this study, per physician discretion. 
This includes blood product support, antibiotic treatment and treatment of other newly 
diagnosed or concurrent medical conditions. All blood products and concomitant 
medications such as antidiarrheals, analgesics, anti-emetics received from the first 
administration of study drugs until 30 days after the final dose are to be recorded in the 
medical record. 
9.2 
Anti-emetics 
Participants may be pretreated for nausea and vomiting with appropriate anti-emetics. 
9.3 
Diarrhea 
Diarrhea could be managed conservatively with loperamide. The recommended dose of 
loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free 
(maximum 16 mg/day). 
In the event of Grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreotide, and antidiarrheals.  
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (Grade 3 or 4), broad-spectrum antibiotics must be prescribed. 
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
9.4 
Prohibited prior treatments and concomitant medications/conditions 
9.41 
Patients who have received systemic antitumor therapy (except topical or 
intracavitary treatments with negligible absorption in systemic circulation) within 
28 days before the start of anetumab ravtansine, or within 5 half-lives of the 
chemotherapeutic agent before the start of anetumab ravtansine, whichever is 
longer. Mitomycin C or nitrosoureas must be excluded within 42 days before the 
start of anetumab ravtansine. 
• 
Systemic antitumor therapy is defined as any agent or combination of 
agents with clinically proven antineoplastic activity that achieves non-
negligible systemic bioavailability after being administered by any route 
for affecting the malignancy, either directly or indirectly, including 
palliative and therapeutic endpoints. This includes, but is not limited to, 
cytotoxic therapy, targeted agents, anti-cancer immunotherapy, hormonal 
therapy, experimental therapy or device. 
9.42 
Patients who have received granulocyte colony-stimulating factors (G-CSFs) or 
granulocyte macrophage-stimulating factors (GM-CSFs) within 21 days before 
the start of screening. 
9.43 
Patients who have received erythropoietin-stimulating agents (epoetin alpha, 
darbepoetin alpha) within 21 days before the start of screening. Patients on 
chronic therapy with erythropoietin-stimulating agents may be eligible at the 
investigator’s discretion, provided no dose adjustment is undertaken from 21 
days before the start of screening until the end of therapy. 
9.44 
Blood transfusions within 21 days before C1D1 
9.45 
Platelet transfusions within 21 days before C1D1 

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9.46 
Anti-arrhythmic therapy other than beta blockers or digoxin during study 
treatment until safety follow-up visit. 
9.47 
Acute steroid therapy or taper. Exceptions include chemotherapy pre- and post-
medication and allergic reaction (e.g. infusion related reaction, contrast media 
reaction, etc.) management. Chronic steroid therapy is allowed provided that the 
dose is stable for 30 days before the start of study treatment and thereafter for the 
duration of study treatment. 
9.48 
Concomitant live attenuated virus vaccines (e.g. yellow fever) within 14 days 
before C1D1 until safety follow-up visit. 
9.49a 
Use of therapeutic oral or parenteral anticoagulation therapy started within 14 
days before the start of anetumab ravtansine until the end of therapy. Aspirin at a 
dose ≤100 mg per day is permitted. 
9.49b No prior treatment with anetumab ravtansine (or any other mesothelin-based 
therapy) or any vinca-containing compound or spindle poison. 
9.49c 
No prior use of experimental therapy (defined as not approved for this indication) 
or device for systemic anti-cancer treatment.   
9.49d Patients who have a recent history (within 28 days before the start of anetumab 
ravtansine) of abusing alcohol, prescription or illicit drugs, or of medical, 
psychological, or social conditions that may interfere with the patient’s 
compliance in this study. 
 

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Events that would not typically be considered to meet the criteria for expedited reporting, but 
that for a specific protocol are being reported via expedited means in order to facilitate the 
review of safety data (may be requested by the FDA or the sponsor).  
Unanticipated Adverse Device Event (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
by, or associated with, a device, if that effect, problem, or death was not previously identified 
in nature, severity, or degree of incidence in the investigational plan or application (including 
a supplementary plan or application), or any other unanticipated serious problem associated 
with a device that relates to the rights, safety, or welfare of subjects. 
 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
 
a. Identify the grade and severity of the event using the CTCAE version 4.0. 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
c. Determine if the adverse event is related to the study intervention (agent, 
treatment or procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
e. Determine if other reporting is required (see Section 10.5). 
f. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in 
Section 10.4. 
10.2 
Expected vs. Unexpected Events  
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 

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An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 
NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure.  Refer to protocol or IB for reporting needs. 
 
10.3 
Attribution to Agent(s) or Procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME (Combination) Arm 
NOTE: When a commercial agent(s) is (are) used on the same treatment arm as 
the investigational agent/intervention (also, investigational drug, biologic, 
cellular product, or other investigational therapy under an IND), the entire 
combination (arm) is then considered an investigational intervention for 
reporting. 
• An AE that occurs on a combination study must be assessed in accordance 
with the guidelines for investigational agents/interventions.  
• An AE that occurs prior to administration of the investigational 
agent/intervention must be assessed as specified in the protocol. In general, 
only Grade 4 and 5 AEs that are unexpected with at least possible attribution 
to the commercial agent require an expedited report, unless hospitalization is 
required. Refer to Section 10.4 for specific AE reporting requirements or 
exceptions. 
An investigational agent/intervention might exacerbate the expected AEs associated 
with a commercial agent.  Therefore, if an expected AE (for the commercial agent) 
occurs with a higher degree of severity or specificity, expedited reporting is 
required. 
• An increased incidence of an expected adverse event (AE) is based on 
the patients treated for this study at their site. A list of known/expected 
AEs is reported in the package insert or the literature, including AEs 
resulting from a drug overdose. 
• Commercial agent expedited reports must be submitted to the FDA via 
MedWatch 3500A for Health Professionals (complete all three pages of 
the form). 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/U
CM048334.pdf 
or 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/ListFormsAlp
habetically/default.htm 
Instructions for completing the MedWatch 3500A: 

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http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/Download
Forms/UCM387002.pdf 
10.32 EXPECTED Serious Adverse Events: Protocol Specific Exceptions to Expedited 
Reporting 
For this protocol only, the following Adverse Events/Grades are expected to occur 
within this population and do not require Expedited Reporting.  These events must 
still be reported via Routine Reporting (see Section 10.6).* 
*Report any clinically important increase in the rate of a serious suspected 
adverse reaction (at your study site) over that which is listed in the protocol or 
investigator brochure as an expedited event.  
*Report an expected event that is greater in severity or specificity than expected 
as an expedited event. 
System Organ Class (SOC) 
Adverse Event/ 
Symptoms 
CTCAE Grade at which the event 
will not be expeditedly reported1. 
General disorders and 
administration site 
conditions 
Fatigue 
Grade 2 
Chills 
Fever 
Flu-like symptoms 
Blood and lymphatic 
systems disorder 
Anemia  
Grade 2 
Metabolism and nutrition 
disorders 
Anorexia 
Grade 2 
Hyperglycemia 
Grade 1 
Investigations 
Alanine aminotransferase 
increased 
Grade 1 
Aspartate aminotransferase 
increased 
 
Lymphocyte count decreased 
Platelet count decreased 
White blood cell count 
decreased 
 
Gastrointestinal disorders 
Nausea 
Grade 2 
Vomiting 
Diarrhea 
Dyspepsia 
Skin and subcutaneous tissue 
disorders 
Rash maculo-papular 
Grade 2 
Pruritus 
Grade 2 
Musculoskeletal and 
Arthralgia 
Grade 2 

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System Organ Class (SOC) 
Adverse Event/ 
Symptoms 
CTCAE Grade at which the event 
will not be expeditedly reported1. 
connective tissue disorders 
Myalgia 
1 These exceptions only apply if the adverse event does not result in hospitalization. If the adverse 
event results in hospitalization, then the standard expedited adverse events reporting 
requirements must be followed.  
Specific protocol exceptions to expedited reporting should be reported 
expeditiously by investigators ONLY if they exceed the expected grade of the 
event. 
The following hospitalizations are not considered to be SAEs because there is no 
“adverse event” (i.e., there is no untoward medical occurrence) associated with 
the hospitalization: 
• 
Hospitalizations for respite care 
• 
Planned hospitalizations required by the protocol 
• 
Hospitalization planned before informed consent (where the condition 
requiring the hospitalization has not changed post study drug 
administration) 
• 
Hospitalization for elective procedures unrelated to the current disease 
and/or treatment on this trial 
• 
Hospitalization for administration of study drug or insertion of access for 
administration of study drug 
• 
Hospitalization for routine maintenance of a device (e.g., battery 
replacement) that was in place before study entry 
• 
Hospitalization or other serious outcomes for signs and symptoms of 
progression of the cancer. 
 
 

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(pregnancy loss)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
10.553 Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration - Other (neonatal loss)” under the 
General disorders and administration SOC.  
10.554 Corneal epitheliopathy is considered as AE of special interest. 
Specific dose modification schemes are defined in the Protocol. 
An alternative severity grading system for corneal epitheliopathy 
will be used in addition to the CTCAE criteria, since the CTCAE 
may not adequately capture the severity of these novel adverse 
reactions (see Table 7–9 and Table 7– 10). The relationship to 
treatment and the intensity of corneal epitheliopathy will be 
determined by the investigator, in consultation with the 
ophthalmologist, using the terms and definitions given in Section 
9.6.1.2.  There is no need for expedited reporting to report corneal 
epitheliopathy, unless it meets the criteria for an SAE; however 
these events will need to be closely monitored. 
10.6 
Required Routine Reporting  
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and adverse events to 
be graded at each evaluation. Grading is per CTCAE v4.0 unless alternate 
grading is indicated in the table below: 
CTCAE 
System Organ Class (SOC) 
Adverse Event/ 
Symptoms 
Baseline 
Each 
Evaluation 
General disorders and site 
administration conditions 
Fatigue 
x 
x 
Fever 
x 
x 
Flu-like symptoms 
x 
x 
Skin and subcutaneous tissue 
disorders 
Rash maculo-papular  
x 
x 
Pruritus 
x 
x 
Gastrointestinal disorders 
#stools each day 
x 
 
diarrhea 
 
x 
nausea 
x 
x 
vomiting 
x 
x 

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11.0 
Treatment Evaluation Using RECIST Guideline  
NOTE:  This study uses protocol RECIST v1.1 template dated 2/16/2011.  See the footnote for 
the table regarding measureable disease in Section 11.44, as it pertains to data collection and 
analysis. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines 
(version 1.1)22.  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the short axis measurements in the case of lymph nodes are used in the RECIST 
guideline. 
11.1 
Schedule of Evaluations:   
For the purposes of this study, patients should be reevaluated every 6 weeks.  In addition 
to a baseline scan, confirmatory scans should also be obtained at least 4 weeks following 
initial documentation of objective response. 
11.2 
Definitions of Measurable and Non-Measurable Disease 
11.21   Measurable Disease 
11.211 A non-nodal lesion is considered measurable if its longest diameter can be 
accurately measured as ≥2.0 cm with chest x-ray, or as ≥1.0 cm with CT 
scan or MRI.  
11.212 A superficial non-nodal lesion is measurable if its longest diameter is ≥ 
1.0 cm in diameter as assessed using calipers (e.g. skin nodules) or 
imaging.  In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
11.213 A malignant lymph node is considered measurable if its short axis is >1.5 
cm when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm).   
 
NOTE: Tumor lesions in a previously irradiated area are not considered 
measurable disease.   
 
11.22 Non-Measurable Disease 
 
11.221 All other lesions (or sites of disease) are considered non-measurable 
disease, including pathological nodes (those with a short axis ≥1.0 to <1.5 
cm).  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-
measurable as well. 
 
NOTE:  ‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.  In addition, lymph nodes that have a short axis <1.0 
cm are considered non-pathological (i.e., normal) and should not be recorded or 
followed. 
 

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11.3 
Guidelines for Evaluation of Measurable Disease 
 
11.31 Measurement Methods:   
 
• 
All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. 
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during follow-
up. For patients having only lesions measuring at least 1 cm to less than 2 cm 
must use CT imaging for both pre- and post-treatment tumor assessments.   
• 
Imaging-based evaluation is preferred to evaluation by clinical examination 
when both methods have been used at the same evaluation to assess the 
antitumor effect of a treatment.  
 
11.32 Acceptable Modalities for Measurable Disease:       
 
• Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm 
or less. If CT scans have slice thickness greater than 5 mm, the minimum size 
for a measurable lesion should be twice the slice thickness.     
• 
As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type 
and site of disease.  The lesions should be measured on the same pulse 
sequence.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  
Body scans should be performed with breath-hold scanning techniques, if 
possible. 
• 
Chest X-ray:  Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  However, CT 
scans are preferable. 
• 
Physical Examination:  For superficial non-nodal lesions, physical 
examination is acceptable, but imaging is preferable, if both can be done. In 
the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
 
11.33 Measurement at Follow-up Evaluation:   
 
• A subsequent scan must be obtained at least 4 weeks following initial 
documentation of an objective status of either complete response (CR) or 
partial response (PR).  
 
• In the case of stable disease (SD), follow-up measurements must have met the 
SD criteria at least once after study entry at a minimum interval of 6 weeks 
(see Section 11.44). 
 
• The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate between 

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response or stable disease (an effusion may be a side effect of the treatment) 
and progressive disease. 
 
• 
Cytologic and histologic techniques can be used to differentiate between PR 
and CR in rare cases (e.g., residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain.) 
 
11.4 
Measurement of Effect 
 
11.41 Target Lesions & Target Lymph Nodes 
 
• 
Measurable lesions (as defined in Section 11.21) up to a maximum of 5 
lesions, representative of all involved organs, should be identified as “Target 
Lesions” and recorded and measured at baseline.  These lesions can be non-
nodal or nodal (as defined in 11.21), where no more than 2 lesions are from 
the same organ and no more than 2 malignant nodal lesions are selected.  
 
Note: If fewer than 5 target lesions and target lymph nodes are identified (as 
there often will be), there is no reason to perform additional studies beyond 
those specified in the protocol to discover new lesions.   
 
• 
Target lesions and target lymph nodes should be selected on the basis of their 
size, be representative of all involved sites of disease, but in addition should 
be those that lend themselves to reproducible repeated measurements.  It may 
be the case that, on occasion, the largest lesion (or malignant lymph node) 
does not lend itself to reproducible measurements in which circumstance the 
next largest lesion (or malignant lymph node) which can be measured 
reproducibly should be selected.   
 
• 
Baseline Sum of Dimensions (BSD):  A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will 
be calculated and reported as the baseline sum of dimensions (BSD).  The 
BSD will be used as reference to further characterize any objective tumor 
response in the measurable dimension of the disease.   
 
• 
Post-Baseline Sum of the Dimensions (PBSD):  A sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the target lymph 
nodes will be calculated and reported as the post-baseline sum of dimensions 
(PBSD).  If the radiologist is able to provide an actual measure for the target 
lesion (or target lymph node), that should be recorded, even if it is below 0.5 
cm.  If the target lesion (or target lymph node) is believed to be present and is 
faintly seen but too small to measure, a default value of 0.5 cm should be 
assigned.  If it is the opinion of the radiologist that the target lesion or target 
lymph node has likely disappeared, the measurement should be recorded as 0 
cm. 
 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and 
the PBSD. 
 

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11.42  Non-Target Lesions & Non-Target Lymph Nodes 
 
Non-measurable sites of disease (Section 11.22) are classified as non- target 
lesions or non-target lymph nodes and should also be recorded at   
baseline.  These lesions and lymph nodes should be followed in accord with 
11.433. 
 
 
11.43 Response Criteria 
 
11.431 All target lesions and target lymph nodes followed by 
 
CT/MRI/Chest X-ray/physical examination must be measured on re-
evaluation at evaluation times specified in Section 11.1.  Specifically, a 
change in objective status to either a PR or CR cannot be done without 
re-measuring target lesions and target lymph nodes.  
 
Note: Non-target lesions and non-target lymph nodes should be 
evaluated at each assessment, especially in the case of first response or 
confirmation of response.  In selected circumstances, certain non-target 
organs may be evaluated less frequently.  For example, bone scans may 
need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
 
11.432 Evaluation of Target Lesions 
 
Complete Response (CR): 
All of the following must be true: 
 
a. Disappearance of all target lesions. 
 
b. Each target lymph node must have 
reduction in short axis to <1.0 cm. 
 
 
Partial Response (PR): 
At least a 30% decrease in PBSD (sum of 
the longest diameter for all target lesions 
plus the sum of the short axis of all the 
target lymph nodes at current evaluation) 
taking as reference the BSD (see Section 
11.41). 
 
Progression (PD): 
At least one of the following must be true: 
 
a. At least one new malignant lesion, 
which also includes any lymph node 
that was normal at baseline (< 1.0 cm 
short axis) and increased to ≥ 1.0 cm 
short axis during follow-up.  
 
b. At least a 20% increase in PBSD (sum 
of the longest diameter for all target 
lesions plus the sum of the short axis 

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of all the target lymph nodes at current 
evaluation) taking as reference the 
MSD (Section 11.41).  In addition, the 
PBSD must also demonstrate an 
absolute increase of at least 0.5 cm 
from the MSD.  
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for 
PR, nor sufficient increase to qualify for 
PD taking as reference the MSD. 
 
11.433 Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
 
Complete Response (CR): 
All of the following must be true: 
 
a. Disappearance of all non-target 
lesions.  
 
b. Each non-target lymph node must 
have a reduction in short axis to <1.0 
cm. 
 
 
Non-CR/Non-PD: 
Persistence of one or more non-target 
lesions or non-target lymph nodes. 
 
Progression (PD): 
At least one of the following must be true: 
 
a. At least one new malignant  lesion, 
which also includes any lymph node 
that was normal at baseline (< 1.0 cm 
short axis) and increased to ≥ 1.0 cm 
short axis during follow-up.   
 
b. Unequivocal progression of existing 
non-target lesions and non-target 
lymph nodes.  (NOTE:  Unequivocal 
progression should not normally 
trump target lesion and target lymph 
node status.  It must be representative 
of overall disease status change.)  
 
11.44 Overall Objective Status 
 
 
The overall objective status for an evaluation is determined by combining the 
patient’s status on target lesions, target lymph nodes, non-target lesions, non-target 
lymph nodes, and new disease as defined in the following table:  
 
 
 

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12.0 
Descriptive Factors 
12.1 
Number of prior regimens ≤2 versus > 2 
12.2 
Dose Level  
To be assigned by Registration Office: -1 vs. 1 vs. 2    
 

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13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
13.1 
Continuation of treatment 
Patients who are CR, PR, or SD will continue treatment per protocol. 
13.2 
Progressive disease (PD) 
Patients who develop PD while receiving therapy will go to the event-monitoring phase. 
13.3 
Off protocol treatment 
Patients who go off protocol treatment for reasons other than PD will go to the event-
monitoring phase per Section 4.0. 
13.4 
CNS PD 
Patients who develop PD in the CNS only should receive local therapy and continue 
treatment on study after completion of local therapy for up to a total of 6 cycles. 
13.5 
Non-CNS PD 
Patients who develop non-CNS PD at any time should go to event monitoring. These 
patients should be treated with alternative chemotherapy if their clinical status is good 
enough to allow further therapy.  
13.6 
Inevaluable patients 
If a patient fails to complete the first cycle (21 days) of treatment for reasons other than 
toxicity, the patient will be regarded as inevaluable and will be replaced during the phase 
I portion of the trial.  
13.7 
Ineligible 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Event monitoring will be required per Section 4.0 of 
the protocol.  
• 
If the patient never received treatment, on-study material must be submitted. Event 
monitoring will be required per Section 4.0 of the protocol.  
13.8 
Major violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. All data up until the point of confirmation of a major violation must be 
submitted. The patient will go directly to the event-monitoring phase of the study. The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered. Event monitoring 
will be required per Section 4.0 of the protocol. 
13.9 
Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 

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15.191 Infusion is over 60 minutes and requires an in line 0.2 micron infusion 
filter. 
15.192 Given the early nature of this agent, not all side effects can be known at 
this time. Monitor patients closely and report any side effects to the study 
team. 
15.193 Monitor LFT’s , instruct patients to report abdominal pain and/or 
jaundice to study team. 
15.194 Gastrointestinal side effects  are common. Treat symptomatically and 
monitor for effectiveness. 
15.195 Infusion related reaction can occur.  Be sure to have emergency 
equipment available during infusion  and monitor patient per protocol 
during infusion. 
15.196 Eye related toxicity can occur and includes corneal epithelial microcysts, 
keratitis, and blurred vision. Instruct patients to report any visual 
changes, pain, tearing, etc to the study team immediately.  
15.197 Fatigue is very common. Instruct patient in energy conserving lifestyle 
and monitor level of fatigue throughout treatment. 
15.198 Peripheral neuropathy can be seen. Instruct patients to report any pain, 
numbness or tingling of the hand or feet to the study team immediately. 
15.2 
Atezolizumab for IV Administration  
15.21 Background:  Atezolizumab is a human immunoglobulin (IgG1) monoclonal 
antibody that is produced in Chinese hamster ovary (CHO) cells.  Atezolizumab 
targets programmed death-ligand 1 (PD-L1) on immune cells or tumor cells and 
prevents interaction with either programmed death−1 (PD-1) receptor or B7.1 
(CD80), both of which function as inhibitory receptors expressed on T cells.  
Interference of the PD-L1:PD-1 and PD-L1:B7.1 interactions may enhance the 
magnitude and quality of the tumor-specific T-cell response through increased T-
cell priming, expansion, and/or effector function. Atezolizumab shows anti-
tumor activity in various nonclinical models and is being investigated as a 
potential therapy for cancer patients with locally advanced or metastatic 
malignancies.  
 
15.22 Formulation:  Atezolizumab is supplied in a single use vial as a colorless-to-
slightly-yellow, sterile, preservative-free clear liquid solution intended for IV 
administration. The vial is designed to deliver 20 mL (1200 mg) of atezolizumab 
solution but may contain more than the stated volume to enable delivery of the 
entire 20 mL volume. The atezolizumab drug product is formulated as 60 mg/mL 
atezolizumab in 20 mM histidine acetate, 120 mM sucrose, 0.04% polysorbate 
20, pH 5.8.  
 
15.23 Preparation and storage: Atezolizumab must be refrigerated at 2°C−8°C 
(36°F−46°F) upon receipt until use.  No preservative is used in atezolizumab 
drug product; therefore, the vial is intended for single use only. Discard any 
unused portion of drug left in a vial. Vial contents should not be frozen or shaken 
and should be protected from direct sunlight.  Atezolizumab is administered 
using 0.9% sodium chloride 250 mL IV bags and infusion lines equipped with 

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0.2 micron in-line filters (filter membrane of polyethersulfone [PES]). Bags may 
be constructed of polyvinyl chloride (PVC) or polyolefin (PO).     
 
15.24 Administration:  The initial dose of atezolizumab will be delivered over 60 (± 
15) minutes. If the first infusion is tolerated without infusion-associated adverse 
effects, the second infusion may be delivered over 30 (± 10) minutes. If the 30-
minute infusion is well tolerated, all subsequent infusions may be delivered over 
30 (± 10) minutes.  
 
 
15.25 Pharmacokinetic information: 
 
Distibution:  Vdss:  6.9 L 
 
Half-life elimination:  27 days 
 
Hepatic Impairment:  No clinically relevant effect with mild hepatic 
impairment.  The effect of moderate or severe hepatic impairment on the 
pharmacokinetics of atezolizumab is unknown. 
Renal Impairment:  No clinically relevant effect with renal impairment. 
 
15.26 Potential Drug Interactions:  No formal PK drug-drug interaction studies have 
been conducted with atezolizumab.  The drug interaction potential of 
atezolizumab is unknown.   
 
15.27 Known potential toxicities:   Consult the package insert and 
investigator’s brochure for the most current and complete information. 
Common known potential toxicities, > 10%: 
Cardiovascular:  Peripheral edema 
Central nervous system:  Fatigue 
Dermatologic:  Skin rash, pruritus 
Endocrine & metabolic:  Hyponatremia 
Gastrointestinal:  Decreased appetite, nausea, constipation, colitis, 
diarrhea, abdominal pain, vomiting 
Genitourinary:  Urinary tract infection, hematuria 
Hematologic & oncologic:  Lymphocytopenia 
Infection:  Infection 
Neuromuscular & skeletal:  Back pain, neck pain, arthralgia 
Respiratory:  Dyspnea, cough 
Miscellaneous:  Fever 
Less common known potential toxicities, 1% - 10%: 
Cardiovascular:  Venous thromboembolism 
Central nervous system:  Guillain-Barre syndrome, meningoencephalitis, 
myasthenia, myasthenia gravis, confusion 
Endocrine & metabolic:  Hyperglycemia, hypothyroidism, 
hypoalbuminemia, hyperthyroidism 
Gastrointestinal:  Increased serum amylase, increased serum lipase, 
pancreatitis, intestinal obstruction 
Genitourinary:  Urinary tract obstruction 
Hematologic & oncologic:  Anemia 
Hepatic:  Increased serum ALT/AST, hepatitis, increased serum alkaline 
phosphatase, serum bilirubin 
Infection:  Sepsis 
Ophthalmic:  Intraocular inflammation 
Renal:  Increased serum creatinine, acute renal failure 

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Respiratory:  Pneumonitis, pneumonia 
Miscellaneous:  Infusion related reaction 
Rare known potential toxicities, <1% (Limited to important or life-
threatening): 
Adrenocortical insufficiency, diabetes mellitus (with ketoacidosis), 
hypophysitis 
 
15.28 Drug procurement:  Atezolizumab will be from commercial sources. 
 
 
15.29 Nursing Guidelines:  
15.291  Anti PD-L1 side effects vary greatly from those of traditional 
chemotherapy and can vary in severity from mild to life threatening. 
Instruct patients to report any side effects to the study team immediately. 
Side effects may be immediate or delayed up to months after 
discontinuation of therapy. Most side effects are reversible with prompt 
intervention of corticosteroids 
15.292 Diarrhea can be common and can be very severe, leading to colonic 
perforation. Instruct patients to report ANY increase in the number of 
stools and/or change in baseline, blood in the stool, abdominal pain to the 
study team immediately.  
15.293 Rash/pruirits/dermatitis is seen. Patients should report any rash to the 
study team. Treat per section 8.0 and monitor for effectiveness.  
15.294 Monitor LFT’s closely as elevations in these levels could indicate early 
onset autoimmune hepatitis. Patients should also be instructed to report 
any jaundice, or right upper quadrant pain to the study team immediately. 
15.295 Pneumonitis can be seen and may be mild (only seen on imaging) to 
severe. Patients should be instructed to report any SOB, dyspnea, cough, 
chest pain, etc. to the study team immediately. Patients reporting these 
symptoms should have a pulse ox checked and consider immediate 
imaging per the treating MD. 
15.296 Endocrinopathies (including hypopituitarism, hypothyroidism, 
hypophysistis, and adrenal insufficiency) are a concern given the 
mechanism of action of this agent.  Patients may present only with the 
vague sense of  fatigue and “not feeling well” . Additional symptoms 
may be that of nausea, sweating and decreased activity tolerance. Instruct 
patients to report these signs or symptoms immediately and obtain 
appropriate labs as ordered by MD.  
15.297  Pancreatitis is possible with anti PD-L1 therapy based on mechanism of 
action. Instruct patients to report abdominal pain, nausea and vomiting to 
the study team. 
15.298 Patients who are started on steroid therapy for any side effects of anti 
PD-L1  toxicity should be instructed to take the steroids as ordered, and 
not to discontinue abruptly as symptoms may return and be severe. 
Patients may be on steroid therapy for weeks. Instruct patients to report 

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any increase or change in side effects with any dosage decrease as 
patients may need a slower taper.  
 

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16.0 
Statistical Considerations and Methodology  
16.1 
Overview 
This is a non-randomized Phase I/II study designed to identify the recommended dose of 
anetumab ravtansine combined with atezolizumab and confirmed response rate in second 
line therapy of advanced NSCLC.   
16.11 Primary Endpoint 
The primary endpoint of the phase I portion of this trial is to assess the maximum 
tolerated dose (MTD) of anetumab ravtansine combined with atezolizumab.  
The primary endpoint of the phase 2 portion is the rate of confirmed response. A 
confirmed response is defined as a patient who has achieved a PR or CR on two 
consecutive evaluations at least 4 weeks apart. All patients meeting the eligibility 
criteria, who have signed a consent form and have begun treatment will be 
evaluable for response, unless they are determined to be a major violation.  The 
first 6 months of treatment (i.e. 8 cycles) will be used to evaluate the primary 
endpoint of confirmed response.   
16.12 Sample Size 
In the phase I portion, the study may involve as few as 6 patients (2 DLTs in 
Dose Level 1 and Dose Level -1) or as many as 12 patients (6 for each Dose 
Level).  In addition, up to 37 patients will be treated at the recommended Phase II 
dose during the study (6 from phase I, 31 from phase II).  Therefore, the 
maximum number of evaluable patients is 43 because the recommended Phase II 
dose will include 6 patients from the phase I portion.  An additional 6 patients 
may be accrued to account for patients that need to be replaced bringing the 
maximum overall accrual to 49.   
16.13 Accrual Rate and Study Duration 
Given previous data from Mayo, it is estimated that this study will accrue 2-3 
patients per month.  Each cohort of 3 will require approximately 2.5 months (1.5 
months for accrual and treatment, and an additional month data maturity and 
evaluation) to assess.  Therefore, the overall study duration (including enrolling, 
treatment and evaluation) will range approximately from minimum of 5 months 
(when only 2 cohorts are required) to a maximum of 10 months (when 4 cohorts 
of 3 are required) for the dose escalation (Phase I) portion of the trial.  The 
additional patients at the MTD will require approximately 16 months to accrue 
and an additional 4 months to assess.  This means the study will take somewhere 
between 25 months and 30 months. 
16.2 
Phase I Study Design 
The primary endpoint of the phase I portion of this trial is to estimate the MTD of 
anetumab ravtansine combined with atezolizumab.  A standard 3+3 phase I design will be 
utilized. Three patients will be treated at each dose level and observed for a minimum of 
three weeks (i.e. one full cycle) before new patients are treated. Doses will not be 
escalated in any individual patient.  
16.21  MTD Definition 
MTD is defined as the dose level below the lowest dose that induces dose-
limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum 
of 6 new patients). A total of 6 patients treated at the MTD will be sufficient to 

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identify common toxicities at the MTD. For instance, those toxicities with an 
incidence of at least 25% will be observed with a probability of at least 82% (1-
(1-0.25)6).  Refer to Section 7.6 for definition of dose-limiting toxicity (DLT). 
16.22 MTD Determination: 
Dose Escalation: The phase I portion of this study will utilize a standard cohort 
of three design.  The first cohort of three patients will be treated at dose level 1. 
Decisions on when and how to dose escalate are described below. 
16.23 The first cohort of three patients will be treated at the starting dose level 1. 
16.24 Three patients will be treated at a given dose level combination and observed for 
at least 21 days from start of treatment to assess toxicity. 
16.25 If DLT is not seen in any of the 3 patients, 3 new patients will be accrued and 
treated at the next higher dose level.  If DLT is seen in 2 or 3 of 3 patients treated 
at a given dose level, then the next 3 patients will be treated at the next lower 
dose level, if only 3 patients were enrolled and treated at this lower level. 
16.26 If DLT is seen in 1 of 3 patients treated at a given dose level, up to 3 additional 
will be enrolled and treated at the same dose level. If DLT is seen in at least one 
of these additional three patients (≥2 of 6), the MTD will have been exceeded, 
and further accrual will cease to this cohort (see 16.113 for further details). If 
dose-limiting toxicity (DLT) is not seen in any of the three additional patients, 3 
new patients will be accrued and treated at the next higher dose level. 
16.27 After enrolling 6 patients on a specific dose level, if DLT is observed in at least 2 
of 6 patients, then the MTD will have been exceeded and defined as the previous 
dose unless only 3 patients were treated at the lower dose level. In that case, 3 
additional patients will be treated at this lower dose level such that a total of 6 
patients are treated at the MTD to more fully assess the toxicities associated with 
the MTD. 
16.28 Dose de-escalation: If DLT meets the stopping boundaries set by the above dose 
escalation algorithm at dose level 1 (for example, more than 1 out of 3 patients or 
more than 1 out of 6 patients), the next cohort of three patients will be entered at 
a dose level of -1. Further dose re-escalation will depend on the toxicity profile 
observed at dose level -1, and re-evaluation of the regimen by the study team 
may be done. 
16.29a If a patient fails to complete the initial course of therapy (defined as drug 
administration and 21 days) for reasons other than DLT defined adverse events, 
the patient will be regarded as uninformative in regard to the primary study goal 
and an additional patient will be treated at the current dose level; however, all 
toxicity information will be utilized in the analysis. 
16.29b Operating Characteristics for Phase I portion of trial 
The following table gives the probability of dose escalation at a single dose level 
as a function of the true probability of DLT at that level using the Cohort 3+3 
design described in section 16.2. 
True Rate 
of DLT (%) 
Probability of Dose Escalation 
10 
0.91 
20 
0.71 

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30 
0.49 
40 
0.31 
50 
0.17 
16.3 
Analysis Plans for Phase I portion: 
All the relevant results pertaining to toxicity, MTD, response, and timed endpoints will 
be examined in an exploratory and hypothesis-generating fashion. The small sample size 
and the heterogeneous patient population associated with phase I studies restricts the 
generalizability of the results. Any notable statistical result should only be viewed as 
preliminary evidence for further study in Phase II trials rather than a definitive finding in 
and of itself.  All results will be shown overall and by dose level.   
16.31 Adverse Events Profile 
The number and severity of all adverse events (overall and by dose-level) 
will be tabulated and summarized in this patient population. The Grade 
3+ adverse events will also be described and summarized in a similar 
fashion. This will provide an indication of the level of tolerance for this 
treatment combination in this patient group.  
16.32 Toxicity Profile 
The term toxicity is defined as adverse events that are classified as either 
possibly, probably, or definitely related to study treatment. Non-
hematologic toxicities will be evaluated via the ordinal CTC standard 
toxicity grading. Hematologic toxicity measures of thrombocytopenia, 
neutropenia, and leukopenia will be assessed using continuous variables 
as the outcome measures (primarily nadir) as well as categorization via 
CTC standard toxicity grading. Overall toxicity incidence as well as 
toxicity profiles by dose level, patient and tumor site will be explored 
and summarized. Frequency distributions, graphical techniques and other 
descriptive measures will form the basis of these analyses.  
16.33 To identify preliminary evidence of clinical activity (i.e. confirmed 
response, timed endpoints, etc.).  A confirmed response is defined to be a 
CR or PR noted as the objective status on two consecutive evaluations at 
least 4 weeks apart. Confirmed response will be evaluated using the first 
6 months of treatment. All patients meeting the eligibility criteria who 
have signed a consent form and have begun treatment will be evaluable 
for response. Responses will be summarized by simple descriptive 
summary statistics delineating complete and partial responses as well as 
stable and progressive disease in this patient population.   
 
The data on time-related variables will be summarized descriptively. 
These include time until any treatment related toxicity, time until 
treatment related grade 3+ toxicity, time until hematologic nadirs (ANC, 
platelets, hemoglobin), time to progression and time to treatment failure, 
where time to treatment failure is defined as the time from registration to 
documentation of progression, unacceptable toxicity, or refusal to 
continue participation by the patient. 
 
Other clinical activity endpoints will also be explored, including overall 
survival, progression-free survival, etc. overall and by dose level.  These 
endpoints will be more fully explored during the Phase II portion of the 

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study.   
16.4  
Phase II Statistical Design 
16.41  Interim Analysis:  In the expanded cohort part of the trial, 17 patients 
will be accrued (this will include the patients treated at the MTD from 
the phase I component).  If 3 confirmed responses or less are observed in 
the first 17 eligible patients, then the trial will be terminated and the 
treatment deemed not worthy of further study. If at least 4 confirmed 
responses are observed among these 17 patients, then an additional 20 
patients will be accrued to the second stage.  
16.42  Final Analysis:  If 11 or more confirmed responses are observed at the 
end of the trial in the first 37 eligible patients, the treatment will be 
considered promising. This design yields at least 90% probability of a 
positive result if the true response rate is at least 40%.  
16.43 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the final decision rule or 
used in any decision making process. Analyses involving over accrued 
patients are discussed in Section 16.54. 
16.44 Other considerations: Adverse events, quality/duration of response, and 
patterns of treatment failure observed in this study, as well as scientific 
discoveries or changes in standard care will be taken into account in any 
decision to terminate the study 
16.5 
Analysis Plan for Phase II portion of trial 
The analysis for this trial will commence at planned time points (see 16.3) and at the time 
the patients have become evaluable for the primary endpoint. The Statistician and Study 
Chair will make the decision, in accord with CCS Standard Operating Procedures, 
availability of data for secondary endpoints (e.g., laboratory correlates), and the level of 
data maturity. It is anticipated that the earliest date in which the results will be made 
available via manuscript, abstract, or presentation format is when last patient has been 
followed for at least 6 months. 
16.51 Primary Outcome Analyses: 
16.511 Definition: The primary endpoint of this trial is the proportion of patients 
who achieve a confirmed response. A confirmed response is defined as 
PR or CR noted as the objective status on two consecutive evaluations at 
least 4 weeks apart. All patients meeting the eligibility criteria who have 
signed a consent form and have begun treatment will be evaluable for 
response, unless they are determined to be a major violation. 
16.512 Estimation: The proportion of successes will be estimated by the number 
of successes divided by the total number of evaluable patients. Exact 
binomial 95% confidence intervals for the true success proportion will be 
calculated. 
 
16.52 Secondary Outcome Analyses 
16.522 Overall survival is defined as the time from registration to death due to 
any cause. The distribution of overall survival will be estimated using 
the method of Kaplan-Meier (Kaplan and Meier, 1958).  

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16.523 Progression-free survival is defined as the time from registration to the 
earliest date of documentation of disease progression or death due to 
any cause. The distribution of progression-free survival will be 
estimated using the method of Kaplan-Meier.  We will also report the 1-
year progression free survival (PFS) rate for the combination of 
anetumab ravtansine  and atezolizumab in 2nd-line NSCLC.   
16.524 Adverse Events: All eligible patients that have initiated treatment will 
be considered evaluable for assessing adverse event rate(s). The 
maximum grade for each type of adverse event will be recorded for each 
patient, and frequency tables will be reviewed to determine patterns. 
Additionally, the relationship of the adverse event(s) to the study 
treatment will be taken into consideration. 
16.53 Correlative Analyses: Due to the small overall sample size, the results of these 
analyses will be considered exploratory and hypothesis-generating in nature. 
To determine using flow cytometry the levels of Bcl-2 interacting mediator of 
cell death (BIM) in circulating CD8+  CD11a+ PD-1+ T-cells, in peripheral 
blood samples collected from patients prior to initiation of therapy (baseline) and 
correlating these with ORR during and following treatment with the combination 
regimen.  We’ll also determine tissue MSLN and PD-L1 expression and correlate 
with response to combination therapy with atezolizumab and anetumab 
ravtansine .  Finally, we’ll correlate baseline serum soluble PDL-1 (sPDL-1) with 
response to therapy.  These data will be explored in a descriptive manner using 
basic data summaries and graphics. 
16.54  Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the final decision rule or used in 
any decision making processes; however, they will be included in final endpoint 
estimates and confidence intervals. 
16.6 
Data & Safety Monitoring: 
16.61 The principal investigator(s) and the study statistician will review the study at 
least twice a year to identify accrual, adverse event, and any endpoint problems 
that might be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety 
Monitoring Board (DSMB) is responsible for reviewing accrual and safety data 
for this trial at least twice a year, based on reports provided by the MCCC 
Statistical Office. 
16.62 Adverse Event Stopping Rules: The stopping rules specified below are based on 
the knowledge available at study development. We note that the Adverse Event 
Stopping Rule may be adjusted in the event of either (1) the study re-opening to 
accrual or (2) at any time during the conduct of the trial and in consideration of 
newly acquired information regarding the adverse event profile of the 
treatment(s) under investigation. The study team may choose to suspend accrual 
because of unexpected adverse event profiles that have not crossed the specified 
rule below. 
16.621 
Phase I (includes all phase I patients):  
By the nature of the “cohorts of three” phase I study design, stopping 
rules are in place for each dose level. Specifically, if 2 or more dose-
limiting toxicities (DLTs) are observed during cycle 1 at any given 
dose level, accrual to that dose level will be stopped, and patients will 

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be accrued to the next lower dose level until a maximum of 6 patients 
are treated at the lower level. Note that a DLT that affects dose 
escalation is only that which is observed in the first cycle of treatment.  
16.622 
Phase II (includes all phase II patients, including phase I patients 
treated at the MTD): 
Accrual will be temporarily suspended to this study if at any time we 
observe events with an attribution of possibly, probably, or definitely 
related to study treatment that satisfy one of the following: 
• If 5 or more patients in the first 15 treated patients experience a 
grade 4 or higher non-hematologic adverse event  
• If after the first 15 patients have been treated, 33% of all patients 
experience a grade 4 or higher non-hematologic adverse event.  
We note that we will review grade 4 and 5 adverse events deemed 
“unrelated” or “unlikely to be related”, to verify their attribution and to 
monitor the emergence of a previously unrecognized treatment-related 
adverse event. 
16.7   Results Reporting on ClinicalTrials.gov: 
At study activation, this study will have been registered within the “ClincialTrials.gov” 
website. The Primary and Secondary Endpoints along with other required information for 
this study will be reported on www.ClinicalTrials.gov. For purposes of timing of the 
Results Reporting, the initial estimated completion date for the Primary Endpoint of this 
study is 3 years after the study opens to accrual. The definition of “Primary Endpoint 
Completion Date” (PECD) for this study is at the time the last patient registered has been 
followed for at least 6 months. 
16.8 
Inclusion of Women and Minorities 
This study will be available to all eligible patients regardless of race, gender, or ethnic 
group.  There is no information currently available regarding differential agent effects of 
either regimen in subsets defined by gender, race, or ethnicity, and there is no reason to 
expect such differences exist. Therefore, although the planned analyses will, as always, 
look for differences in treatment effect based on gender and racial groupings, the samples 
sizes are not increased in order to provide additional power for such subset analyses.  
To predict the characteristics of patients likely to enroll in this trial we have reviewed the 
Mayo registration classified by race and gender.  This revealed that roughly 3% of 
patients registered into cancer trials during the past three years could be classified as 
minorities and about 60% of patients were women.  This would suggest that only 2 
patients in the study sample are expected to be classified as minorities.  This precludes 
the possibility of a separate subset analysis beyond simple inspection of results for the 
minority patients. Expected sizes of racial by gender subsets are shown in the following 
table: 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
1 
2 
Not Hispanic or Latino 
28 
19 
47 
Ethnic Category: Total of all subjects 
29 
20 
49 

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Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
1 
1 
Black or African American 
1 
0 
1 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
28 
19 
47 
Racial Category: Total of all subjects 
29 
20 
49 
 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
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17.0 
Tissue Biospecimens/Pathology Considerations 
17.1 
Summary Table of Research Tissue Specimens to be collected 
Correlative Study 
(Section for more 
information) 
Mandatory or 
Optional 
Type of 
Tissue to 
Collect 
Blocks/Slides
/Cores 
Collection 
Process 
at site 
Storage 
/Shipping 
Archived   
Mandatory 
Paraffin 
embedded 
1 H&E slide 
and 2 
unstained 4 
micron plus 
slides  
Pre-
registration 
Yes 
Ambient 
Fresh tissue biopsy 
Mandatory 
only if 
archival not 
available 
Fresh 
1-2 cores 
Pre-
registration 
Yes 
Ambient  
17.2 
Tissue collection and processing 
Mandatory tissue collection at baseline for IHC mesothelin testing.  If archival tissue is 
not available, a fresh biopsy must be completed Criteria for the submission of tissue are: 
• 
Archival tissue must have been collected within 36 months prior to registration, 
not previously irradiated, and after diagnosis of metastatic disease. 
17.21 Biopsy Procedure 
If archival tissue not available a tumor biopsy will be obtained at baseline. If a 
site is deemed appropriate for biopsy with minimal risk to the participant by 
agreement between the investigators an attempt for biopsy will be made. Because 
approximately 20% of tumor biopsies collected on research trials are not usable 
due to the presence of stroma or normal and/or necrotic tissue and paired biopsies 
are necessary for analysis, up to 5 core biopsies 18-gauge in diameter and ≥1 cm 
in length will be obtained during each procedure to try and ensure adequate 
tumor content and quality. Cores from different areas of the tumor are preferred 
when feasible. An H&E stain for each core to identify whether the core actually 
contains tumor or not. Unstained slides for staining will need to be prepared from 
the cores. Acceptable biopsy procedures are: 
• 
Percutaneous biopsy with local anesthetic. 
• 
Excisional cutaneous biopsy with local anesthetic 
• 
Other biopsy with local anesthetic and/or sedation that has been shown to 
have a risk of severe complications < 2% 
17.22 Tissue kits will not be provided for this protocol. 
17.23 Tissue submission  
17.231 Submit 1 H&E slide and 2 unstained 4 micron plus slides for archival 
tissue and 1-2 tissue cores at baseline and if applicable, at disease 
progression.  
17.232  The samples should be sent directly to the IHC Lab.  If lab is not local, 
send by FedEx standard next day delivery service.  Ship only Monday to 
Thursday to avoid delivery on a weekend.  Ship samples to: 
 

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18.0  
Records and Data Collection Procedures   
Baseline data will be entered ≤10 working days of patient registration.  This will include patient 
ID, age, gender, tumor type, dose level, and baseline symptoms. 
Cycle 1 toxicity data will be entered ≤24 hours after evaluation of the patient and ≤10 working 
days after evaluation on all other cycles. 
Response status will be entered ≤10 working days of evaluation for response as defined by 
protocol. 
Phase I only: Three months after the patient goes off treatment, follow-up information will be 
collected and entered.  This includes off treatment, off study, survival, and death data.  After 3 
months have elapsed from off treatment date, no further follow-up is required (i.e., patient goes 
off study). 
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
18.2 
Event monitoring (Phase II only) 
See Section 4.0 and data submission table for the event monitoring schedule. 
18.3 
CRF completion 
This study will use Medidata Rave for remote data capture (rdc) of all study data. 
18.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation 
This study requires supporting documentation for evidence of response to study therapy 
and progression after study therapy.  
18.6 
Labelling of materials 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.7 
Incomplete materials 
Any data entered into a form will result in that form being marked as “received.” 
However, missing data will be flagged by edit checks in the database. 
18.8 
Overdue lists 
A list of overdue materials is automatically available to each site at any time. A list of 
overdue materials and forms for study patients will be generated monthly. The listings 
will be sorted by location and will include the patient study registration number. The 
appropriate co-sponsor/participant will be responsible to submit the overdue material. 
18.9 
Corrections forms 
If a correction is necessary the QAS will query the site. The query will be sent to the 
appropriate site to make the correction in the database and respond back to the QAS.  

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19.0 
Budget  
19.1 
Costs charged to patient: Routine clinical care 
 
19.2 
Tests to be research funded: Research blood, ECG, Echocardiogram, Anetumab 
ravtansine and the administration, biopsy costs, if necessary

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20.0 
References 
 
1. 
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer 
J Clin. 2011;61(2):69-90. 
2. 
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four 
chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 
2002;346(2):92-8. 
3. 
Sequist LV, Heist RS, Shaw AT, Fidias P, Rosovsky R, Temel JS, et al. Implementing 
multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol. 
2011;22(12):2616-24. 
4. 
Frierson HF, Jr., Moskaluk CA, Powell SM, Zhang H, Cerilli LA, Stoler MH, et al. Large-scale 
molecular and tissue microarray analysis of mesothelin expression in common human 
carcinomas. Hum Pathol. 2003;34(6):605-9. 
5. 
Miettinen M, Sarlomo-Rikala M. Expression of calretinin, thrombomodulin, keratin 5, and 
mesothelin in lung carcinomas of different types: an immunohistochemical analysis of 596 
tumors in comparison with epithelioid mesotheliomas of the pleura. Am J Surg Pathol. 
2003;27(2):150-8. 
6. 
Bera TK, Pastan I. Mesothelin is not required for normal mouse development or reproduction. 
Mol Cell Biol. 2000;20(8):2902-6. 
7. 
Golfier S, Kopitz C, Kahnert A, Heisler I, Schatz CA, Stelte-Ludwig B, 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):1537-48. 
8. 
Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 
interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. 
Immunity. 2007;27(1):111-22. 
9. 
Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates 
of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 
2014;515(7528):563-7. 
10. 
Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. Programmed 
cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of 
human ovarian cancer. Proc Natl Acad Sci U S A. 2007;104(9):3360-5. 
11. 
Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int 
Immunol. 2007;19(7):813-24. 
12. 
Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, et al. Tumor cell expression of 
programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. 
2010;116(7):1757-66. 
13. 
Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-
specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. 
Cancer Immunol Immunother. 2005;54(4):307-14. 
14. 
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. 
Annu Rev Immunol. 2008;26:677-704. 
15. 
Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an 
update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother. 
2007;56(5):739-45. 
16. 
Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy--inhibiting 
programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18(24):6580-7. 

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17. 
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor 
cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. 
Proc Natl Acad Sci U S A. 2002;99(19):12293-7. 
18. 
Strome SE, Dong H, Tamura H, Voss SG, Flies DB, Tamada K, et al. B7-H1 blockade augments 
adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res. 2003;63(19):6501-5. 
19. 
Muller P, Kreuzaler M, Khan T, Thommen DS, Martin K, Glatz K, et al. Trastuzumab emtansine 
(T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci Transl 
Med. 2015;7(315):315ra188. 
20. 
Di Giacomo AM, Biagioli M, Maio M. The emerging toxicity profiles of anti-CTLA-4 
antibodies across clinical indications. Semin Oncol. 2010;37(5):499-507. 
21. 
Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin 
Cancer Res. 2009;15(23):7412-20. 
  
 
 

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APPENDIX A: ECOG PERFORMANCE STATUS SCORES 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate 
the scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert 
Comis M.D., Group Chair. 
From http://www.ecog.org/general/perf stat.html 
 
 
 

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APPENDIX B: 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.