Randomized Phase II Study of Standard Chemotherapy With Docetaxel With or Without Bintrafusp Alfa in Patients With Advanced NSCLC After Progressing on a Combination of Anti-PD-1/PD-L1 Agents and Chemotherapy
Phase: PHASE2
Conditions: Advanced Lung Non-Small Cell Carcinoma, Stage III Lung Cancer AJCC v8, Stage IIIA Lung Cancer AJCC v8, Stage IIIB Lung Cancer AJCC v8, Stage IIIC Lung Cancer AJCC v8, Stage IV Lung Cancer AJCC v8, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8
Sponsor: Mayo Clinic

 
 
 
 
 
MC1821 / 19-010887 
 
 
Randomized Phase II Study of Standard Chemotherapy with 
Docetaxel with or without Bintrafusp Alfa in Patients with 
Advanced NSCLC after Progressing on a Combination of Anti-
PD-1/PD-L1 Agents and Chemotherapy 
 
 
NCT04396535 
 
 
Document Date: 06/22/2022 

MC1821 
Protocol Version Date: 22Jun2022 
Mayo Clinic Cancer Center 
Randomized Phase II Study of Standard Chemotherapy with Docetaxel with or without Bintrafusp 
Alfa in Patients with Advanced NSCLC after Progressing on a Combination of Anti-PD-1/PD-L1 
Agents and Chemotherapy 
Sponsor/Principal Investigator: Konstantinos Leventakos MD PhD 
Mayo Clinic 
200 First Street SW 
Rochester MN 55905 
507/284-2511 
Co-Investigators: 
Dipesh Uprety MD√ 
Alex A Adjei MD PhD  
Anja C Roden MD 
Yanyan Lou MD PhD 
Panayiotis (Panos) S Savvides MD PhD 
 
Statistician: 
Nathan R Foster MS√ 
√Study contributor(s) not responsible for patient care 
Trial Supported by:  
Funding: EMD Serono MS200647_0002 
Drug Availability:  
Commercial Agents: docetaxel 
Drug Company Supplied: bintrafusp alfa (M7824) (IND 147341) 
Site Investigators & Participating sites:  
Panayiotis (Panos) S Savvides MD PhD 
Mayo Clinic  
13400 East Shea Boulevard  
Scottsdale, AZ 85259  
480/301-8000 
Yanyan Lou MD PhD 
Mayo Clinic  
4500 San Pablo Road  
Jacksonville, FL 32224  
904/953-2000 
 
Document History 
(Effective Date) 
Activation 
23Oct2020 
MCCC Amendment 1 
25Nov2020 
MCCC Amendment 2 
01Oct2021 
MCCC Amendment 3 
pending 
 
 
 
 
 
 
 

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Protocol Resources 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/ interruptions/ 
adjustments, dose modifications, 
adverse events, forms completion and 
submission 
Sharon F Solinger 
Quality Assurance Specialist/Data Manager 
Phone: 507/266-1714 
E-mail: solinger.sharon@mayo.edu 
 
Clinical coordinators (lead site first) 
Amanda M Nielsen 
Phone: 507/538-0152 
Email: nielsen.amanda@mayo.edu 
 
Sarah A Thiele or Omar M Sh Ahmed 
Phone: 904/953-3559 or 904/953-3974 
Email: thiele.sarah@mayo.edu or shahmed.omar@mayo.edu  
 
Yojan S Shah 
Phone: 480/574-1077 
Email: shah.yojan@mayo.edu 
Forms completion and submission 
(lead site first) 
Stephanie S Abel 
Phone: 507/538-3476 
E-mail: abel.stephanie@mayo.edu  
 
Xxxxxxxxx 
Phone:  
E-mail: 
 
Xxxxxxxxx 
Phone:  
E-mail: 
Protocol document, consent form, 
regulatory issues 
Lynn M Flickinger MA 
Senior Research Protocol Specialist 
Phone: 507/538-7034 
Email: flickinger.lynn@mayo.edu 
Mitchell (Mitch) G Perrizo 
Research Protocol Specialist 
Phone: 507/284-9104 
Email: perrizo.mitchell@mayo.edu  
Laboratory Contact 
Michael A Strausbauch 
Laboratory Contact for Correlative Studies 
Phone: 507-284-8177 
Email: strausbauch@mayo.edu  
Pathology Coordinator 
Amanda R Sand 
Pathology Coordinator 
Phone: 507/284-3559 
Email: sand.amanda@mayo.edu  
Serious Adverse Event Reporting 
Patricia G McNamara 
SAE Coordinator 
Phone: 507/266-3028 
E-mail: RSTP2CSAES@mayo.edu  
*No waivers of eligibility allowed  
 

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Table of Contents 
Randomized Phase II Study of Standard Chemotherapy with Docetaxel with or without Bintrafusp Alfa in 
Patients with Advanced NSCLC after Progressing on a Combination of Anti-PD-1/PD-L1 Agents and 
Chemotherapy ............................................................................................................................................... 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema .......................................................................................................................................................... 4 
1.0 
Background ................................................................................................................................... 5 
2.0 
Goals ............................................................................................................................................. 9 
3.0 
Patient Eligibility ........................................................................................................................ 10 
4.0 
Test Schedule .............................................................................................................................. 14 
5.0 
Stratification Factors ................................................................................................................... 15 
6.0 
Registration/Randomization Procedures ..................................................................................... 15 
7.0 
Protocol Treatment ...................................................................................................................... 18 
8.0 
Dosage Modification Based on Adverse Events ......................................................................... 20 
9.0 
Ancillary Treatment/Supportive Care ......................................................................................... 29 
10.0 
Adverse Event (AE) Monitoring and Reporting ......................................................................... 33 
11.0 
Treatment Evaluation/Measurement of Effect ............................................................................ 43 
12.0 
Descriptive Factors ..................................................................................................................... 47 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................ 47 
14.0 
Body Fluid Biospecimens ........................................................................................................... 49 
15.0 
Drug Information ........................................................................................................................ 54 
16.0 
Statistical Considerations and Methodology ............................................................................... 62 
17.0  
Pathology Considerations/Tissue Biospecimens......................................................................... 66 
18.0 
Records and Data Collection Procedures .................................................................................... 69 
19.0  
Budget ......................................................................................................................................... 69 
20.0 
References ................................................................................................................................... 70 
Appendix I 
ECOG Performance Status ............................................................................................... 71 
Appendix II 
Peripheral Blood Mononuclear Cells (PBMC) Panel for Cytof Analysis ......................... 72 
.

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Schema 
 
 
Randomization 
 
 
 
 
 
 
 
Group A 
Treatment: 
docetaxel plus  
bintrafusp alfa  
for 4 cycles 
 
Intolerable AEs 
 
Group B 
Treatment: 
docetaxel alone  
until PD or intolerable 
adverse effects 
↓ 
 
Off docetaxel waiting 
for PD 
→ 
↓PD  
bintrafusp alfa alone 
for up to 2 years 
 
↓ 
Refusal, ineligible, or 
start of other non-
protocoltreatment 
 
Optional crossover to 
bintrafusp alfa alone 
for up to 2 years 
 
 
↓ 
 
 
 
 
Events at any time: 
Disease Progression 
Intolerable adverse 
effects 
Patient refusal 
 
 
 
 
↓ 
 
 
 
 
Event monitoring* 
 
 
 
*NOTE: Survival follow-up will cease for all patients as of MCCC Amendment 3. 
Cycle = 21 days 
Generic name: bintrafusp alfa (M7824)  
Brand name(s): n/a 
Mayo Abbreviation: n/a 
Availability: Provided by EMD Serono Inc  
Generic name: Docetaxel 
Brand name(s): Taxotere®  
Mayo Abbreviation: TATER  
Availability: Commercial 
 
SD= stable disease, PR= partial response, CR= complete response, PD= progressive disease, n/a= not 
available/not applicable 
 

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1.0 
Background  
Approximately three-fourths of patients with non-small cell lung cancer (NSCLC) have advanced 
disease at diagnosis (Molina JR, 2008). The majority of these patients lack actionable driver 
mutation. For these patients, pembrolizumab in combination with a platinum-doublet is the 
preferred treatment option irrespective of PD-L1 expression. This usage is based on data from 
two landmark phase-3 studies, namely KEYNOTE-189 and KEYNOTE-407 which showed 
significantly longer overall survival with the addition of pembrolizumab to platinum doublet 
chemotherapy than chemotherapy alone (Gandhi L, 2018 May 31) (Paz-Ares L, 2018 Nov 22). 
For those patients with PD-L1 ≥50%, pembrolizumab monotherapy is also a preferred option 
(Reck M, 2016 Nov 10). Thus, standard front-line treatment of NSCLC with advanced disease 
without an actionable driver mutation will either include pembrolizumab as monotherapy or in 
combination with a platinum-doublet. Unfortunately, most of these patients will ultimately 
develop disease progression. In this situation, therapeutic options outside of a clinical trial are 
limited to second-line docetaxel. 
Autocrine and paracrine secretion of transforming growth factor β (TGFβ) in the tumor 
microenvironment is associated with epithelial-mesenchymal transition, a known resistance 
mechanism to immunotherapy in lung cancers (Xiao D, 2010). This mesenchymalization is 
associated with disease metastasis and progression. TGFβ isoforms are also involved in stromal 
modification, angiogenesis, and can directly inhibit T-cell division and NK cell function. TGFβ 
overexpression in the serum is associated with inferior outcomes in several malignancies.  
Upregulation of TGFβ signaling-associated genes in melanoma has been associated with anti-
PD1 antibody resistance in melanoma (Seidel JA, 2018); thus blocking TGFβ signaling may 
overcome resistance to anti-PD1/PD-L1 inhibitors. 
1.1 
Bintrafusp alfa (M7824) 
1.11 
Description 
Bintrafusp alfa (MSB0011359C) is a first-in-class, intravenously administered 
bifunctional fusion protein that combines the soluble extracellular domain of the human 
transforming growth factor β (TGFβ) receptor II (RII) as a TGFβ neutralizing ‘trap’ and 
an anti-programmed death ligand 1 (PD-L1) antibody, into a single molecule. 
Specifically, the protein is a heterotetramer, consisting of the 2 immunoglobulin light 
chains of anti-PD-L1, and 2 heavy chains comprising the heavy chain of anti-PD-L1 
genetically fused via a flexible glycine-serine linker to the extracellular domain of the 
human TGFβRII. The use of a bifunctional molecule targeting PD-L1 and TGFβ enables 
block tumor cell-intrinsic and tumor cell-extrinsic immunosuppressive pathways, 
respectively. Bintrafusp alfa-mediated simultaneous inhibition of the TGFβ and PD1/PD-
L1 pathway may overcome treatment failure to anti-PD1/PD-L1 agents. 
1.12 
Non-Clinical experience 
In vitro, bintrafusp alfa bound to ectopic PD-L1 overexpressed on the human embryonic 
kidney (HEK) 293 cell line at a similar concentration to the anti-PD-L1 agent [half-
maximal effective concentration (EC50) = 48 (average of three lots) and 34 ng/ml, or 0.27 
and 0.24 nM, respectively]. The TGFβ trap bound to both plate-bound TGF-β1 and TGF- 
β3 (EC50 = 215.3 and 651.4 ng/ml, respectively) as well in-solution TGF-β1 at an EC50 of 
7.1 ng/ml.  
Bintrafusp alfa showed potent growth inhibition in tumor xenograft models. In EMT-6 
orthoptic breast tumor mice models, bintrafusp alfa caused tumor regression in 92% (12 

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out of 13) of models; higher than the equimolar doses of either anti-PD-L1 (54%, 7 of 13 
mice) or trap control (8%, 1 of 13 mice). In the MC38 colon cancer models, bintrafusp 
alfa inhibited tumor growth more strongly than either anti-PD-L1 or TGFβ trap. 
1.13 
Clinical experience 
Bintrafusp alfa has demonstrated an acceptable safety profile to date in patients with solid 
tumors, including NSCLC. The pooled safety from 10 expansion cohorts from 
EMR200647-001 showed that most of the observed events were either in line with those 
expected in participants with advanced solid tumors or with similar class effects of 
monoclonal antibodies (mAbs) blocking the PD1/PD-L1 axis. Immune-related AEs 
(irAEs) and infusion-related reactions (IRRs) are identified as risks for bintrafusp alfa. In 
addition, skin adverse events (AEs) attributed to TGFβ are an identified risk for 
bintrafusp alfa, however, they have been manageable and have not led to permanent 
discontinuations in bintrafusp alfa. Bintrafusp alfa was evaluated at 2 dose levels (500 
and 1,200 mg) in a total of 80 participants in the second-line (2L) NSCLC cohort in 
EMR200647-001, the safety profiles were comparable at the 2 dose levels. Bintrafusp 
alfa has demonstrated promising antitumor activities in Phase I studies. At the cutoff for 
the analysis (24 weeks after the 1st dose in the last participant, 12 March 2018), the 80 
participants in the NSCLC cohort (40 participants at 500 or 1,200 mg every 2 weeks) had 
median follow-up of 51.1 weeks (range: 1.3 to 67.0 weeks) and had a median duration of 
treatment of 11.3 weeks (range: 2.0 to 66.1 weeks). Clinical activity was observed across 
PD-L1 expression levels and improved at higher PD-L1 tumor cell expression. Median 
progression-free survival (PFS) as assessed by the investigator for the 1,200 mg every 2 
weeks cohort was 2.7 and 6.8 months for participants regardless of PD-L1 expression 
status and PD-L1 ≥1%, respectively, and was not reached for PD-L1-high patients. 
Responses with bintrafusp alfa were durable: median duration of response (DoR) was not 
reached in the 1,200 mg every 2 weeks cohort, with responses ongoing in 8/11 patients at 
data cutoff. However, it is unclear whether bintrafusp alfa in combination with docetaxel 
will be the optimal approach compared to docetaxel alone in the second-line therapy of 
patients with NSCLC who have progressed on a combination of anti-PD1/PD-L1 agents 
and chemotherapy. We hypothesize that bintrafusp alfa will overcome checkpoint 
inhibitor resistance by modulating the tumor microenvironment and synergize with 
docetaxel in the treatment of NSCLC. We propose a randomized phase II study to 
address this question. 
1.14  
Justification for dose 
The dose for bintrafusp alfa in this study is 2,400 mg administered as an intravenous 
infusion once every 3 weeks.  
Per the current investigator’s brochure (IB) (M7824 Investigator's Brochure, 2019) 
integration of all available Phase I data and modeling and simulations support the 
selection of 1200 mg as the recommended phase two dose (RP2D) for every two-week 
(q2w) dosing of bintrafusp alfa. Since most chemotherapies are administered q3w, the 
same dosing interval for bintrafusp alfa is preferred for convenience and compliance. 
Therefore, 2400 mg once every three weeks (q3w) is the RP2D for q3w dosing of 
bintrafusp alfa in combination with chemotherapies (for details see IB). 
1.2 
Docetaxel 
Docetaxel is a semisynthetic taxane that binds to β tubulin and stabilizes microtubules, 
thus leading to cell cycle arrest and apoptosis. Docetaxel is approved in a variety of 
human malignancies such as breast cancer, gastro-esophageal cancers, prostate cancers 

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and non-small cell lung cancers. In the TAX-320 trial, docetaxel improved response rate, 
duration of response and one year survival when compared to vinorelbine or ifosfamide 
in platinum-refractory NSCLC (Fossella FV, 2000). Two doses of docetaxel were 
examined – 75 mg/m2 and 100 mg/m2. While both doses were equally effective, the lower 
dose was better tolerated. The TAX-317 trial showed that docetaxel improved survival 
over best supportive care by 2.9 months (7.5m vs 4.6m; RR 0.56, 95% CI 0.35-0.88) 
(Shepherd FA, 2000). Based on the above trial results, docetaxel at 75 mg/m2 was 
approved as second-line therapy in platinum-refractory metastatic non-small cell lung 
cancer. To date, this dose remains the preferred second line treatment for patients 
progressing on the combination of platinum-based chemotherapy and pembrolizumab. 
There is increasing evidence that responses to chemotherapy are accentuated if 
administered following immune checkpoint inhibitors. A recent study showed that 
response to single agent chemotherapy was significantly higher after immunotherapy than 
when compared with pre-immunotherapeutic historical control and almost equaled the 
ORR to first-line chemotherapy. The ORR to chemotherapy (50% patients had docetaxel) 
after immunotherapy (68% patients had nivolumab) was 39% compared to 37% ORR to 
first line chemotherapy. Historically, in the TAX 320 trial, docetaxel 75 mg/m2 had a 
response rate of 6.7%. It is postulated that immunotherapy sensitizes tumors to 
subsequent chemotherapeutic agents. The exact mechanisms leading to this effect are not 
clearly understood. We aim to explore the synergy of an immunotherapy and docetaxel 
when combined with a checkpoint inhibitor and a microenvironment modulating TGFβ 
trap. 
1.3 
Trial Design 
This is a phase II trial of bintrafusp alfa in combination with standard therapy in the 
treatment of adult patients with non-small cell lung cancer (NSCLC) that has progressed 
on combination chemotherapy and anti-PD-L1 immuno-therapy. Treatment will be 
administered as  
1) Docetaxel with bintrafusp alfa for 4 cycles, followed by bintrafusp alfa alone for up to 
2 years.  
OR 
2) Docetaxel alone until docetaxel is permanently discontinued due to disease 
progression or intolerable adverse events.  
When a patient discontinues docetaxel alone, the patient may be offered optional 
crossover to bintrafusp alfa alone when disease progression is diagnosed, as long as all 
eligibility criteria for crossover are met. 
NOTE: If patient on docetaxel-alone discontinues docetaxel due to intolerable adverse 
events, patient will be monitored every 6 weeks until disease progression. 
NOTE: If patient on docetaxel-alone does not meet criteria for crossover at the time of 
disease progression, then patient will go off study per Section 13.0, and may be treated 
per institutional standard of care. 
More than 650 patients have been treated with single-agent bintrafusp alfa. The toxicity 
profile is similar to those described for other PD1/PD-L1 inhibitors. 
Bintrafusp alfa is in a phase II/III trial combined with chemotherapy: cisplatin/etoposide 
or paclitaxel/carboplatin and radiation therapy for NSCLC (NCT03840902). Over 
20 patients have been evaluated to date, and the combination is well-tolerated. There is 
no reason to expect any significant safety concerns with a combination of bintrafusp alfa 
and docetaxel based on these chemo/radiation combination data. 

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In addition, there is an ongoing international multicenter study of chemotherapy + M7824 
(NCT03840915). One arm is a combination of docetaxel + M7824 arm (75 mg/m2 + 
2400 mg). There will be adequate safety data for us to adjust our drug doses by the time 
this present study is open for accrual, in the unlikely circumstance that concerning 
toxicities are found. 
1.4 
Correlative Research 
The following samples for biomarker research are required and will be collected from all 
participants in this study: Tumor samples obtained by endoscopic biopsies, core needle 
biopsies, excisional biopsies, punch biopsies, and surgical specimens that are <6 months 
old and adequate for biomarker analysis are mandatory at Baseline to evaluate the 
association of PD-L1 protein expression as well as other immune or tumor cell markers 
with the observed clinical responses. Biopsies obtained by fine needle aspiration are not 
acceptable. Fresh biopsies are mandatory at W4D1 (prior to Cycle 2). 
Tumor mutational burden (TMB) status in tumor tissue may be also evaluated to 
determine the correlation with clinical outcome. In addition, tumor samples may be 
analyzed for genetic variants of biomarkers which could play a role in the biology of the 
drug targets, the tumor or the tumor microenvironment including, but not limited to, 
specific gene mutations, genome-wide analysis for RNA, or protein biomarkers to 
evaluate their association with observed clinical responses. 
Optional collection of tissue procured outside of specified procedures, as part of routine 
care, at the discretion of Investigator (e.g., skin biopsies or tumors obtained as part of 
unscheduled interventions) may be analyzed for genetic variants of biomarkers thought to 
play a role in the biology of the drug targets, the tumor, or the tumor microenvironment, 
including, but not limited to, specific gene mutations, genome-wide analysis for RNA, or 
protein biomarkers to evaluate their association with observed clinical responses. 
Blood and tumor samples will be tested for 1) PD-L1 expression in tumor at Baseline 
assessed with IHC to evaluate the association of PD-L1 expression at Baseline with 
efficacy; and 2) TMB status in plasma ctDNA and in tumor tissue as well as level of 
ctDNA in plasma to evaluate the correlation with clinical outcome. 
In addition, tumor samples may be analyzed for genetic variants of biomarkers which 
could play a role in the biology of the drug targets, the tumor or the tumor 
microenvironment including, but not limited to, specific gene mutations, genome-wide 
analysis for RNA, or protein biomarkers to evaluate their association with observed 
clinical responses. 
1) Biopsies will be performed at study entry and after one cycle of treatment to explore 
biomarkers related to inhibition of TGFβ and PD-L1. 
2) Peripheral blood will be collected at study entry and prespecified time points to 
explore biomarkers related to inhibition of TGFβ and PD-L1. 
3) Peripheral blood will also be collected at study entry and prespecified time points for 
understanding the immune status of patients in response to therapy using mass 
cytometry. 
 

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2.0 
Goals  
2.1 
Primary Goal 
To compare the progression-free survival (PFS) of bintrafusp alfa in combination with 
docetaxel vs docetaxel alone. 
2.2 
Secondary Goals 
2.21 
To evaluate overall survival of bintrafusp alfa in combination with docetaxel vs 
docetaxel alone. 
2.22 
To evaluate overall response rates of bintrafusp alfa in combination with 
docetaxel vs docetaxel alone. 
2.23 
To evaluate duration of response of bintrafusp alfa in combination with docetaxel 
vs docetaxel alone. 
2.24 
To evaluate the safety of bintrafusp alfa in combination with docetaxel vs 
docetaxel alone. 
2.3 
Correlative Research 
2.31 
To evaluate PD-L1, TGFβ, and TMB as potential predictive markers of clinical 
response in tumor biopsies and in plasma. 
2.32 
To evaluate biomarkers associated with inhibition of TGF β and PD-L1 
2.33 
To evaluate the changes in immune system using mass cytometry in response to 
TGF β and PD-L1 inhibition. 
 

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3.0 
Patient Eligibility 
3.1 
Randomization – Inclusion Criteria 
3.11 
Age ≥18 years 
3.12 
Histological confirmation of non-small cell lung cancer (NSCLC) with advanced 
disease. 
3.13 
Prior treatment required: 
• 
Anti-PD1/PD-L1 agent in combination with platinum-based chemotherapy 
3.14 
Measurable disease as defined in Section 11.0.  
NOTE: Tumor lesions in a previously irradiated area are not considered 
measurable disease; Disease that is measurable by physical examination only is 
not eligible. 
3.15 
ECOG Performance Status (PS) 0 or 1 (Appendix I).  
3.16 
The following laboratory values obtained ≤14 days prior to registration: 
• 
Hemoglobin ≥9.0 g/dL 
• 
Absolute neutrophil count (ANC) ≥1500/mm3 
• 
Platelet count ≥100,000/mm3 
• 
Total bilirubin ≤ULN 
• 
Alanine aminotransferase (ALT/SGPT) and aspartate transaminase 
(AST/SGOT) ≤1.5 × ULN 
• 
Alkaline phosphatase ≤2.5 × ULN 
• 
PT/INR/aPTT ≤1.5 × ULN  
OR if patient is receiving anticoagulant therapy INR or aPTT is within target 
range of therapy 
• 
Calculated creatinine clearance ≥30 ml/min using the Cockcroft-Gault 
formula below: 
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) 
3.17 
Negative pregnancy test done ≤7 days prior to registration, for persons of 
childbearing potential only. 
NOTE: If a urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required.  
3.18 
Willing to use birth control as follows: 
3.181 
If able to become pregnant: Willing to use birth control during 
treatment and for 6 months after last dose of docetaxel and/or 
bintrafusp alfa, whichever is later. 
3.182 
If able to father a child: Willing to use birth control with partners able 
to become pregnant during treatment and for 3 months after last dose 
of docetaxel and/or bintrafusp alfa, whichever is later. 
3.19a 
Provide written informed consent. 

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3.19b Willingness to provide mandatory blood specimens for correlative research (see 
Section 14.0). 
3.19c 
Willingness to provide mandatory tissue specimens for correlative research (see 
Section 17.0).  
3.19d Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study).  
3.2 
Randomization - Exclusion Criteria 
3.21 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
• 
Pregnant persons 
• 
Nursing persons 
• 
Persons of childbearing potential who are unwilling to employ adequate 
contraception 
3.22 
Any of the following prior therapies:  
• 
Surgery ≤4 weeks prior to registration  
• 
Chemotherapy ≤4 weeks prior to registration  
• 
Received single agent anti-PD1/PD-L1 as first line therapy for metastatic 
disease 
3.23 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
3.24 
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. 
3.25 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 
3.26 
Other active malignancy ≤5 years prior to registration.  
EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.  
NOTE: If there is a history of prior malignancy, they must not be receiving other 
specific treatment for their cancer.  
3.27 
History of myocardial infarction ≤6 months, or congestive heart failure requiring 
use of ongoing maintenance therapy for life-threatening ventricular arrhythmias. 
3.28  
Known primary central nervous system (CNS) malignancy or symptomatic CNS 
metastases are excluded, with the following exceptions:  
3.281 
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  

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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  
3.282 
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  
3.29a 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins 
3.29b History or current evidence of bleeding disorder, including bleeding diathesis, 
i.e., any hemorrhage/bleeding event of CTCAE Grade ≥2 in ≤28 days prior to 
registration. 
3.29c 
Taking oral prednisone of ≥10 mg daily or equivalent.  
3.29d Known clinically significant liver disease, including active viral, alcoholic, or 
other hepatitis; cirrhosis; fatty liver; and inherited liver disease. 
Notes: 
• 
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 
3.29e  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. 
Notes: 
• 
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 

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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 
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) 
3.29f 
Known active human immunodeficiency virus (HIV) infection (defined as 
patients who are not on anti-retroviral treatment and have detectable viral load 
and CD4+ <500/ml). 
NOTE: HIV-positive patients who are well controlled on anti-retroviral therapy 
are allowed to enroll. 
3.29g 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. 
3.29h Severe infections ≤4 weeks prior to registration, including, but not limited to, 
hospitalization for complications of infection, bacteremia, or severe pneumonia. 
3.29i 
History of peripheral neuropathy ≥Grade 2. 
3.29j 
Known hypersensitivity to docetaxel or polysorbate 80. 
3.3 
Crossover Eligibility 
Crossover is allowed for patients in the docetaxel alone arm upon disease progression. 
3.31 
Documented disease progression ≤28 days prior to crossover registration. 
3.32 
No contratindications to bintrafusp alfa at the time of crossover registration. 
3.33 
Patient and physician agree to try crossover treatment with bintrafusp alfa. 
3.34 
Provide written informed consent. 
 

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4.0 
Test Schedule 
4.1 
Test schedule  
 
≤14 days 
prior to 
registration 
Active Monitoring Phase 
Tests and procedures 
Prior to 
Treatment 
on C1D1 
End of 
Cycle 1 prior 
to C2D1 
Day 8 
during 
docetaxel1 
Prior to subsequent 
cycle/ treatment 
(≥Cycle 2) 
End of 
every other 
cycle2 
End of 
treatment3 
Crossover: 
Prior to 
each cycle 
Safety 
followup4 
Window 
 
 
 
±3 days 
±7 days 
 
±7 days 
±7 days 
 
History and exam, Wt, PS  
X 
 
 
 
X 
 
X 
X 
X 
Adverse event assessment 
X 
 
 
 
X 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Pregnancy test5 
 
X 
 
 
 
 
 
 
 
Hematology group: CBC /w 5 part diff 
X 
 
 
X6 
X 
 
X 
X 
X 
Coagulation (PT/INR/aPTT as applicable) 
X 
 
 
 
 
 
 
 
 
Chemistry group7 
X 
 
 
 
X 
 
X 
X 
X 
TSH8 
X 
 
 
 
 
 
 
 
 
Tumor measurement9 
X 
 
 
 
 
X 
X 
X10 
 
ECG 
X11 
 
 
 
 
 
 
 
 
Research biopsy12R 
 
X 
X 
 
 
 
 
 
 
Mandatory research blood specimens13,R 
 
X 
 
 
 
X 
X 
 
 
Mandatory research tissue specimens14,R 
 
X 
X 
 
 
 
 
 
 
Cycle = 21 days; R=Research funded (see Section 19.0) 
 
1 Only needed for first four cycles of docetaxel 
2 End of Cycle 2, 4, 6, etc. NOTE: Maintain imaging schedule for patients on docetaxel alone after docetaxel is stopped due to AEs if prior to PD. 
3 End of treatment with docetaxel (prior to crossover) for patients on docetaxel alone; or end of all study treatment for patients on combination 
4 Single visit approximately 30 days ±5 days after last dose of bintrafusp alfa (due to timing, this visit may coincide with EOT visit) 
5 For persons of childbearing potential only. Baseline must be done ≤7 days prior to registration. Subsequent testing should be done as needed for clinical care. 
6 Blood draw one week after docetaxel is given – may be done locally and results transmitted to Mayo Clinic 
7 Albumin, alk phos, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, magnesium 
8 Baseline TSH testing is required; then monitor clinically if symptomatic 
9 Standard clinical imaging should be used. Contrast-enhanced CT/MRI is acceptable as a baseline scan if done≤28 days prior to C1D1. Subsequent visit window of ≤7 days is allowed. 
Tumor measurements are repeated prior to every odd cycle starting with Cycle 3. Once patient has achieved CR or SD, frequency may be reduced  per clinical guidelines. Documentation 
(radiologic) must be provided for patients removed from study for progressive disease. 
10 Most recent imaging while on study should be ≤28 days prior to crossover. Continue prior to every odd cycle per footnote above. 
11 12-lead ECG at screening only; may be repeated at any time if clinically indicated 
12 Consultation with Interventional Radiology is required prior to scheduling research lung biopsy (not needed for liver, lymph node, abdomen) 
13 Blood samples are collected per Section 14.0. Kits are required for sites outside of Rochester, MN. 
14 Tissue specimens are collected per Section 17.0. 

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4.2 
Survival Follow-up/Event Monitoring 
NOTE: Survival follow-up will cease for all patients as of MCCC Amendment 3. 
 
Survival Follow-up 
q. 3 
months 
until PD At PD 
After PD  
q. 3 months 
Death 
New Primary 
Survival Follow-up 
X 
X 
X 
X 
At each occurrence 
1. If a patient is still alive 5 years after registration, no further follow-up is required. 
5.0 
Stratification Factors  
5.1 
Primary PD during Chemo+Anti-PDx: Yes vs. No 
5.2 
Acquired resistance PD after SD as best response during Chemo+Anti-PDx: Yes vs. No 
5.3 
Acquired resistance PD after PR/CR during Chemo+Anti-PDx: Yes vs. No 
5.4 
Diagnosis: Squamous cell carcinoma vs non-squamous cell carcinoma 
6.0 
Registration/Randomization Procedures 
6.1 
Registration (Step 1) 
To register a patient, access the Mayo Clinic Research Registration Application at 
www.registration.mayo.edu. The Research Registration 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, contact the Mayo Clinic Research Site 
Management Office at (507) 284-2753 or ResearchSiteManagement@mayo.edu between 
the hours of 8 a.m. and 4:30 p.m. Central Time (Monday through Friday). 
Access and training instructions for the Research Registration Application are available 
on the Office of Clinical Trials web page (https://www.mayo.edu/research/centers-
programs/center-clinical-translational-science/offices/office-of-clinical-trials/research-
registration-application) 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 an MCCC subject ID number must be available as noted in the instructions. 
It is the responsibility of the individual 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 Mayo Clinic Research Site Management Office (507) 284-2753. If 
the patient was fully registered, the Research Site Management 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.” 
6.2 
Verification of materials 
Prior to accepting the registration, the Research Registration Application will verify the 
following: 
• 
IRB approval at the registering institution 

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• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
6.3 
Documentation of IRB approval 
Documentation of IRB approval must be on file in the Research Site Management 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 Mayo Clinic Research Site 
Management Office (fax: 507-284-0885). 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 Research Site Management Office is no longer necessary. 
6.4 
Correlative Research 
6.41 
Mandatory 
A mandatory correlative research component is part of this study, the patient will 
be automatically registered onto this component (see Sections 3.19c, 3.19d, 14.0, 
17.0). 
6.5 
Banking of data and specimens 
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 on cancer at Mayo Clinic. 
• 
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. 
• 
Patient has/has not given permission for Mayo Clinic to give his/her sample(s) to 
researchers at other institutions. 
6.6 
Treatment on protocol 
Treatment on this protocol must commence at Mayo Clinic under the supervision of a 
medical oncologist. 
6.7 
Treatment start 
Treatment cannot begin prior to registration and must begin ≤14 days after registration. 
6.8 
Pretreatment 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
6.9a 
Baseline symptoms 
All required baseline symptoms (see Section 10.6) must be documented and graded. 

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6.9c 
Study drug 
Study drug is available on site.  
6.9f 
Study Conduct 
The clinical trial will be conducted in compliance with regulations (21 CFR 312, 50, and 
56), guidelines for Good Clinical Practice (ICH Guidance E6), and in accordance with 
general ethical principles outlined in the Declaration of Helsinki; informed consent will 
be obtained from all participating patients; the protocol and any amendments will be 
subject to approval by the designated IRB prior to implementation, in accordance with 
21 CFR 56.103(a); and subject records will be stored in a secure location and subject 
confidentiality will be maintained. The investigator will be thoroughly familiar with the 
appropriate use of the study drug as described in the protocol and Investigator’s 
Brochure. Essential clinical documents will be maintained to demonstrate the validity of 
the study and the integrity of the data collected. Master files should be established at the 
beginning of the study, maintained for the duration of the study and retained according to 
the appropriate regulations. 
6.9g 
Randomization Procedures 
6.9g1 The factors defined in Section 5.0, together with the registering membership, will 
be used as stratification factors. 
6.9g2  After the patient has been registered into the study, the values of the stratification 
factors will be recorded, and the patient will be assigned to one of the following 
treatment groups using the Pocock and Simon dynamic allocation procedure 
which balances the marginal distributions of the stratification factors between the 
treatment groups.  
{Reference: Pocock SJ, Simon R. Sequential Treatment Assignment with 
Balancing for Prognostic Factors in the Controlled Clinical Trial. Biometrics 
31(1):103-115, 1975 Mar}  
• 
Bintrafusp alfa and docetaxel 
• 
Docetaxel alone 
6.9h 
Crossover for Patients on Docetaxel Alone Arm after Progression  
If the patient was on the docetaxel alone arm at the time of disease progression, then the 
patient can be offered the opportunity to crossover to treatment with bintrafusp alfa. 
Eligibility is determined by the treating physician and the patient. Patient must be 
reconsented and may be enrolled in the crossover through the remote registration 
application. 
To register a patient, access the Mayo Clinic  Research Registration Application at 
www.registration.mayo.edu. The Research Registration 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 Research Site Management Office at 
(507) 284-2753 between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday 
through Friday). 
 

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7.0 
Protocol Treatment 
7.1 
Treatment Schedule 
Use actual weight or estimated dry weight if fluid retention 
7.11 
Suggested pretreatment medication tables  
7.111 
Suggested pretreatment for docetaxel (please follow institutional 
guidelines) 
Agent 
Dose 
Route 
Day (include +/-buffer) 
Dexamethasone (DXM) 10-20 mg 
IV* 
Per institutional guidelines 
(prior to docetaxel) 
*Research test results may be affected by oral DXM if given prior to research 
sample collection 
7.112 Optional pretreatment for bintrafusp alfa 
Agent 
Dose 
Route 
Day (include +/-buffer) 
Acetaminophen 
500-650mg 
Oral 
1 of each cycle PRN 
Diphenhydramine  
25mg 
Oral 
1 of each cycle PRN 
7.12 
Treatment medication table  
Note: Docetaxel in combination with bintrafusp alfa should be given for four 
cycles. Docetaxel alone should be given until disease progression or intolerable 
adverse events. 
Group Agent 
Dose Level 
Route 
Day 
ReRx 
A 
Bintrafusp alfa 2400 mg 
IVPB 
1 
Q3w for up to 2 years 
Docetaxel 
75 mg/m2 
IVPB 
1 
Q3w for 4 cycles 
 
OR 
B 
Docetaxel 
75 mg/m2 
IVPB 
1 
Q3w 
IVPB = intravenous piggyback; Q3w = once every 3 weeks 
7.13 
Treatment medication table: Crossover for up to 2 years 
Patients assigned to docetaxel alone may crossover ≤28 days after scan showing 
progressive disease. 
Agent 
Dose Level 
Route 
Day 
ReRx 
Bintrafusp alfa 2400 mg 
IVPB 
1 
Q3w 
IVPB = intravenous piggyback; Q3w = once every 3 weeks 
7.2 
Bintrafusp alfa  
7.21 
Bintrafusp alfa  
Bintrafusp alfa is an intravenous medication administered once every three weeks 
for up to 2 years (35 doses). 
7.22 
Timing of drug administration 
Bintrafusp alfa will be administered as a 1 hour infusion  
(-10 minutes/+20 minutes, i.e., 50-80 minutes).  
After bintrafusp alfa, docetaxel at the dose of 75 mg/m2 should be administered 
as an intravenous infusion over approximately one hour. 

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7.3 
Docetaxel 
Docetaxel is administered according to institutional standards for four cycles only in 
combination with bintrafusp alfa; and until disease progression or intolerable adverse 
events when given alone. 
If patient on docetaxel alone discontinues docetaxel for intolerable adverse events, the 
patient should continue to be monitored every 6 weeks until disease progression (PD). At 
time of PD, patient may be offered option to crossover to bintrafusp alfa alone (see 
Section 7.4). 
7.4 
Crossover for patients on docetaxel alone 
Patients on docetaxel alone may crossover once disease progression is diagnosed. 
Patients should crossover within 28 days after the scan showing progressive disease. 
Crossover patients may be treated with bintrafusp alfa for up to 2 years. 
NOTE: If patient on docetaxel-alone does not meet criteria for crossover at the time of 
disease progression, then patient will go off study per Section 13.2, and may be offered 
other treatment per institutional standard of care. 
7.5 
Return to consenting institution  
For this protocol, the patient must return to the consenting institution for evaluation at 
least every 21 days during treatment (Active Monitoring Phase). 
7.6 
Treatment by local medical doctor (LMD) 
Treatment by a local medical doctor (LMD) is not allowed. 
Blood draws (CBC with differential) one week after docetaxel dose may be done locally 
and submitted to Mayo Clinic. (This check is only needed while patient is being treated 
with docetaxel.) 
 
 

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8.0 
Dosage Modification Based on Adverse Events  
Follow the modifications in these tables for the first two cycles, until individual treatment 
tolerance can be ascertained. Thereafter, these modifications should be regarded as guidelines to 
produce mild-to-moderate, but not debilitating, side effects. If multiple adverse events are seen, 
administer dose based on greatest reduction required for any single adverse event observed. 
Reductions or increases apply to treatment given in the preceding cycle and are based on adverse 
events observed since the prior dose. 
Providers may hold, delay, or reduce (in line with Section 8.1) doses, even in the absence of a 
requirement to do so in this section per clinical judgement to maximize patient safety. For 
example, if the patient’s AE is Grade 2, and the tables do not indicate a change in action, if the 
provider determines that the patient’s Grade 2 AE is severe enough to warrant a change in the 
patient’s clinical care (i.e., for medically significant or intolerable Grade 2 AE despite appropriate 
(maximal) supportive care), then the provider may make that change, as long as the reason for the 
change is discussed with the PI, and documented in the medical record. 
→ ALERT: 
ADR reporting may be required for some adverse events (See Section 10.0) ← 
8.1 
Dose Levels  
(Based on Adverse Events in Tables 8.2 and 8.3) 
Dose 
Level 
Bintrafusp alfa 
Docetaxel 
1* 
2400 mg 
75 mg /m2 
-1 
NA 
60 mg/m2 
-2 
NA 
50 mg//m2 
*Dose level 1 refers to the starting dose. 
Bintrafusp alfa dose is always 2400 mg. It may be held or discontinued but dose 
reduction is not allowed. If bintrafusp alfa is discontinued, docetaxel should be continued 
for a minimum of 4 cycles or until disease progression or unacceptable toxicity, 
whichever is first. 
Docetaxel will not be re-escalated once reduced. If dose reduction for docetaxel beyond 
Dose Level -2 is required or if docetaxel is held for more than 6 weeks (from the date of 
last docetaxel treatment), docetaxel should be discontinued. In that case, bintrafusp alfa 
should be continued until disease progression or unacceptable toxicity.  
NOTE: If either of docetaxel or bintrafusp alfa is discontinued, the patient can continue 
on the other drug, unless specified otherwise in the dose modification tables. If both are 
discontinued, the patient will go to survival follow-up (Section 4.2). 
NOTE: Adverse events requiring a dose-reduction step for any or all drugs beyond the 
two dose-reduction steps (levels –1 and –2) will be at the discretion of the treating 
physician, if the decision is made for the patient to be kept on study. These dose 
reductions must be clearly recorded in reported clinical data.  
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) current version 5.0* 
unless otherwise specified   
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic_applications.ctc.htm 

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8.2 
Dose Modifications for Bintrafusp Alfa Guidelines 
There will be no dose reduction for bintrafusp alfa in this study. Patients may temporarily 
suspend study treatment for up to 6 weeks beyond the last infusion if study drug-related 
toxicity requiring dose suspension is experienced. If bintrafusp alfa is held because of 
AEs for >6 weeks beyond the last date of infusion, the patient will be discontinued from 
bintrafusp alfa 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, bintrafusp alfa may be held for 
≤6 weeks from last infusion 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 or medical 
events, may be allowed. The reason for interruption should be documented. The 
acceptable length of interruption is less than 6 weeks and should be discussed with lead 
investigator. 
Any adverse event associated or possibly associated with bintrafusp alfa 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 immuno-
modulatory agents have been mild and self-limiting, such events should be recognized 
early and treated promptly to avoid potential major complications. Discontinuation of 
bintrafusp alfa may not have an immediate therapeutic effect, and there is no available 
antidote for bintrafusp alfa. 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 bintrafusp alfa. In patients who have met the criteria for 
permanent discontinuation, resumption of bintrafusp alfa 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 bintrafusp alfa ONLY after careful consideration of 
benefit- risk balance and medical judgment by the trial Principal Investigator. Bintrafusp 
alfa 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 
The table below presents dose modification guidelines of bintrafusp alfa for immune 
related adverse events. For recommendations to hold bintrafusp alfa and begin 
corticosteroid treatment, use the following guidance for tapering the corticosteroid and 
resuming bintrafusp alfa therapy after resolution of the event: 
• 
Corticosteroids must be tapered over ≥1 month to <10 mg/day oral prednisone or 
equivalent before bintrafusp alfa can be resumed. 

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• 
Bintrafusp alfa may be held for a period of time of 6 weeks to allow for 
corticosteroids to be reduced to ≤10 mg/day oral prednisone or equivalent. 
Use the following to describe actions in the Action column: 
 Omit = The current dose(s) for the specified drug(s) during a cycle is 
skipped. The patient does not make up the omitted dose(s) at a later time. 
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The 
patient does make up the delayed dose(s) when the patient meets the protocol 
criteria to restart drugs. 
 Discontinue = The specified drug(s) are totally stopped. 
8.3 
Dose Modifications for Bintrafusp Alfa Day 1 of Subsequent Cycles 
CTCAE  
System/Organ/Class 
(SOC) 
Adverse Event 
Grade 
Dose Adjustment and Management 
Recommendations 
Endocrine disorders Adrenal insufficiency Grade 2+ 
(symptomatic) 
Hold bintrafusp alfa. 
Resume bintrafusp alfa if event resolves 
to Grade 1 or better and patient is stable 
on replacement therapy (if required) 
within 6 weeks. 
Permanently discontinue bintrafusp alfa 
and contact Study Chair if event does not 
resolve to Grade 1 or better or patient is 
not stable on replacement therapy within 
6 weeks. 
 
Hyperthyroidism 
Grade 1 
(asymptomatic) 
TSH ≥0.1 mU/L and <0.5 mU/L: 
Continue bintrafusp alfa.  
(See Section 9.5 for supportive care 
guidelines) 
TSH <0.1 mU/L: 
Follow guidelines for symptomatic 
hyperthyroidism 
 
 
Grade 2+ 
(symptomatic) 
Hold bintrafusp alfa. 
(See Section 9.5 for supportive care 
guidelines) 
Resume bintrafusp alfa when symptoms 
are controlled and thyroid function is 
improving 
Permanently discontinue bintrafusp alfa 
and contact Study Chair for life-
threatening immune-related 
hyperthyroidism 
Endocrine disorders Hypothyroidism 
Grade 1 
(asymptomatic) 
Continue bintrafusp alfa. 
(See Section 9.5 for supportive care 
guidelines) 

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CTCAE  
System/Organ/Class 
(SOC) 
Adverse Event 
Grade 
Dose Adjustment and Management 
Recommendations 
Endocrine disorders 
Hypothyroidism 
(continued) 
Grades 2+ 
(symptomatic) 
Hold bintrafusp alfa 
(See Section 9.5 for supportive care 
guidelines) 
Restart bintrafusp alfa when symptoms 
are controlled and thyroid function is 
improving 
Gastrointestinal 
disorders 
Diarrhea or 
Entercolitis 
Any grade 
Patients should be advised to inform the 
investigator if any diarrhea occurs, even 
if it is mild. 
(See Section 9.4 for supportive care 
guidelines) 
 
 
Grade 1 
Continue bintrafusp alfa. Initiate 
symptomatic treatment.  
(See Section 9.4 for supportive care 
guidelines) 
 
 
Grade 2 
Hold bintrafusp alfa. 
(See Section 9.4 for supportive care 
guidelines) 
If event resolves to Grade 1 or better 
within 6 weeks, taper corticosteroids and 
resume bintrafusp alfa according to the 
guidelines above. 
Permanently discontinue bintrafusp alfa 
and contact Study Chair if event does not 
resolve to ≤Grade 1 within 6 weeks. 
Resumption of bintrafusp alfa may be 
considered in patients who are deriving 
benefit and have fully recovered from the 
immune- related event. 
Gastrointestinal 
disorders 
Diarrhea or 
Entercolitis 
Grade 3 
Hold bintrafusp alfa 
(See Section 9.4 for supportive care 
guidelines) 
If event resolves to ≤Grade 1 within 
6 weeks, taper corticosteroids and resume 
bintrafusp alfa according to the 
guidelines above. 
Permanently discontinue bintrafusp alfa 
and contact Study Chair if event does not 
resolve to ≤Grade 1 within 6 weeks. 
Resumption of bintrafusp alfa may be 
considered in patients who are deriving 
benefit and have fully recovered from the 
immune- related event 

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CTCAE  
System/Organ/Class 
(SOC) 
Adverse Event 
Grade 
Dose Adjustment and Management 
Recommendations 
Gastrointestinal 
disorders 
Diarrhea or  
Enterocolitis 
(continued) 
Grade 4 
Permanently discontinue bintrafusp alfa. 
Patient may not resume treatment, 
regardless of benefit. 
(See Section 9.4 for supportive care 
guidelines) 
Hepatobiliary 
disorders 
Hepatic Failure 
≥Grade 3 
Permanently discontinue bintrafusp alfa 
and contact Study Chair.  
Patient may not resume treatment, 
regardless of benefit. 
Immune system 
disorders 
Anaphylaxis 
≥Grade 3 
If hypersensitivity reaction occurs, 
participant should be treated according to 
the best available medical practice 
Permanently discontinue bintrafusp alfa 
Patient should go to Event Monitoring 
Infections and 
infestations 
Encephalitis infection 
or  
Meningitis 
All grades 
Permanently discontinue bintrafusp alfa 
and contact Study Chair. Patient may not 
resume treatment, regardless of benefit. 
(See Section 9.6 for supportive care 
guidelines) 
Injury, poisoning or 
procedural 
complications 
Infusion related 
reaction 
Grade 1 
Increased monitoring of vital signs as 
medically indicated 
Consider interrupting or slow the rate of 
infusion, and use premedication for 
subsequent doses 
 
 
Grade 2 
Stop infusion 
Increased monitoring of vital signs as 
medically indicated 
If symptoms resolve quickly or decrease 
to Grade 1, resume infusion at 50% of 
original rate with close monitoring of any 
worsening otherwise dosing held until 
resolution of symptoms with mandated 
pre-medication for the next schedule 
At the next infusion, H2 blockers (e.g., 
famotidine or ranitidine) may be 
considered as clinically indicated. 
Participants with a second Grade ≥2 IRR 
on the reduced-rate infusion with the 
suggested medication, the infusion 
should be stopped, and if clinically 
indicated the participant should be 
removed from study intervention 

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CTCAE  
System/Organ/Class 
(SOC) 
Adverse Event 
Grade 
Dose Adjustment and Management 
Recommendations 
Injury, poisoning or 
procedural 
complications 
Infusion related 
reaction 
Grade 3 or  
Grade 4 
Stop infusion immediately and 
disconnect tubing from the participant 
Take additional appropriate medical 
measures and close monitoring until 
deemed medically stable by attending 
Investigator 
Participants must be immediately 
withdrawn and must NOT receive any 
further infusions 
Investigations 
Lipase increased  
or  
 
Grade 1 
(>ULN - 1.5 x 
ULN) 
Continue bintrafusp alfa. 
(See Section 9.7 for supportive care 
guidelines) 
 
Serum amylase 
increased 
Grade 2  
(>1.5 - 2.0 x 
ULN) 
Continue bintrafusp alfa. 
(See Section 9.7 for supportive care 
guidelines) 
 
 
Grade 3  
(>2.0 - 5.0 x 
ULN) 
or Grade 4  
(>5.0 x ULN) 
Hold bintrafusp alfa. 
(See Section 9.7 for supportive care 
guidelines) 
Resume bintrafusp alfa if event resolves 
to Grade 1 or better within 6 weeks. 
Permanently discontinue bintrafusp alfa 
and contact Study Chair if event does not 
resolve to Grade 1 or better within 
6 weeks. 
For recurrent events associated with 
pancreatitis symptoms, permanently 
discontinue bintrafusp alfa and contact 
Study Chair. Treatment for recurrent 
events not associated with pancreatitis 
symptoms may be resumed after 
consultation with the trial Study Chair. 
Metabolism and 
nutrition disorders 
Hyperglycemia 
Grade 1 or 2 
Continue bintrafusp alfa. 
(See Section 9.8 for supportive care 
guidelines) 
 
Hypoglycemia 
Grade 3 or 4 
Hold bintrafusp alfa. 
(See Section 9.8 for supportive care 
guidelines) 
Resume bintrafusp alfa when symptoms 
resolve and glucose levels are stable. 

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CTCAE  
System/Organ/Class 
(SOC) 
Adverse Event 
Grade 
Dose Adjustment and Management 
Recommendations 
Musculoskeletal and 
connective tissue 
disorders 
Arthritis 
Grade 3 
Hold bintrafusp alfa. 
Evaluate for alternative etiologies. 
Initiate treatment per institutional 
guidelines. 
Resume bintrafusp alfa if event resolves 
to Grade 1 or better within 6 weeks. 
Permanently discontinue bintrafusp alfa 
and contact Study Chair if event does not 
resolve to Grade 1 or better within 6 
weeks. 
 
Nervous system 
disorders 
Peripheral motor 
neuropathy 
Grade 1 
Continue bintrafusp alfa. 
Evaluate for alternative etiologies. 
 
OR 
Peripheral sensory 
neuropathy 
Grade 2 
Hold bintrafusp alfa. 
Evaluate for alternative etiologies. 
Initiate treatment per institutional 
guidelines. 
Resume bintrafusp alfa if event resolves 
to Grade 1 or better within 6 weeks. 
Permanently discontinue bintrafusp alfa 
and contact Study Chair if event does not 
resolve to Grade 1 or better within 6 
weeks. 
 
 
Grade 3 or 4 
Permanently discontinue bintrafusp alfa 
and contact Study Chair.  
Initiate treatment per institutional 
guidelines. 
Renal and urinary 
disorders 
Acute kidney injury 
Grade 3 or 4 
Permanently discontinue bintrafusp alfa 
and contact Study Chair.  
Initiate treatment per institutional 
guidelines. 
Respiratory, 
thoracic and  
All pulmonary events  
All grades 
(See Section 9.9a for supportive care 
guidelines) 
 
(such as Cough, 
Pneumonitis, 
Bronchospasm, 
Pulmonary edema, or 
any other respiratory 
tract AE) 
Grade 1 
Continue bintrafusp alfa and monitor 
closely.  
(See Section 9.9a for supportive care 
guidelines) 
For recurrent pneumonitis, treat as a 
Grade 3 or 4 event. 
 
 
Grade 2 
Hold bintrafusp alfa. 
(See Section 9.9a for supportive care 
guidelines) 
Permanently discontinue bintrafusp alfa 

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CTCAE  
System/Organ/Class 
(SOC) 
Adverse Event 
Grade 
Dose Adjustment and Management 
Recommendations 
and contact Principal Investigator if 
event does not resolve to Grade 1 or 
better within 6 weeks. 
For recurrent events, treat as a Grade 3 or 
4 event. 
Respiratory, 
thoracic and 
mediastinal 
disorders 
All pulmonary events 
(continued) 
Grade 3 or 4 
Permanently discontinue bintrafusp alfa 
and contact Study Chair. For Grade 3, 
patient may only resume treatment after 
consultation with the trial PI (Study 
Chair) 
For Grade 4, patient may not resume 
treatment, regardless of benefit. 
(See Section 9.9a for supportive care 
guidelines) 
Skin and 
subcutaneous tissue 
disorders 
Rash maculo-papular 
or  
Purpura 
Grade 1 
Continue bintrafusp alfa. 
(See Section 9.9b for supportive care 
guidelines) 
 
 
Grade 2 lasting 
>7 days 
Hold bintrafusp alfa until resolution to 
≤Grade 1.  
(See Section 9.9b for supportive care 
guidelines) 
 
 
Grade 3 
Hold bintrafusp alfa. 
(See Section 9.9b for supportive care 
guidelines) 
Restart bintrafusp alfa if event resolves to 
Grade 1 or better within 6 weeks. 
Permanently discontinue bintrafusp alfa 
and consult Study Chair if event does not 
resolve to Grade 1 or better within 
6 weeks. 
 
 
Grade 4 
Permanently discontinue bintrafusp alfa 
and contact Study Chair. Patient may not 
resume treatment, regardless of benefit. 
 

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8.4 
Dose Modifications for Docetaxel 
Docetaxel administration should follow institutional guidelines. The information below 
may serve as a guideline. 
8.41 
Initiation of new cycle for docetaxel 
Instruction for initiation of a new cycle of therapy or restarting therapy after 
interruption during a cycle for adverse events. A new cycle of treatment may 
begin on the scheduled Day 1 of a new cycle if: 
Neutrophil Count 
 
Platelet Count 
Docetaxel 
≥1,500/μL 
AND 
≥100,000/μL 
100% 
<1500/μL 
OR 
<100,000/μL 
Hold 
If these conditions are not met on Day 1 of a new cycle, the subject will be 
evaluated weekly and a new cycle of therapy will be held until the adverse event 
has resolved as described above. If dose is held for longer than 1 week, resume 
with docetaxel at one lower level. 
If any drug dosing was halted during the previous cycle and was restarted with a 
one-level dose reduction without requiring an interruption for the remainder of 
the cycle, then that reduced dose level will be initiated on Day 1 of the new 
cycle. 
If any drug dosing was held for the remainder of the previous cycle or if the new 
cycle is held due to known cytopenia newly encountered on the scheduled Day 1, 
then the new cycle will be started with a one-level dose reduction. If a new cycle 
of therapy cannot be restarted within 6 weeks due to non-resolution of drug 
related adverse events, the patient will be removed from protocol therapy and 
will go to survival follow-up. 
For febrile neutropenia during any cycle, defined at ANC <500/μL and 
temperature ≥38°C (100.4°F), docetaxel should be decreased one dose level for 
all subsequent cycles. 
8.42 
Dose Modification of Docetaxel for Hepatic Dysfunction 
Parameter 
 
Other Parameters 
Action for Docetaxel 
Bili ≤ULN 
AND 
AST >1.5 - 5.0 × ULN 
Decrease by one dose level 
Bili >ULN 
 
 
Hold 
Alk phos >2.5 × ULN AND 
AST and/or ALT>1.5 × ULN 
Hold 
8.43 
Dose Modification for Neurotoxicity 
For Grade 3 or 4 neurotoxicity, hold docetaxel until the adverse event resolves to 
Grade 2 or less and then resume therapy at one lower dose level. If symptoms 
worsen or persist despite dose reduction, hold docetaxel until adverse event 
resolves to Grade 2 or less and then resume therapy at one more lower dose level. 
If therapy is held for more than 6 weeks (from date of last docetaxel treatment) or 
symptoms persist despite 2 dose reductions, discontinue docetaxel. 
8.44 
Dose Modification for Gastrointestinal Toxicity 
For Grade ≥3 mucositis, diarrhea, nausea or vomiting, omit docetaxel. Resume at 
1 lower dose level when symptoms resolve to Grade 1 or less. 

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9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full supportive care 
Patients should receive full supportive care while on this study. 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, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
9.2 
Blood products and growth factors 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the Journal of Clinical Oncology, Volume 33, No 28 
(October 1), 2015: pp. 3199-3212 (WBC growth factors) AND Journal of Clinical 
Oncology, Volume 28, No 33 (November 20), 2010: pp. 4955-5010 
(darbepoetin/epoetin). 
9.3 
Antiemetics 
Antiemetics may be used at the discretion of the attending physician. 
9.4 
Diarrhea or Enterocolitis 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies. For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased CRP, f count, or 
bandemia): Perform sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy, 
with three to five specimens for standard paraffin block to check for inflammation and 
lymphocytic infiltrates to confirm colitis diagnosis. 
9.41 
Grade 1 
Endoscopy is recommended if symptoms persist for ≥7 days 
Monitor closely 
9.42 
Grade 2 
Initiate symptomatic treatment.  
Patient referral to GI specialist is recommended. 
For recurrent events or events that persist >5 days, initiate treatment with  
1-2 mg/kg/day oral prednisone or equivalent. 
9.43 
Grade 3 
Refer patient to GI specialist for evaluation and confirmatory biopsy.  
Initiate treatment with 1-2 mg/kg/day intravenous methylprednisolone or 
equivalent and convert to 1-2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
If event resolves to Grade 1 or better within 12 weeks, taper corticosteroids and 
resume bintrafusp alfa according to guidelines in Section 8.0. 
9.44 
Grade 4 
Refer patient to GI specialist for evaluation and confirmation biopsy.  
Initiate treatment with 1-2 mg/kg/day intravenous methylprednisolone or 

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equivalent and convert to 1-2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
If event resolves to Grade 1 or better, taper corticosteroids over ≥1 month. 
9.5 
Endocrine Disorders 
9.51 
Adrenal insufficiency 
Refer patient to endocrinologist.  
Perform appropriate imaging. 
Initiate treatment with hydrocortisone. . 
9.52 
Hyperthyroidism 
For asymptomatic (Grade 1) (TSH ≥0.1 mU/L and <0.5 mU/L):  
Monitor TSH every 4 weeks. 
For asymptomatic (Grade 1) (TSH <0.1 mU/L) or symptomatic (Grade 2+): 
Initiate treatment with anti-thyroid drug such as methimazole or carbimazole as 
needed. 
Consider patient referral to endocrinologist. 
9.53 
Hypothyroidism 
For Grade 1: 
Start thyroid-replacement hormone.  
Monitor TSH weekly. 
For Grade 2+: 
Start thyroid-replacement hormone.  
Consider referral to an endocrinologist.  
Monitor TSH weekly. 
9.6 
Encephalitis infection or Meningitis 
Refer patient to neurologist. 
Initiate treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent and convert to 
1-2 mg/kg/day oral prednisone or equivalent upon improvement. 
If event resolves to Grade 1 or better, taper corticosteroids over ≥28 days.  
If event does not improve within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent. 
9.7 
Immune-related Pancreatitis or Lipase increased and/or Serum amylase increased 
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with administration of other 
immunomodulatory agents. The differential diagnosis of acute abdominal pain should 
include pancreatitis. Appropriate workup should include an evaluation for obstruction, as 
well as serum amylase and lipase tests. See the guidelines for “Amylase and/or lipase 
increase” and “Immune- related pancreatitis” elsewhere in this document, as needed. 
9.71 
Grade 1 
Monitor amylase and lipase prior to dosing bintrafusp alfa (approximately every 
3 weeks) 

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9.72 
Grade 2 
Monitor amylase and lipase weekly 
9.73 
Grade 3 or 4 
Refer patient to gastrointestinal (GI) specialist.  
Monitor amylase and lipase every other day. 
If no improvement, consider treatment with 1-2 mg/kg/day oral prednisone or 
equivalent. 
9.8 
Hyperglycemia (all grades) 
Initiate treatment with insulin if needed.  
Monitor for glucose control. 
9.9a 
Pulmonary events 
For all pulmonary events (such as, but NOT limited to: Cough, Pneumonitis, 
Bronchospasm, Pulmonary edema, or any other respiratory tract AE) 
Evaluate thoroughly for other commonly reported etiologies such as 
pneumonia/infection, lymphangitic carcinomatosis, pulmonary embolism, heart failure, 
chronic obstructive pulmonary disease (COPD), or pulmonary hypertension. 
9.9a1 
Grade 1 
Re-evaluate on serial imaging.  
Consider patient referral to a pulmonary specialist. 
9.9a2 
Grade 2 
Refer patient to pulmonary and infectious disease specialists and consider 
bronchoscopy or bronchoscopic alveolar lavage (BAL). 
Initiate treatment with 1-2 mg/kg/day oral prednisone or equivalent. Resume 
bintrafusp alfa if event resolves to Grade 1 or better within 12 weeks (consult 
tapering guideline above). 
9.9a3 
Grade 3 or 4 
Bronchoscopy or BAL is recommended.  
Initiate treatment with 1-2 mg/kg/day oral prednisone or equivalent. 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
If event resolves to Grade 1 or better, taper corticosteroids over ≥1 month. 
9.9b 
Skin and subcutaneous tissue disorders: Rash maculo-papular or Purpura 
9.9b1 Grade 1 
Consider topical steroids and/or other symptomatic therapy (e.g., antihistamines) 
9.9b2 Grade 2 
Consider dermatologist referral.  
Administer topical corticosteroids. 
Consider higher potency topical corticosteroids if event does not improve. 

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9.9b3 Grade 3 or higher 
Refer patient to dermatologist.  
Administer oral prednisone 10 mg or equivalent.  
If the event does not improve within 48-72 hours, increase dose to1–2 mg/kg/day 
or equivalent. 
9.9b4 Persistent and/or severe rash or pruritus 
A dermatologist should evaluate the event.  
A biopsy should be performed unless contraindicated. 
9.9c 
Hepatoxicity 
Right upper-quadrant abdominal pain and/or unexplained nausea or vomiting should be 
evaluated for potential hepatotoxicity. 
 

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10.0 
Adverse Event (AE) Monitoring and Reporting  
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure. 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following: 
• 
Any suspected adverse reaction that is both serious and unexpected. 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB). 
Summary of SAE Reporting for this study  
(please read entire section for specific instructions): 
WHO: 
WHAT form: 
WHERE to send: 
Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting 
Form:http://livecycle2.mayo.edu/workspace/?startEnd
point=MC4158-56/Processes/MC4158-56-
Process.MC4158-56  
AND attach 
Pregnancy Reporting 
http://ctep.cancer.gov/protocolDevelopment/electronic_a
pplications/docs/PregnancyReportFormUpdated.pdf 
Send to EMD Serono: 
ICSR_CT_GPS@merckgroup.co
m 
Will automatically be sent to 
CANCERCROSAFETYIN@mayo
.edu and 
RSTP2CSAES@mayo.edu 
Non Mayo sites – complete and 
forward to 
RSTP2CSAES@mayo.edu 
Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting 
Form:http://livecycle2.mayo.edu/workspace/?startEnd
point=MC4158-56/Processes/MC4158-56-
Process.MC4158-56  
AND attach 
MedWatch 3500A: 
http://www.fda.gov/downloads/AboutFDA/ReportsMa
nualsForms/Forms/UCM048334.pdf 
Send to EMD Serono: 
ICSR_CT_GPS@merckgroup.co
m 
Will automatically be sent to 
CANCERCROSAFETYIN@mayo
.edu and 
RSTP2CSAES@mayo.edu 
Definitions 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related.  

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Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming aware 
of the event. 
Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 
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).  
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 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0 A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) 
a. Identify the grade and severity of the event using the CTCAE version 5.0. 
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/UCM0
48334.pdf 
 
 

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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. 
*Specific protocol exceptions to expedited reporting should be reported 
expeditiously by investigators ONLY if they exceed the expected grade of the 
event. 
CTCAE  
System/Organ/Class (SOC) 
Adverse Event/ Symptoms 
CTCAE Grade at which the event 
will not be expeditedly reported1 
Blood and lymphatic system 
disorders 
Anemia 
≤Grade 3 
Investigations 
Lymphocyte count decreased 
≤Grade 4 
Platelet count decreased 
≤Grade 4 
White blood cell count decreased 
≤Grade 4 
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.  
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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10.4 
Expedited Reporting Requirements for IND Agents  
10.41 Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND within 30 Days of the Last 
Administration of the Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
sponsor within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥24 hrs 
7 Calendar Days 
24-Hour  
3 Calendar 
Days 
Not resulting in 
Hospitalization 
≥24 hrs 
Not required 
7 Calendar Days 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-
lives, rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote 
“1” above applies after this reporting period. 
Effective Date: May 5, 2011 
NOTE: Refer to Section 10.32 for exceptions to Expedited Reporting 

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10.42 General reporting instructions 
The Mayo IND and/or MCCC Compliance will assist the sponsor-investigator in 
the processing of expedited adverse events and forwarding of suspected 
unexpected serious adverse reactions (SUSARs) to the FDA and IRB. 
Use Mayo Expedited Event Report form 
http://livecycle2.mayo.edu/workspace/?startEndpoint=MC4158-
56/Processes/MC4158-56-Process.MC4158-56 for investigational agents or 
commercial/investigational agents on the same arm.  
For commercial agents (for commercial agent(s) on its own arm):  
Attach the MedWatch 3500A form to the Mayo Expedited Event Report form 
https://www.fda.gov/safety/medical-product-safety-information/forms-reporting-
fda 
Submit to EMD Serono via fax/email to the following: 
Fax No.: +49 6151 72 6914 
Email address: ICSR_CT_GPS@merckgroup.com 
10.43 Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in table10.41 
MUST be immediately reported to the sponsor within the timeframes detailed in 
the corresponding table. This reporting includes, but is not limited to SAEs that 
re-occur again after resolution. 
10.5 
Other Required Reporting 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 

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reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 
Mayo Clinic Cancer Center (MCCC) Institutions: 
If the event meets the criteria for IRB submission as a Reportable 
Event/UPIRTSO, provide the appropriate documentation and use the Mayo 
Clinic Cancer Center Expedited Event Report form 
http://livecycle2.mayo.edu/workspace/?startEndpoint=MC4158-
56/Processes/MC4158-56-Process.MC4158-56, to submit to 
CANCERCROSAFETYIN@mayo.edu. The Mayo Clinic Compliance Unit will 
review and process the submission to the Mayo Clinic IRB and work with the 
IND Coordinator for submission to FDA. 
10.52 Death 
Note: A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below. Attribution to treatment or 
other cause must be provided. 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND requires expedited reporting within 24-
hours. 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND requires expedited 
reporting within 24-hours. 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life.  
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 “Disease 
progression” under the system organ class (SOC) ”General disorders and 
administrative site condition.” Evidence that the death was a manifestation 
of underlying disease (e.g., radiological changes suggesting tumor growth 
or progression: clinical deterioration associated with a disease process) 
should be submitted. 
10.53 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy). A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent under 
an IND will be reported. Three options are available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 

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o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting unless otherwise specified. 
10.55 Pregnancy, Fetal Death, and Death Neonatal  
If a female subject (or female partner of a male subject) taking investigational 
product becomes pregnant, the subject taking should notify the Investigator, and 
the pregnant female should be advised to call her healthcare provider 
immediately. The patient should have appropriate follow-up as deemed necessary 
by her physician. If the baby is born with a birth defect or anomaly, a second 
expedited report is required. 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn 
infant’s parent or legal guardian before any data collection can occur. A consent 
form will need to be submitted to the IRB for these subjects if a pregnancy 
occurs. If informed consent is not obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion, the mother is the patient. In cases 
where the child/fetus experiences a serious adverse event other than fetal death, 
the child/fetus is the patient. 
NOTE: When submitting Mayo Expedited Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation. Include this form: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportFormUpdated.pdf 
10.551 
Pregnancy 
Pregnancy should be reported in an expedited manner as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. Pregnancy should be followed until the outcome is 
known. 
10.552 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 

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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.  
10.6 
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 v5.0 unless alternate grading is indicated in the table 
below: 
CTCAE  
System/Organ/Class 
(SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Blood and lymphatic 
system disorders 
Anemia 
X 
X 
Endocrine disorders 
Hypothyroidism 
X 
 
Gastrointestinal disorders 
# of stools at baseline 
X 
 
 
Diarrhea 
 
X 
Injury, poisoning and 
procedural complications 
Infusion-related reaction 
 
X 
Investigations 
Alanine aminotransferase increased 
X 
X 
 
Aspartate aminotransferase increased 
X 
X 
 
Blood bilirubin in creased 
X 
X 
 
Creatinine increased 
X 
X 
Skin and subcutaneous 
Purpura 
X 
X 
tissue disorders 
Rash maculopapular 
X 
X 
10.62 All other AEs 
Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.621 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.623 Grade 5 AEs (Deaths) 
10.6231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
10.6232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 

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treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
10.7 
Late Occurring Adverse Events 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
10.8 
EMD Serono Additional Event Reporting Instructions 
The exchange of AEs between the sponsor and EMD Serono will be outlined in the ISS 
agreement. 
 
 

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11.0 
Treatment Evaluation/Measurement of Effect  
NOTE: This study uses protocol irRECIST for measurement of treatment effect. 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 immune related Response Evaluation Criteria in Solid Tumors (irRECIST) 
guidelines. 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 irRECIST 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 or progressive disease. 
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 
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. 
11.3 
Guidelines for Evaluation of Measurable Disease 
11.31 Measurement Methods: 
• 
All measurements should be recorded in metric notation (i.e., decimal 

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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). 
• 
In case of progressive disease (PD), confirmatory scan must be obtained at 
least 4 weeks following initial documentation of PD. In case confirmatory 
scan shows progression, first scan date should be used as the date of 
progression. 
• 
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate between 
response or stable disease (an effusion may be a side effect of the treatment) 
and progressive disease. 
• 
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.) 

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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. 
11.42 Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease (Section 11.22) are classified as non- 
targetlesions 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 
Measurement 
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. 

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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 (irCR): 
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 (irPR): 
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). 
Progressive Disease (irPD): 
At least a 20% increase 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 MSD 
(Section 11.41). In addition, the PBSD 
must also demonstrate an absolute 
increase of at least 0.5 cm from the 
MSD. 
Death or immunotherapy 
discontinuation due to clinical 
progression is considered as 
confirmation of progression 
Stable Disease (irSD): 
Neither sufficient shrinkage to qualify 
for PR, nor sufficient increase to qualify 
for PD taking as reference the MSD. 
New Lesion: 
The presence of a new lesion does not 
define progression. The measurements 
of the new lesion(s) are included in the 
sum of all measurements. 
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. 

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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.)  
c. See Section 11.32 for details in 
regards to the requirements for PD 
via FDG-PET imaging. 
12.0 
Descriptive Factors  
12.1 
Smoking status: Current vs Past vs Never 
12.2 
Diagnosis: Squamous cell carcinoma vs non-squamous cell carcinoma 
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, up to 2 years. 
13.2 
Progressive disease (PD) 
Patients on docetaxel alone who develop PD while receiving therapy may crossover to 
treatment with bintrafusp alfa, if they meet eligibility criteria, otherwise they will go off 
protocol treatment and go to the event monitoring phase per Section 4.0. 
Patients who develop PD while receiving bintrafusp alfa therapy alone will go to the 
survival follow-up/event monitoring phase. 
13.3 
Off protocol treatment 
Patients in the docetaxel alone arm who go off protocol treatment for reasons other than 
PD will be monitored on study every 6 weeks for disease progression, and may be offered 
crossover to the treatment arm at the time of PD.  
NOTE: If the patient does not meet eligibility for crossover or does not go to crossover 
treatment for other reasons, they will go off protocol treatment and go to event 
monitoring. These patients should be treated with alternative chemotherapy (off protocol) 
if their clinical status is good enough to allow further therapy. 
Patients in the combination arm who go off protocol treatment for reasons other than PD 
will go to the event-monitoring phase per Section 4.0. 
Patients in either group who start non-protocol anti-cancer treatment will be considered 
“off protocol treatment” and go to event monitoring. 

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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. 
13.5 
Non-CNS PD  
Patients in the combination arm who develop non-CNS PD at any time should go to event 
monitoring. These patients should be treated with alternative chemotherapy (off protocol) 
if their clinical status is good enough to allow further therapy.  
Patients in the docetaxel alone arm who develop non-CNS PD at any time may be 
eligible for crossover to treatment arm per physician discretion.  
NOTE: If the patient does not meet eligibility for crossover or does not go to crossover 
treatment for other reasons, they will go off protocol treatment and go to event 
monitoring. These patients should be treated with alternative chemotherapy (off protocol) 
if their clinical status is good enough to allow further therapy. 
13.6 
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. If 
the patient received treatment, the patient may continue treatment at the discretion of the 
physician as long as there are not safety concerns. The patient will continue in the Active 
Monitoring/Treatment phase of the study, as per section 4.0 of the protocol.  
• 
If the patient never received treatment, on-study material must be submitted.  
13.7 
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. If the patient received treatment, the patient may continue treatment at 
the discretion of the physician as long as there are not safety concerns. The patient will 
continue in the Active Monitoring/Treatment phase of the study, as per section 4.0 of the 
protocol. 
13.8 
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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14.0 
Body Fluid Biospecimens 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this Protocol 
Research  
(Section for more 
information) 
Specimen 
Purpose  
(check all that 
apply) 
Mandatory 
or Optional 
Blood or 
Body Fluid 
being 
Collected 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Baseline 
(≥2 hours 
prior to tx 
on C1D1) 
End of 
Cycles 2 
and 415 
End of 
treatment 
for any 
reason16 
Process 
at site? 
(Yes or 
No) 
Temperature 
Conditions 
for Storage 
/Shipping 
Immune profiling ☒ Correlative Mandatory 
PBMC 
Heparin 
(green) 
10 mL 
X 
X 
X 
No 
Ship 
refrigerated 
Circulating tumor 
DNA (ctDNA) 
☒ Correlative Mandatory 
Whole 
blood 
Streck 
10 mL 
(2) 
X 
X 
X 
No 
Ship ambient 
Banking: DNA, 
plasma, buffy coat 
☒ Banking Mandatory 
Whole 
blood 
K2 EDTA 
10 mL 
(1) 
X 
 
 
No 
Ship 
refrigerated 
PBMC= peripheral blood mononuclear cells 
 
 
 
 
15 Samples should be obtained at time of imaging at end of Cycle 2, then end of Cycle 4. 
16 End of docetaxel (prior to crossover) for patients on docetaxel alone; or end of all study treatment for patients on combination 

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14.2 
Collection and Processing  
14.21 Sample collection should be restricted to Monday – Thursday. However, if the 
subject can only be seen on a Friday, please contact the Biospecimen Resource 
Manager for additional instructions (see protocol resource pages for contact 
information). 
14.22 Specimen tube(s) must be labeled with the protocol number, study patient ID 
number, and the time and date of the blood draw. 
14.23  Blood/blood products must be collected and shipped according to specific 
instructions provided in the kit and the table above. 
14.21 Immune profiling 
Using the kit provided by BAP, AZ and FL sites will ship whole blood 
refrigerated overnight to BAP at Mayo Clinic in Rochester, MN for future 
processing in the Immune Monitoring Core. 
14.22 Banking 
Using the kit provided by BAP, AZ and FL sites will ship whole blood ambient 
overnight to Mayo Clinic in Rochester, MN. 
Send to: 
BAP Freezer 
Stabile SL-39 
150 Third Street SW 
Rochester, MN 55902 
Phone: 507/538-0602 
14.3 
Shipping and Handling 
14.31 Kits will be used for this study for sites outside of Rochester, MN. 
14.311 
Kits will be supplied by the Biospecimen Accessioning and Processing 
Shared Resource (BAP).  
14.312 
The kit contains supplies and instructions for collecting, processing 
and shipping specimens. 
14.313 
Participating institutions may obtain kits by faxing the Supply Order 
Form to the number listed on the form. Because we are charged for all 
outgoing kits, a small, but sufficient, supply of the specimen collection 
kits should be ordered prior to patient entry. Supply Order Forms 
must be filled in completely and legibly for quick processing. 
14.314 
Kits will be sent via Fed Ex Ground at no additional cost to the 
participating institutions. Allow at least two weeks to receive the kits. 
14.315 
Kits will not be sent via rush delivery service unless the participating 
institution provides their own Fed Ex account number or alternate 
billing number for express mail. Cost for rush delivery of kits will 
not be covered by the study. 
14.316 
All specimens must be collected and shipped Monday – Thursday 
ONLY. 

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14.32 Shipping Specimens 
14.321 
Mayo Clinic Rochester samples will be routed through BAP for lab 
pickup. 
14.322 
All other sites will use kits as described in Section 14.31, shipped to 
BAP Mayo Clinic in Rochester 
14.33 Verify that ALL sections of the Blood Specimen Submission Form (see Forms 
Packet), BAP Requisition Form (provided in kit), and specimen collection labels 
are completed and filled in correctly. Enter information from the Blood Specimen 
Submission Form into the remote data entry system within 7 days after specimen 
collection (see Forms Packet). 
14.34 Specimens collected in the Streck cfDNA tubes should be shipped at ambient 
temperature on the same day they are drawn. 
14.35 Samples should be shipped to BAP Freezer Mondays – Thursdays (with arrival 
Tue-Fri) according to kit instructions. Samples should not be sent on weekends 
or just prior to federal holidays. (If samples can only be shipped on Fridays, 
please contact the Biospecimen Resource Manager for additional instructions.) 
14.36 Handling Specimens (once received in destination laboratory) 
NOTE: BAP Shared Resource will process the specimens including prepping 
PBMCs for immune profiling (Immune Monitoring Core – Jolaine Hines/Kevin 
Pavelko PhD) 
14.361 
PBMC Handling and Isolation 
Patient donors will provide 10 mL of whole blood drawn into a green 
top heparin tube. The whole blood sample will be layered over Ficoll-
Paque for enrichment of peripheral blood mononuclear cells (PBMC). 
After centrifugation of the sample at 1500g, the enriched PBMC cells 
are washed with RPMI media. After washing with PBS cells are 
counted and prepared for cryopreservation. Cells are resuspended in 
cryopreservation media (10% DMSO in RPMI supplemented with fetal 
bovine serum and a penicillin streptomycin glutamine cocktail). 
Controlled rate freezing methods are then used to freeze the samples 
prior to storage in liquid nitrogen. 
14.362 
Sample Thawing and Preparation for Mass Cytometry 
Cells will be thawed and resuspended in complete media (RPMI 
supplemented with fetal bovine serum) containing 2.5 units/mL of 
Benzonase Nuclease (Sigma-Aldrich). After washing, cells are rested 
for 1 hour in complete media at 37°C before staining. After resting 
4x106 cells are resuspended in 1 mL of CSB. FcR-block will be added 
to block non-specific staining due to Fc receptor antibody interactions. 
Each sample will then be incubated for 5 minutes with 0.5 μm 
Cisplatin solution in PBS. Cells are then transferred to the 5 mL tubes 
containing the dry antibody pellet cocktail (Table 1). Samples are then 
incubated at room temperature for 30 minutes. After washing twice 
with CSB, samples are then fixed with 2% PFA in PBS. After fixation 
and wash, samples are resuspended in 30 nM intercalation solution and 
incubated overnight at 4°C. On the following morning cells are washed 
with PBS and pooled prior to resuspension in a 1:10 solution of 

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calibration beads and cell acquisition solution at a concentration of 
0.5x106 cells/mL. Prior to data acquisition samples were filtered 
through a 35 μm blue cap tube (Falcon).  
14.363 
Mass Cytometry and Data Acquisition 
The prepared samples are loaded onto a Helios CyTOF® system 
(Fluidigm) using an attached autosampler and cellular events are 
acquired at a rate of 200-400 events per second. Data are collected as 
.FCS files using the Cytof software (Version 6.7.1014). After 
acquisition intrafile signal drift is normalized to the acquired 
calibration bead signal using the Cytof software. File cleanup and 
analysis will be performed using the Pathsetter software (Verity 
Software House) cleanup protocol.  
14.37 Double spun, platelet poor plasma will be derived from the Streck cfDNA BCT 
tubes using established laboratory processes, and stored at ≤-65ºC by BAP. 
14.38 For banking: DNA will be extracted from whole blood, and white blood cells and 
plasma will be derived from remaining blood from the EDTA tubes, divided into 
aliquots, and stored at ≤-65ºC by BAP according to patient consent information. 
14.39a As part of ongoing research at the Mayo Clinic, we will retain residual whole 
blood, white blood cells, CTCs, DNA, and plasma for future research studies, 
according to patient consent information. Samples will be stored until specific 
analyses are identified and may be used for exploratory biomarker analyses, 
validation studies, or potential diagnostic development. As protocols are 
developed, they will be presented for IRB review and approval. 
14.4 
Background and Methodology 
Each potential biomarker (ctDNA amounts, tumor mutation profile and TMB) will be 
evaluated versus the observed clinical responses. 
14.41 Immune Profiling 
14.411 
Mass Cytometry (CyTOF) 
Maxpar ® Direct Immune Profiling System provides a comprehensive 
evaluation and analysis tool for assessing the abundance and 
phenotypic characteristics of peripheral mononuclear cells (PBMC). 
This system is designed using industry-proven antibody clones that can 
analyze 37 immune cell types from PBMC or whole blood with an 
optimized 30-marker panel (see table in appendix II) 
Whole blood (10 ml) is collected in a heparinized green top tube. 
PBMC are isolated from whole blood samples using Ficoll-Hypaque at 
the Biospecimens Accessioning and Processing laboratory (BAP) prior 
to cryopreservation. Cryopreserved samples are sent in batches to the 
Mayo Clinic Immune Monitoring Core for analysis by mass cytometry. 
A concentration of 6 X 107 viable cells/mL is prepared from the 
cryopreserved sample in Maxpar Cell Staining Buffer (Fluidigm). Fc 
receptors are blocked by adding Human TruStain FcX (BioLegend) to 
4X10 ^6 cells in 50 µL followed by incubation for 10 minutes at room 
temperature. PBMC are added directly to the ready to assay tubes 
containing 30 lyophilized metal-conjugated antibodies. After a 45-
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paraformaldehyde. The fixed cells are spun to a pellet, fixative is 
removed, followed by resuspension in 1 mL of the 125 nM cell-ID 
Intercalator-Ir (Fluidigm) and incubated overnight at 4°C. Following 
the overnight incubation, PBMC are resuspended in MaxPar Cell 
Acquisition Solution (Fluidigm) at 0.5x10 ^6 cells/mL with 0.1X 
EQ™ Four Element Calibration Beads (Fluidigm). 300,000 events are 
acquired per sample at an acquisition rate of 250–500 events/second 
using the Fluidigm Helios mass cytometry platform. Data will be 
normalized for intra-sample signal drift using EQ™ Four Element 
Calibration Beads as a calibrator with the CyTOF Software v.6.7.1016. 
FCS files generated by the Helios are analyzed by Maxpar Pathsetter, 
an automated analysis system based on GemStoneTM 2.0.41 (Verity 
Software House, Topsham, ME). The results are reported as numbers 
of cells exhibiting distinct phenotypes. See Appendix II.  
14.412 
Tumor mutation profile and tumor mutation burden (TMB) 
Samples will be tested for TMB status in plasma as well as level of 
ctDNA in plasma to evaluate the correlation with clinical outcome. 
 
 

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15.0 
Drug Information 
15.1 
Bintrafusp Alfa (M7824, MSB0011359C)  
15.11 Background 
Bintrafusp alfa is an innovative first-in-class bifunctional fusion protein 
composed of the extracellular domain of the human transforming growth factor β 
receptor II (TGFβRII or TGFβ Trap) covalently linked via a flexible linker to the 
C-terminus of each heavy chain of an immunoglobulin (IgG1) antibody blocking 
programmed death-ligand 1 (anti-PD-L1). 
15.12 Formulation 
Bintrafusp alfa drug product is provided as a sterile liquid formulation. 
The bintrafusp alfa concentrate for solution for infusion (liquid formulation) is 
packaged at a 10 mg/mL concentration in USP / Ph. Eur. Type I 50R or 20R vials 
which are filled with drug product solution to allow an extractable volume of 60 
mL (600 mg/60 mL) or 20 mL (200mg/20mL)  
15.13 Preparation, Storage, and Stability 
Bintrafusp alfa must be stored at 2°C to 8°C until use. The storage condition is 
based on data from ongoing long-term stability studies. 
For the preparation of bintrafusp alfa, use the following supplies: 
Ancillary supplies 
Item 
Acronym of approved materials 
IV bags 
Main material: PE, PP, EVA, LDPE bags that are 
DEHP free and latex free 
Infusion set 
PUR, PVC, PP, PS, LDPE, PC, PB 
Port 
Titanium 
Catheter 
PUR, PVC, PP, PS, LDPE, PB 
Adaptor 
PUR, PVC, PP, PS, LDPE, silicone 
Filter 
Membrane material: PES, PSU, Nylon 
Tubing and connections: PUR, PVC, PP,PS, LDPE 
Needle 
Steel, preferably 18G needles 
Syringe 
PP 
PE = Polyethylene, PP=Polypropylene, EVA=Ethylene Vinyl Acetate, 
LDPE=Low Density Poly Ethylene, DEHP = Di(2-ethylhexyl)phthalate, 
PUR=Polyurethane, PVC=Polyvinylchloride, PS=Polystyrene, 
PC=Polycarbonate, PB=Polybutadiene 
Allow each vial to equilibrate to room temperature (15-25°C) for a minimum of 
30 minutes; and may be used up to 24 hours after equilibration start. A vial that is 
removed from the refrigerator for equilibration at room temperature may not be 
stored again at 2-8°C for re-use.  
Gently invert the bintrafusp alfa vial(s) several times before use. Do not shake or 
agitate vigorously. Remove the desired volume of bintrafusp alfa, preferably with 
a 18G needle, and dilute in 0.9% sodium chloride to a total volume of 250 mL or 
500 mL in an empty viaflex bag. The final concentration must be 0.5 mg/mL to 
9.6 mg/mL. Gently invert the prepared IV bag 10 times to mix. Do not shake or 

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agitate the final preparation vigorously. Prime the tubing with and 0.2 micron 
PES-inline filter with bintrafusp alfa.  
The prepared bintrafusp alfa infusion should be kept at room temperature (15-
25°C) and used immediately after preparation. In case the prepared infusion 
cannot be administered immediately after preparation, the acceptable holding 
time is: no more than 4 hours at room temperature (15-25°C) under aseptic 
conditions, including infusion time, or no more than 72 hours under refrigerated 
conditions (2-8°C), including infusion time. Do not freeze or shake the diluted 
solution. No other drugs should be added to the infusion containers containing 
bintrafusp alfa. 
15.14 Administration 
Administer over 60 minutes -10/+20 minutes by intravenous infusion with a 
0.2 micron PES-inline filter. A constant infusion rate is achieved by using a 
microprocessor-controlled infusion pump.  
It is recommended (but not mandatory) that immediately following the bintrafusp 
alfa infusion, using the same tubing, 25-100 mL normal saline are flushed and 
infused at the same rate to clear the infusion set of residual drug. 
15.15 Pharmacokinetic information 
The PK profile of bintrafusp alfa is in general typical for a human antibody, with 
a low clearance and volume of distribution. Its apparent elimination t1/2 is 
approximately 7 days, which is shorter than that for a typical human antibody. 
The mean volume of distribution at steady state (Vss) was calculated to be 
3.72 L. No time-dependent changes in clearance were observed for any tumor 
type in the population. Based on the PK profile after the first dose of bintrafusp 
alfa evaluated by NCA , bintrafusp alfa exposures (Cmax, AUC, and Ctrough) 
increased in approximately dose-proportional manner at doses >3 mg/kg.  
15.16 Potential drug interactions 
Bintrafusp alfa is not expected to have DDI potential because it is primarily 
metabolized through catabolic pathways, does not cause significant cytokine 
modulation in vivo or systemic inflammation based on available cytokine data, 
and does not cause modulation (increase) of 4β-hydroxycholesterol (an 
endogenous marker of CYP3A4/5 activity) levels based on available exploratory 
analyses. The expected low risk of DDI for bintrafusp alfa is consistent with lack 
of reported DDI risk for other anti-TGFβ or anti-PD-L1 antibodies or targeted 
inhibitors that are in clinical development. Therefore, a dedicated DDI study to 
investigate the in vivo effects of bintrafusp alfa is not planned. Additionally, 
preliminary analysis of QT data from 19 participants from study EMR200647-
001 dose escalation cohorts up to a dose of bintrafusp alfa 20 mg/kg and a 
nonclinical safety study revealed no identified proarrhythmic risk. 
15.17 Known potential adverse events 
Most Common Treatment Emergent Adverse Events (TEAEs) by 
System/Organ/Class (SOC) and Preferred Term (PT) (≥10% of participants) 
Blood and lymphatic system disorders: 
Anaemia 
Gastrointestinal disorders:  
Constipation 

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Nausea 
Abdominal pain 
Diarrhoea 
Vomiting 
General disorders and administration site conditions 
Fatigue 
Pyrexia 
Asthenia 
Oedema peripheral 
Investigations 
Aspartate aminotransferase increased 
Metabolism and nutrition disorders 
Decreased appetite 
Nervous system disorders 
Headache 
Respiratory, thoracic and mediastinal disorders 
Dyspnoea 
Cough 
Epistaxis 
Skin and subcutaneous tissue disorders 
Pruritus 
Rash 
Most Common Treatment-Related TEAEs by SOC and PT (≥5% of 
participants) 
Blood and lymphatic system disorders 
Anaemia 
Endocrine disorders 
Hypothyroidism 
Gastrointestinal disorders 
Diarrhoea 
Nausea 
General disorders and administration site conditions 
Asthenia 
Fatigue 
Metabolism and nutrition disorders 
Decreased appetite 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
Keratoacanthoma 
Skin and subcutaneous tissue disorders 
Pruritus 
Rash maculo-papular 
Rash 
15.18 Drug procurement 
EMD Serono Research and Development Institute, Inc. will supply the bintrafusp 
alfa to each enrolling site. 

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15.19 Nursing guidelines 
15.191 
Infusion must include a 0.2 micron PES- inline filter and after infusion, 
line must be flushed with 25-100 ml of NS to finish clearing the line. 
15.192 
Monitor LFTs. 
15.193 
Patients may experience gastrointestinal side effects including but not 
limited to: constipation, diarrhea, and nausea. Treat symptomatically 
and monitor for effectiveness. 
15.194 
Pancreatic enzyme elevations have been noted. Monitor patients for 
signs of pancreatitis, including but not limited to: postprandial pain, 
generalized abdominal pain, steatorrhea, nausea, and vomiting. Instruct 
patient to report these to the study team immediately. 
15.195 
Rash has been reported and is generally maculo-papular in nature. 
15.196 
Monitor electrolytes, as hyponatremia, and hypokalemia have been 
reported.  
 
 

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15.2 
Docetaxel (Taxotere®, TATER) Commercial Supply 
15.21 Background 
Antineoplastic Agent, Antimicrotubular, Taxane derivative. Docetaxel promotes 
the assembly of microtubules from tubulin dimers, and inhibits the 
depolymerization of tubulin which stabilizes microtubules in the cell. This results 
in inhibition of DNA, RNA, and protein synthesis. Most activity occurs during 
the M phase of the cell cycle. 
15.22 Formulation 
Docetaxel is now available as a one-vial formulation in two concentrations: 
10 mg/mL and 20 mg/mL. The older formulation included 2 vials which 
consisted of a concentrated docetaxel vial and a diluent vial, resulting in a 
reconstituted concentration of 10 mg/mL. Admixture errors could occur due to 
the concentration difference between the new formulations of 10 mg/mL and 20 
mg/mL and the old formulation (10 mg/mL). Do not use the two-vial formulation 
with the one-vial formulation for the same admixture product. 
15.23 Preparation, storage, and stability 
Storage conditions: Store the packaged docetaxel between 2 and 25°C (36 and 
77°F). Retain in the original package to protect from bright light. Freezing does 
not adversely affect the product. 
One-vial formulation: Note: One-vial formulation is available in two 
concentrations: 10 mg/mL and 20 mg/mL. Further reconstitution with diluent is 
not required. Further dilute for infusion in 250-500 mL of NS or D5W in a non-
DEHP container (e.g., glass, polypropylene, polyolefin) to a final concentration 
of 0.3-0.74 mg/mL. Gently rotate to mix thoroughly. Solutions prepared from the 
one-vial formulation and diluted for infusion should be used within 4 hours of 
preparation (infusion should be completed within 4 hours). 
15.24 Administration 
Administer IV infusion over 1-hour through nonsorbing polyethylene lined (non-
DEHP) tubing; in-line filter is not necessary. Note: Premedication with 
dexamethasone 8 – 10 mg orally twice daily for 3-5 days, beginning the day 
before docetaxel administration is recommended to decrease the incidence and 
severity of fluid retention and prevent hypersensitivity reactions and 
pulmonary/peripheral edema. When administered as sequential infusions, taxane 
derivatives should be administered before platinum derivatives (cisplatin, 
carboplatin) to limit myelosuppression and to enhance efficacy. Infusion should 
be completed within 4 hours of final preparation. 
15.25 Pharmacokinetic information 
Docetaxel exhibits linear pharmacokinetics at the recommended dosage range. 
Distribution: Extensive extravascular distribution and/or tissue binding; Vd: 80-
90 L/m2, Vdss: 113 L (mean steady state) 
Protein binding: ~94% to 97% 
Metabolism: Hepatic; oxidation via CYP3A4 to metabolites 
Half-life elimination: Terminal: ~11 hours 
Excretion: Feces (~75%, <8% as unchanged drug); Urine (~6%)  

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15.26 Potential Drug Interactions 
Cytochrome P450 Effect: Substrate (major) of CYP3A4; Inhibits CYP3A4 
(weak).  
Increased Effect/Toxicity: CYP3A4 inhibitors may increase the levels/effects of 
docetaxel. Concomitant use of docetaxel with a potent CYP3A4 inhibitor 
should be avoided. If systemic administration of a potent CYP3A4 
inhibitor cannot be avoided, a 50% reduction in docetaxel dose should be 
considered along with close monitoring for docetaxel toxicity. Refer to 
the package insert or LexiComp1 for example inhibitors. When 
administered as sequential infusions, observational studies indicate a 
potential for increased toxicity when platinum derivatives (carboplatin, 
cisplatin) are administered before taxane derivatives (docetaxel, 
paclitaxel). Taxane derivatives may enhance the adverse/toxic effect of 
anthracyclines. 
Decreased Effect: CYP3A4 inducers may decrease the levels/effects of 
paclitaxel. Refer to the package insert or LexiComp1 for example 
inducers. 
Ethanol/Herb/Nutraceutical Interactions: Avoid ethanol (due to GI irritation). 
Avoid St John’s wort (may decrease docetaxel levels).  
Immunosuppressants: (ex: denosumab, pimecrolimus, tacrolimus, etc.) 
docetaxel may enhance the adverse/toxic effect of immunosuppressants 
(risk for serious infections may increase) 
Myleosuppressived Agents: increased risk of agranulocytosis and/or 
pancytopenia (ex: clozapine, dipyrone) 
BCG: Immunosuppressants may diminish the therapeutic effect of BCG 
Treatment with Docetaxel Products May Cause Symptoms of Alcohol 
Intoxication June 2014  
The FDA is warning health care providers and patients that docetaxel injection 
products contain ethanol, which may cause patients to experience symptoms of 
alcohol intoxication during and after treatment. The FDA is revising the labels of 
all docetaxel drug products to warn about this risk. Health care providers should 
consider the alcohol content of docetaxel products when prescribing or 
administering the drug to patients, particularly in those whom alcohol intake 
should be avoided or minimized and when using it in conjunction with other 
medications.Patients should avoid driving, operating machinery, or performing 
other activities that are dangerous for one to two hours after docetaxel infusion. 
15.27 Known potential adverse events 
Consult the package insert for the most current and complete information. 
Percentages reported for docetaxel Monotherapy; frequency may vary depending 
on diagnosis, dose, liver function, prior treatment, and premedication. The 
incidence of adverse events was usually higher in patients with elevated liver 
function tests. 
Common known potential adverse events, >10%: 
Cardiovascular: Fluid retention 
Central nervous system: Neurosensory events including neuropathy, fever, 
neuromotor events. 
Dermatologic: Alopecia, cutaneous events, nail disorder 

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Gastrointestinal: Stomatitis, diarrhea, nausea, vomiting 
Hematologic: Neutropenia, leukopenia, anemia, thrombocytopenia, febrile 
neutropenia 
Hepatic: Transaminases increased 
Neuromuscular & skeletal: Weakness, myalgia 
Respiratory: Pulmonary events 
Miscellaneous: Infection, hypersensitivity 
Less common known potential adverse events, 1% - 10%:  
Cardiovascular: Left ventricular ejection fraction decreased, hypotension 
Central nervous system: Peripheral motor neuropathy 
Dermatologic: Rash/erythema 
Gastrointestinal: Taste perversion 
Hepatic: Bilirubin increased, alkaline phosphatase increased 
Local: Infusion-site reactions including hyperpigmentation, inflammation, 
redness, dryness, phlebitis, extravasation, swelling of the vein 
Neuromuscular and skeletal: Arthralgia 
Ocular: Epiphora associated with canalicular stenosis 
Rare known potential adverse events, <1% (Limited to important or life-
threatening):  
Acute myeloid leukemia, acute respiratory distress syndrome, anaphylactic 
shock, angina, ascites, atrial fibrillation, atrial flutter, bleeding episodes, 
bronchospasm, cardiac tamponade, chest pain, chest tightness, colitis, 
conjunctivitis, constipation, cutaneous lupus erythematosus, deep vein 
thrombosis, dehydration, disseminated intravascular coagulation, drug fever, 
duodenal ulcer, Dyspnea, dysrhythmia, ECG abnormalities, erythema 
multiforme, esophagitis, gastrointestinal hemorrhage, gastrointestinal 
obstruction, gastrointestinal perforation, hand and foot syndrome, hearing loss, 
heart failure, hepatitis, hypertension, ileus, intestinal pneumonia, ischemic colitis, 
lacrimal duct obstruction, loss of consciousness (transient), MI, multiorgan 
failure, Myelodysplastic syndrome, neutropenic enterocolitis, ototoxicity, pleural 
effusion, pruritus, pulmonary edema, pulmonary embolism, pulmonary fibrosis, 
radiation pneumonitis, radiation recall, renal insufficiency, seizure, sepsis, sinus 
tachycardia, Stevens-Johnson syndrome, syncope, toxic epidermal necrolysis, 
tachycardia, thrombophlebitis, unstable angina, visual disturbances (transient) 
15.28 Drug procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal 
commercial supply chain or wholesaler. 
15.29 Nursing Guidelines 
15.291 
Monitor CBC closely, as neutropenia, and thrombocytopenia are 
common and may be life threatening, and dose limiting. Instruct 
patient to report any signs or symptoms of infection, any unusual 
bruising, or bleeding.  
15.292 
Administer antiemetics as ordered. Evaluate for their effectiveness. 
15.293 
Monitor for signs/symptoms of hypersensitivity reactions that may 
include chills, rigors, dyspnea, bronchospasms, etc. Stop infusion 
immediately and administer proper emergency treatment. 

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15.294 
Because of the risk of anaphylaxis and development of edema, instruct 
patient that is imperative to take steroid premedications as ordered.  
15,295 
Instruct patient on proper oral care, as mucositis may occur. 
15.296 
Advise patient about alopecia. 
15.297 
Monitor liver function tests. 
15.298 
Drug is a vesicant. Monitor infusion site frequently for signs of 
irritation or infiltration. Drug extravasation causes acute streaking, 
burning pain, and discoloration at the site. Skin may be reddened for 
several weeks and occasionally blister and/or peel. Reactions are 
usually reversible over time. Because of this central venous access may 
be necessary. Discuss with MD if patient has poor peripheral venous 
access. If docetaxel concentrate or diluted solution comes into contact 
with skin, wash with soapy water immediately. If it comes into contact 
with mucosa, wash with warm water immediately. 
15.299a Instruct patient to report any signs of peripheral neuropathy to the 
health care team (pain, numbness, tingling). 
15.299b Monitor for signs and symptoms of fluid retention, weight gain, ascites 
and CHF. 
15.299c Instruct patient about possible facial flushing, rash, and skin and nail 
changes. Monitor for signs and symptoms of hand/foot syndrome. 
However premedication with steroids can minimize this side effect. 
Discuss with MD possible ways to manage itching and skin changes 
that may occur up to a week after docetaxel administration. Advise 
patients that nails may crack, peel, or fall off all together. This may be 
a chronic toxicity. Instruct patient to keep nails clean, short and to 
avoid wearing nail polish or artificial nails. 
15.299d In case of overdose, patient should be hospitalized and vital signs 
monitored. Patient should receive therapeutic G-CSF ASAP after 
discovery of the overdose. 
 

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16.0 
Statistical Considerations and Methodology  
16.1 
Primary Endpoint and Analysis 
This randomized Phase II trial will compare the progression-free survival (PFS) of 
bintrafusp alfa in combination with docetaxel vs. docetaxel alone in patients with 
advanced NSCLC in the 2nd line setting. Prior studies have shown that the median PFS is 
generally around 3.8 months for docetaxel alone (Horn L, 2017). It is hoped that the 
combination of bintrafusp alfa and docetaxel can increase the median PFS rate to at least 
7.3 months, which corresponds to a hazard ratio of around 0.52 for comparing PFS 
between the arms. Prior phase I data suggests that the experimental arm can reach a 
median PFS of around 7.3 months (ongoing phase I study [EMR200647-
001; https://clinicaltrials.gov/ct2/show/NCT02517398] demonstrated a median PFS of 
6.8 months for bintrafusp alfa, where the bintrafusp alfa dose was only half the dose that 
will be used in this study). In addition to PFS, this trial will also compare the overall 
survival (OS), confirmed response rates, duration of response, and adverse event rates 
between the treatment arms. In addition, exploratory translational studies will be done as 
well.  
The primary endpoint for this study will compare PFS between bintrafusp alfa combined 
with docetaxel vs. docetaxel alone in patients with advanced NSCLC. PFS is defined as 
the time from randomization to the first of either disease progression or death from any 
cause, where disease progression will be determined based on irRECIST criteria and will 
be documented at each enrolling site with no central review planned.  
16.11 Final Analysis 
The primary goal is to compare bintrafusp alfa plus docetaxel vs. docetaxel 
alone, where the alternative hypothesis is that bintrafusp alfa combined with 
docetaxel has improved PFS compared to docetaxel alone. We will enter 33 
evaluable patients to each arm of the study using a 1:1 randomization scheme (66 
evaluable patients in total), unless the study is stopped early at the time of the 
interim futility analysis (see below). The null hypothesis is that the hazard ratio 
(HR) ≥1. The alternative hypothesis is that the HR <1. With 66 evaluable patients 
(33 per arm) and an alpha of 5% (1-sided), we have 80% power to detect a 
hazard ratio of 0.52 or less, assuming an accrual rate of 3 patients per month. The 
primary analysis of PFS will be a comparison of the Kaplan-Meier curves for 
docetaxel + bintrafusp alfa vs. docetaxel alone using a one-sided log-rank test. 
This analysis will take place after an approximate 27 month accrual period, and 
after 60 total events have occurred across both arms combined (which should 
happen after about 12 months of follow-up in all evaluable patients). All patients 
who meet the eligibility criteria, sign the consent form, and are randomized will 
be considered evaluable for this endpoint. To account for possible drop-outs, 
ineligibles, cancellations, etc., we plan to randomize a total of 80 patients (40 
per arm). Cross-over to bintrafusp alfa will be allowed after progression or 
intolerable effects on docetaxel alone treatment arm. (Patients already on 
bintrafusp alfa, will be allowed to continue.) 
16.12 Interim Futility Analysis 
The interim futility analysis will happen after 30 events are observed across both 
arms combined. The interim futility boundary was selected using EAST software. 
We selected a Rho family "Beta" spending function with rho parameter "equal" 
2.42. To reject the alternative hypothesis at the interim analysis (i.e., reject 

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docetaxel + bintrafusp alfa as promising), the HR will need to be >1 for 
docetaxel + bintrafusp alfa vs. docetaxel alone, which corresponds to a 1-sided p-
value greater than 0.50. If the HR is less than or equal to 1 (1-sided p <=0.50), 
the study will continue to full accrual and the final analysis will be conducted as 
discussed above.  
16.2 
Secondary Endpoints and Analysis 
The following endpoints will be compared between the two arms: overall survival (OS), 
confirmed response rates, duration of response, and adverse event rates.  
16.21 Overall Survival 
Overall survival (OS) is defined as the time from study entry to death from any 
cause. OS will be estimated using the Kaplan-Meier method, where the log-rank 
test will be used to compare the 2 treatment arms. 
16.22 Confirmed Response Rate 
A patient will be classified as a confirmed response per the irRECIST criteria, if 
they have a partial or complete response for 2 consecutive evaluations at least 
4 weeks apart. The proportion of patients with a confirmed response will be 
calculated and compared between the 2 arms using a Chi-square or Fisher’s 
Exact test. 
16.23 Duration of Response 
The duration of confirmed responses will be assessed using the Kaplan-Meier 
method, where the duration of confirmed response will be defined as the time 
from the first documented date of response (CR or PR) to the date at which 
progression is first documented. Duration of response will be estimated using the 
Kaplan-Meier method, where the log-rank test will be used to compare the 
2 treatment arms. 
16.24 Adverse events 
The maximum grade for each type of adverse event will be summarized using 
CTCAE version 5.0. The frequency and percentage of Grade 3+ adverse events 
will be compared between the 2 treatment arms. Comparisons between arms will 
be made by using either the Chi-square or Fisher’s Exact test.  
16.25 Crossover patients exploratory analysis 
In the crossover group that receives bintrafusp alfa alone after disease 
progression on docetaxel alone, we will assess both the response rate and 
progression-free survival as an exploratory analysis. 
16.3 
Translational endpoints 
The goals of the translational studies are to evaluate PD-L1 and TGFβ as potential 
predictive markers of clinical response in tumor biopsies, to evaluate mutation types and 
numbers (TMB) in plasma or in tumor tissue, assess the association between TMB and 
clinical outcome, and to evaluate genes or gene signatures as a potential predictive 
biomarkers of clinical response in tumor biopsies. Due to the limited sample size, these 
analyses will be hypothesis generating and descriptive in nature. Descriptive statistics 
will be summarized and the blood and tissue marker data will be correlated with clinical 
endpoints (response, duration of response, OS, PFS, etc.). For time-to-event data, the 
Kaplan-Meier method, log-rank tests, and Cox proportional hazards models will be used. 

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For categorical data, we’ll use the Fisher’s exact or Chi-square test. For marker data used 
to predict binary outcomes (i.e. response vs. no response), we’ll use Logistic regression 
models. 
16.4 
Total Sample Size and study duration 
A maximum of 66 evaluable patients (33 per arm) will be accrued onto this randomized 
phase II study unless the study is closed early for excessive toxicity or lack of efficacy. 
To account for possible drop-outs, ineligibles, cancellations, etc., we plan to randomize a 
total of 80 patients (40 per arm). The expected accrual rate is about 3 patients per month. 
With this accrual rate, we expect to finish accrual within about 27 months, assuming we 
accrue 80 total patients. We anticipate that the study will take approximately 42 months 
to complete. This allows a 12-month follow-up for the final patient enrolled, along with 
data entry, data clean-up, and analysis.  
16.5 
Data & Safety Monitoring 
16.51 Safety review 
The principal investigator(s) and the study statistician will review the study 
monthly 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 biannually, based on reports provided by the MCCC Statistical Office. 
16.52 Adverse Event Stopping Rules  
The stopping rule specified below is 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. Accrual may be temporarily suspended 
to this study if at any time we observe events considered at least possibly related 
to study treatment (ie, an adverse event with attribute specified as “possible”, 
“probable”, or “definite”) that satisfy the following in each arm separately: 
 
If 4 or more of the first 10 patients (or 40% or more of all patients after 
10 are accrued) experience a Grade 4 non-laboratory AE.  
 
If 2 or more experience a Grade 5 AE at any time. 
After consideration by the study team (study chair, statistician, etc.), a decision 
will be made as to whether accrual can be resumed. 
16.6 
Subset Analyses for Minorities 
16.61 Study availability 
This study will be available to all eligible patients, regardless of gender, race or 
ethnic origin.  
16.62 Statistical analysis by subset 
There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analyses will 

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look for differences in treatment effect based on racial groupings, the sample size 
is not increased in order to provide additional power for subset analyses.  
16.63 Regional population 
The geographical region served by MCCC has a population which includes 
approximately 3% minorities. 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 
3 
3 
6 
Not Hispanic or Latino 
37 
37 
74 
Ethnic Category: Total of all subjects 
40 
40 
80 
Racial Category 
American Indian or Alaskan Native 
1 
0 
1 
Asian 
0 
1 
1 
Black or African American 
1 
1 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
38 
38 
76 
Racial Category: Total of all subjects 
40 
40 
80 
 
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. 
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 
East, or North Africa. 

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17.0  
Pathology Considerations/Tissue Biospecimens 
17.1  
Summary Table of Research Tissue Specimens to be Collected for this Protocol 
Research Study 
(Section for more 
information) 
Specimen 
Purpose 
(check all that 
apply) 
Mandatory 
or 
Optional 
Type of 
Tissue to 
Collect 
Block, Slides, 
Core, etc.  
(# of each to 
submit) 
Baseline – 
after 
Registration 
and prior to 
treatment 
on C1D117 
End of 
Cycle 1 
Prior to 
Cycle 218 
Process at 
site?  
(Yes or 
No) 
Temperature 
Conditions for 
Storage 
/Shipping 
PD-L1 
☒ Correlative 
Mandatory 
FFPE 
1 cores 
X 
X 
No 
Ambient 
DNA seq (TMB) 
☒ Correlative 
Mandatory 
FFPE 
10 slides 
X 
X 
No 
Ambient 
RNA seq (TGFβ) 
☒ Correlative Mandatory 
FFPE 
2 cores 
X 
X 
No 
Ambient 
Future research  
☒ Banking 
Mandatory 
FFPE 
1 core 
X 
X 
No 
Ambient 
 
 
 
 
17 Baseline samples must be from fresh biopsy. If biopsy is attempted and tissue is not obtained the patient is still eligible. 
18 Mandatory fresh biopsy required at end of Cycle 1, prior to treatment on Cycle 2, Day 1. 

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17.2 
Diagnostic Slides from Original and /or Recurrent Tissue 
If fresh biopsy tissue is not available after biopsy is attempted (per Section 17.311 
below), study pathologist will request blocks from Tissue Registry to determine best 
option for study use. Pathologist will request a minimum of 4 slides including one H&E 
cut at 4 microns. These slides will be used for PD-L1, and, if sufficient tissue is available, 
RNA and/or DNA sequencing per Section 17.1. 
17.3 
Correlative Tissue Collection 
17.31 Biopsies for research tissue collection 
NOTE: Consultation with Interventional Radiology is required prior to 
scheduling lung biopsy (not needed for liver, lymph node, or abdominal/ 
retroperitoneal) 
17.311 
Baseline biopsy 
Fresh biopsy is mandatory at Baseline (prior to treatment on Cycle 1, 
Day 1). If biopsy is attempted and tissue is not obtained for any reason, 
the patient is still eligible provided previously obtained tissue is 
available. 
If fresh biopsy at baseline is unsuccessful, tumor samples obtained by 
endoscopic biopsies, core needle biopsies, excisional biopsies, punch 
biopsies, and surgical specimens that are <6 months old and adequate 
for biomarker analysis are mandatory to evaluate the association of 
PD-L1 protein expression as well as other immune or tumor cell 
markers with the observed clinical responses. Biopsies obtained by fine 
needle aspiration are not acceptable.  
17.312 
Biopsy at End of Cycle 1 (prior to C2D1) 
Fresh biopsies are mandatory prior to Cycle 2, Day 1, unless deemed 
unfeasible by the investigator or interventional radiologist. 
17.31 Tissue kits will not be provided for this protocol. 
17.32 Paraffin Embedded Tissue 
17.321 
Rochester 
Tissue sections can be picked up from Interventional Radiology by the 
study coordinator for routing. 
Coordinator will route tissue samples for formalin fixing/paraffin 
embedding (block creation and one H&E per block).  
Once blocks and slides are created, coordinator will route to Study 
Pathologist (Dr Anja Roden) for review with MC1821 Tissue 
Specimen Submission Form so all blocks can be noted on form. 
Once pathologist has reviewed blocks/slides can be sent to the 
Pathology Coordinator Office at NW Clinic via General Service. 
Be sure to include the pathology report and the completed MC1821 
Specimen Submission Tissue Form with patient ID/protocol #, 
collection date, tissue submitted, and a contact person for questions 

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17.322 
Arizona and Florida 
FFPE blocks will be created at the time of the research biopsy with one 
block per core and one H&E per block. 
AZ and FL will ship FFPE tissue blocks with accompanying H&E to 
Rochester, MN, at the address below and include the completed 
MC1821 Specimen Submission Tissue Form with patient ID/protocol 
#, collection date, list of tissue blocks submitted, and a contact person 
for questions.  
NOTE: Please include room temperature cool pack if weather 
conditions are hot in either shipping or receiving location. 
Send blocks/slides and forms to: 
Pathology Coordinators Operations Office 
Attn: PC office (Amanda Sand/MC 1821) 
RO-FF-3-24-CC/NW Clinic 
200 First Street SW 
Rochester, MN 55905 
Telephone: 507/284-3559 
17.323 
Pathology Coordinator in Rochester will accession. 
17.324 
All tissue will be stored in Rochester until the end of the study. 
17.33 Frozen Tissue - NONE 
17.4 
Background and Methodology 
17.41 PD-L1 
PD-L1 will be processed through Mayo Clinical Laboratory in Rochester, MN 
using best available clone at the time the assay is being run. Current expectation 
is to use 22C3. 
17.43 DNA sequencing (TMB) 
At the end of the study, tissue samples will be processed for DNA seq per best 
available methods at that time. 
17.42 RNA sequencing (TGFβ) 
At the end of the study, tissue samples will be processed for RNA seq per best 
available methods at that time 
17.44 Banking for future research 
As part of ongoing research at the Mayo Clinic, we will retain tissue for future 
research studies, according to patient consent information. Samples will be stored 
until specific analyses are identified and may be used for exploratory biomarker 
analyses, validation studies, or potential diagnostic development. As protocols 
are developed, they will be presented for IRB review and approval. 
 
 

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18.0 
Records and Data Collection Procedures  
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission Schedule. 
18.2 
Survival Follow-up 
See Section 4.  
18.3 
CRF completion 
This study will use Medidata Rave® for remote data capture (rdc) of all study data. Data 
collection for this study will be done exclusively through the Medidata Rave® clinical 
data management system. Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support 
System (RSS). To access Rave via iMedidata, the site user must have an active account 
and the appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on the 
organization roster at the enrolling site. 
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 diagnosis and progression prior to 
study entry as well as for evidence of response to study therapy and progression after 
study therapy. These documents should be submitted within 14 days of registration (for 
prior to study entry materials) or within 14 days after the visit at which response or 
progression is determined. 
18.6 
Overdue lists 
A list of overdue forms and outstanding queries will be available in Rave through the 
Rave Task Summary. In addition to this, the Overdue Materials report is available on the 
Cancer Center Systems homepage. 
19.0  
Budget 
19.1 
Costs charged to patient 
Routine clinical care including the cost of docetaxel and its administration. 
19.2 
Tests to be research funded 
Research testing on blood and tissue specimens 
Research biopsy prior to treatment and at end of Cycle 1 (prior to Cycle 2, Day 1) 
19.3 
Other budget concerns: 
EMD-Serono will provide Mayo Clinic with funding to support the costs of running this 
study. 
EMD-Serono will provide study drug, bintrafusp alfa, for use in this study 

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20.0 
References 
EMD Serono Research and Development Institute Inc. (2019, April 10). M7824 Investigator's 
Brochure. Version 5.0. Billerica, MA, USA: EMD Serono Research and Development 
Institute Inc. 
Fossella FV, D. R. (2000). Randomized phase III trial of docetaxel versus vinorelbine or 
ifosfamide in patients with advanced non-small-cell lung cancer previously treated with 
platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung 
Cancer Study Group. J Clin Oncol, Jun; 18(12): 2354-62. 
Gandhi L, R.-A. D. (2018 May 31). Pembrolizumab plus Chemotherapy in Metastatic Non-
Small-Cell Lung Cancer. NEJM, 378 (22): 2078-2092. 
Horn L, S. D. (2017). Nivolumab Versus Docetaxel in Previously Treated Patients With 
Advanced Non-Small-Cell Lung Cancer: Two-Year Outcomes From Two Randomized, 
Open-Label, Phase III Trials (CheckMate 017 and CheckMate 057)[J]. Journal of 
Clinical Oncology, JCO2017743062. 
Molina JR, Y. P. (2008). Non-small cell lung cancer: epidemiology, risk factors, treatment, and 
survivorship. Mayo Clin Proc, 83 (5): 584-94. 
Paz-Ares L, L. A. (2018 Nov 22). Pembrolizumab plus Chemotherapy for Squamous Non-Small-
Cell Lung Cancer. NEJM, 379 (21): 2040-2051. 
Reck M, R.-A. D. (2016 Nov 10). Pembrolizumab versus Chemotherapy for PD-L1-Positive 
Non-Small-Cell Lung Cancer. NEJM, 375 (19): 1823-1833. 
Seidel JA, O. A. (2018). Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of 
Action, Efficacy, and Limitations. Front Oncol, Mar 28; 8: 86. 
Shepherd FA, D. J. (2000). Prospective randomized trial of docetaxel versus best supportive care 
in patients with non-small-cell lung cancer previously treated with platinum-based 
chemotherapy. J Clin Oncol, May; 18 (10): 2095-103. 
Xiao D, H. J. (2010). Epithelial mesenchymal transition and lung cancer. J Thorac Dis, Sep; 2 
(3): 154-9. 
 
 

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Appendix I 
ECOG Performance Status 
 
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 II 
Peripheral Blood Mononuclear Cells (PBMC) Panel for Cytof Analysis 
Mayo Immune Monitoring Core, Guggenheim 5-27 
No.  Species 
Clone 
Metal 
Target 
1 
Human 
HI30 
089Y 
CD45 
2 
Human 
G034E3 
141Pr 
CD196/CCR6 
3 
Human 
6H6 
143Nd 
CD123/IL-3R 
4 
Human 
HIB19 
144Nd 
CD19 
5 
Human 
RPA-T8 
145Nd 
CD4 
6 
Human 
RPA-T8 
146Nd 
CD8a 
7 
Human 
Bu15 
147Sm 
CD11c 
8 
Human 
3G8 
148Nd 
CD16 
9 
Human 
UCHL1 
149Sm 
CD45RO 
10 
Human 
HI100 
150Nd 
CD45RA 
11 
Human 
HP_3G10 
151Eu 
CD161 
12 
Human 
L291H4 
152Sm 
CD194/CCR4 
13 
Human 
BC96 
153Eu 
CD25/IL-2R 
14 
Human 
O323 
154Sm 
CD27 
15 
Human 
HCD57 
155Gd 
CD57 
16 
Human 
G025H7 
156Gd 
CD183/CXCR3 
17 
Human 
J252D4 
158Gd 
CD185/CXCR5 
18 
Human 
CD28.2 
160Gd 
CD28 
19 
Human 
HB-7 
161Dy 
CD38 
20 
Human 
NCAM16.2 163Dy 
CD56/NCAM 
21 
Human 
B1 
164Dy 
TCRgd 
22 
Human 
BM16 
166Er 
CD294 
23 
Human 
G043H7 
167Er 
CD197/CCR7 
24 
Human 
63D3 
168Er 
CD14 
25 
Human 
UCHT1 
170Er 
CD3 
26 
Human 
2H7 
171Yb 
CD20 
27 
Human 
G10F5 
172Yb 
CD66b 
28 
Human 
LN3 
173Yb 
HLA-DR 
29 
Human 
IA6-2 
174Yb 
IgD 
30 
Human 
A019D5 
176Yb 
CD127/IL-7Ra