Clinical trial NCT03713944
Conditions: NSCLC Stage IV NSCLC, Recurrent
Sponsor: Nasser Hanna
Start date: 2018-11-15; Completion date: 2021-12-16
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multicenter single arm phase II clinical trial. All eligible patients will receive:

Carboplatin (AUC 5) i.v. day 1 plus pemetrexed (500 mg/m2) i.v. day 1 plus atezolizumab 1200 mg i.v. day 1 plus bevacizumab 15 mg/kg i.v. day 1 every 3 weeks for up to 4 cycles.

Patients with non-PD after 4 cycles will be permitted to continue with maintenance therapy with pemetrexed plus atezolizumab plus bevacizumab every 3 weeks until the time of disease progression or intolerable toxicities.

Detailed description:
The hypothesis of this study is that the addition of Atezolizumab (an anti-PD-L1 antibody), to the combination of Carboplatin plus Pemetrexed plus Bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, for the treatment of patients with stage IV non-squamous, non-small cell lung cancer (NSCLC) will improve progression free survival (PFS) compared with a historical control of carboplatin plus pemetrexed plus bevacizumab.

Arms: arm 1: Carboplatin (AUC 5) i.v. day 1 plus pemetrexed (500 mg/m2) i.v. day 1 plus atezolizumab 1200 mg i.v. day 1 plus bevacizumab 15 mg/kg i.v. day 1 every 3 weeks for up to 4 cycles.

Patients with non-PD after 4 cycles will be permitted to continue with maintenance therapy with pemetrexed plus atezolizumab plus bevacizumab every 3 weeks until the time of disease progression or intolerable toxicities.
Interventions: intervention 1: Carboplatin intervention 2: Pemetrexed intervention 3: Atezolizumab intervention 4: Bevacizumab
Intervention descriptions: intervention 1: Carboplatin, AUC 5 intervention 2: Pemetrexed 500mg/m2 intervention 3: Atezolizumab 1200mg intervention 4: Bevacizumab 15mg/kg

Protocol documents:
Prot_SAP_000.pdf: 
  
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
 
A phase II study of Carboplatin plus Pemetrexed plus Atezolizumab plus Bevacizumab in chemotherapy 
and immunotherapy-naïve patients with stage IV non-squamous non-small cell lung cancer: 
Big Ten Cancer Research Consortium BTCRC-LUN17-139 
 
 
Sponsor Investigator 
Nasser Hanna, MD 
Indiana University Melvin and Bren Simon Cancer Center 
 
 
Co-Investigators 
Lawrence Einhorn, MD 
Shadia Jalal, MD 
Gregory Durm, MD 
 
 
Statistician 
Hao Liu, PhD 
 
 
Trial Management 
Big Ten CRC Administrative Headquarters at Hoosier Cancer Research Network, Inc. 
500 N. Meridian, Suite 100 
Indianapolis, IN 46204 
 
 
Trial Support 
Genentech 
(RO-IIS-2017-10459) 
 
 
Investigational New Drug (IND) Number: 
140077 
 
 
Protocol Version Date: 16OCT2018 
 
 
Amendment Version Date:  
29MAR2019  
07APR2020 (current) 
 


Big Ten Cancer Research Consortium 
  
 
 Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 2 of 77 
PROTOCOL SIGNATURE PAGE 
 
A phase II study of Carboplatin plus Pemetrexed plus Atezolizumab plus Bevacizumab in chemotherapy 
and immunotherapy-naïve patients with stage IV non-squamous non-small cell lung cancer 
 
 
 
VERSION DATE:  07APR2020 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and to the 
ethical principles stated in the latest version of the Declaration of Helsinki, the applicable guidelines for 
good clinical practices, whichever provides the greater protection of the individual.  I will accept the 
monitor’s overseeing of the study.  I will promptly submit the protocol to applicable ethical review 
board(s). 
 
 
 
 
____________________________________ 
________________________ 
 Signature of Site Investigator 
 
 
  
 Date 
 
 
____________________________________ 
 Site Investigator Name (printed) 
 
 
____________________________________ 
 Site Investigator Title 
 
 
____________________________________ 
 Name of Facility 
 
 
____________________________________ 
 Location of Facility (City and State) 
 
 
 
PLEASE EMAIL COMPLETED FORM TO  
BIG TEN CRC ADMINISTRATIVE HEADQUARTERS 
 
 
 


Big Ten Cancer Research Consortium 
  
 
 Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 3 of 77 
SYNOPSIS 
TITLE 
A phase II study of Carboplatin plus Pemetrexed plus Atezolizumab plus 
Bevacizumab in chemotherapy and immunotherapy-naïve patients with 
stage IV non-squamous non-small cell lung cancer 
PHASE  
Phase II 
OBJECTIVES 
Primary Objective: 
To estimate the progression free survival (PFS) of the combination of 
Carboplatin plus Pemetrexed plus Atezolizumab plus Bevacizumab for 
patients with stage IV non-squamous NSCLC who are chemotherapy and 
immunotherapy naïve.  
 Progression free survival (PFS) defined as the time from the initiation 
of treatment to the time when the criteria for disease progression is met 
as defined by RECIST v1.1 or death of any cause. 
 1 year PFS will be estimated. 
 
Secondary Objectives: 
1) To estimate the overall response rate (CR + PR), as well as the disease 
control rate (CR + PR + SD) of carboplatin plus pemetrexed plus 
atezolizumab plus bevacizumab in immunotherapy and chemotherapy-
naïve patients with stage IV non-squamous non-small cell lung cancer.  
 Overall Response rate will include confirmed complete response (CR) 
+ confirmed partial response (PR), as determined as per RECIST v1.1 
criteria and assessed by the local investigator or designee. 
 disease control rate will include complete response (CR], partial 
response (PR), and stable disease (SD), as per RECIST v1.1 criteria. 
2) To estimate the overall survival (OS) of carboplatin plus pemetrexed 
plus atezolizumab plus bevacizumab in immunotherapy and 
chemotherapy-naïve patients with stage IV non-squamous non-small cell 
lung cancer. 
3) To characterize the toxicity of carboplatin plus pemetrexed plus 
atezolizumab plus bevacizumab in immunotherapy and chemotherapy-
naïve patients with stage IV non-squamous non-small cell lung cancer 
 Toxicity as defined by the NCI Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v5. 
Tertiary Objectives: 
To characterize the association of tissue and blood markers with efficacy 
and toxicity.  These may include genomic, proteomic, methalomic, and 
immune markers 
STUDY DESIGN 
This is a multicenter single arm phase II clinical trial. All eligible patients 
will receive: 
Carboplatin (AUC 5) i.v. day 1 plus pemetrexed (500 mg/m2) i.v. day 1 
plus atezolizumab 1200 mg i.v. day 1 plus bevacizumab 15 mg/kg i.v. day 
1 every 3 weeks for up to 4 cycles. 
Patients with non-PD after 4 cycles will be permitted to continue with 
maintenance therapy with pemetrexed plus atezolizumab plus 


Big Ten Cancer Research Consortium 
  
 
 Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 4 of 77 
bevacizumab every 3 weeks until the time of disease progression or 
intolerable toxicities. 
KEY ELIGIBILITY 
CRITERIA 
 Age ≥ 18 years at the time of consent. 
 ECOG Performance Status of 0-1 within 21 days prior to registration. 
 Histological or cytological confirmation of non-squamous cell non-
small cell lung cancer 
 Patients with known EGFR mutations, BRAF mutations, ALK 
translocations or ROS1 translocations are eligible once they have 
received approved molecularly targeted therapy. A 1-week washout 
prior to enrollment is strongly encouraged (3 weeks preferred). 
 Must have PD-L1 IHC results available using the Dako 22C3 antibody 
OR must have at least 5 unstained slides to perform PD-L1 testing 
(results not required for eligibility). If tissue is not available, subjects 
may choose to have a standard of care biopsy to meet eligibility. 
 Measurable disease according to RECIST v1.1 criteria within 21 days 
prior to registration with either PET/CT scan, CT scan of chest and 
abdomen, or CT chest including upper abdomen and adrenal glands 
which define stage IV disease. 
 Patients who had disease progression greater than 1 year after 
completing prior adjuvant therapy for stage I – III are eligible as long 
as no systemic therapy was given at time of recurrence.  
 No prior immunotherapy or antiangiogenic therapy.  Prior platinum or 
pemetrexed are permissible if previously given in the adjuvant setting 
for stage I-III disease and disease recurrence is > 1 year from 
completion of treatment.   
 If subject received major surgery or radiation therapy of > 30 Gy, they 
must have recovered from the toxicity and/or complications from the 
intervention. 
 A subject with CNS disease may be considered if they have completed 
their treatment for brain metastasis at least 2 weeks prior to study 
registration, have been off corticosteroids for ≥ 2 weeks, and are 
asymptomatic. Asymptomatic patients with CNS metastases newly 
detected at screening are eligible for the study after receiving 
radiotherapy or surgery, with no need to repeat the screening brain 
scan, if other specified eligibility criteria for CNS disease are met. 
 Demonstrate adequate organ function as defined in the body of the 
protocol.
STATISTICAL 
CONSIDERATIONS 
The study will evaluate whether carboplatin plus pemetrexed plus 
atezolizumab plus bevacizumab will improve the PFS compared to the 
PFS of carboplatin plus pemetrexed plus bevacizumab as reported in the 
literature. According to the current knowledge as reported in the literature, 
the median PFS for patients treated with carboplatin plus pemetrexed plus 
bevacizumab is approximately 6 months. We hypothesize that carboplatin 
plus pemetrexed plus atezolizumab plus bevacizumab will improve the 
median PFS to 9.6 months. 
 


Big Ten Cancer Research Consortium 
  
 
 Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 5 of 77 
The total study duration is 30 months, where the accrual period for the 
trial is 18 months and each patient will have a pre-scheduled follow-up of 
12 months except for reason due to death. The test statistic is the 
nonparametric one-sample log-rank test [28]. The sample size calculation 
was based on the assumptions of uniform accrual over time, no loss to 
follow-up, exponentially distributed PFS times. A sample size of 42 
would detect the hypothesized PFS difference with an 87% power with 1-
sided type I error of 0.05. To ensure the power of study, the study would 
require at least 42 patients to complete the 1-year follow-up or until death. 
Suppose a rate of loss to follow-up of 5%. Then we anticipate recruiting 
46 patients. If all 46 patients finish their pre-scheduled follow-up, then the 
power of the study is 90%. We thus propose a total sample size of 46. 
 
Because of the short accrual period (1 year), no interim analysis is 
planned to avoid the interruption of the study flow.  
TOTAL NUMBER OF 
SUBJECTS 
N= 46 
ESTIMATED 
ENROLLMENT 
PERIOD 
18 months 
ESTIMATED STUDY 
DURATION  
30 months 
 
 


Big Ten Cancer Research Consortium 
  
 
 Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 6 of 77 
TABLE OF CONTENTS 
Schema ........................................................................................................................................................ 8 
1. 
Background and Rationale .................................................................................................................. 9 
1.1 
Non-Small Cell Lung Cancer...................................................................................................... 9 
1.2 
Squamous cell and non-squamous cell histology of NSCLC ..................................................... 9 
1.3 
Cisplatin + Pemetrexed ............................................................................................................... 9 
1.4 
Maintenance Pemetrexed .......................................................................................................... 10 
1.5 
Addition of VEGF inhibitor bevacizumab to chemotherapy .................................................... 10 
1.6 
Carboplatin plus pemetrexed plus bevacizumab ....................................................................... 10 
1.7 
Carboplatin plus pemetrexed plus immunotherapy for NSCLC ............................................... 10 
1.8 
VEGF inhibitors combined with PD-L1 inhibitors ................................................................... 11 
1.9 
Carboplatin plus paclitaxel plus atezolizumab or bevacizumab for metastatic NSCLC .......... 11 
1.10 
Rationale ................................................................................................................................... 12 
2. 
Study Objectives ............................................................................................................................... 12 
2.1 
Objectives ................................................................................................................................. 12 
3. 
Eligibility Criteria ............................................................................................................................. 13 
3.1 
Inclusion Criteria ...................................................................................................................... 13 
3.2 
Exclusion Criteria ..................................................................................................................... 15 
4. 
Subject Registration .......................................................................................................................... 19 
5. 
Treatment Plan .................................................................................................................................. 19 
5.1 
Initial therapy: Cycles 1-4 ......................................................................................................... 19 
5.2 
Maintenance Therapy: Cycle 5+ ............................................................................................... 19 
5.3 
Pre-medication and Hydration .................................................................................................. 19 
5.4 
Study Drug Administration: Initial Therapy ............................................................................. 20 
5.5 
Study Drug Administration: Maintenance Therapy .................................................................. 20 
5.6 
Concomitant Medications ......................................................................................................... 21 
5.7 
Atezolizumab Related Assessment of Safety ........................................................................... 22 
6. 
Toxicities and Dose Delays/Dose Modifications .............................................................................. 24 
6.1 
Dose Delays/Dose Modifications ............................................................................................. 24 
6.2 
Dose Levels for Dose Reductions ............................................................................................. 24 
6.3 
Bevacizumab ............................................................................................................................. 25 
6.4 
Atezolizumab Dose Modifications ........................................................................................... 26 
6.5 
Pemetrexed and Carboplatin Dose Modifications .................................................................... 27 
6.6 
Dose modifications for hematologic toxicities ......................................................................... 27 
6.7 
Dose Modifications for Renal Toxicity .................................................................................... 28 
6.8 
Dose reductions for Hepatic Toxicity ....................................................................................... 28 
6.9 
Dose Modifications for sensory peripheral neuropathy toxicity ............................................... 28 
6.10 
Protocol Therapy Discontinuation ............................................................................................ 29 
6.11 
Protocol Discontinuation .......................................................................................................... 29 
7. 
Study Calendar & Evaluations .......................................................................................................... 30 
7.1 
Safety Follow-up Evaluations ................................................................................................... 32 
7.2 
Long Term Follow-up Evaluations ........................................................................................... 32 
8. 
Biospecimen Studies and Procedures ............................................................................................... 32 
8.1 
Source and Timing of Biospecimen Collections ...................................................................... 32 
8.2 
Banking of Leftover Biospecimens .......................................................................................... 34 
8.3 
Banking Samples for Future Unspecified Research ................................................................. 34 
8.4 
Confidentiality of Biospecimens ............................................................................................... 34 


Big Ten Cancer Research Consortium 
  
 
 Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 7 of 77 
9. 
Criteria for Disease Evaluation ......................................................................................................... 34 
9.1 
Measurable Disease .................................................................................................................. 34 
9.2 
Non-measurable Lesions ........................................................................................................... 35 
9.3 
Target Lesions ........................................................................................................................... 35 
9.4 
Non-target Lesions .................................................................................................................... 35 
9.5 
Evaluation of Target Lesions .................................................................................................... 35 
9.6 
Evaluation of Non-target Lesions ............................................................................................. 36 
9.7 
Evaluation of Best Overall Response ....................................................................................... 36 
9.8 
Definitions for Response Evaluation – RECIST v1.1 .............................................................. 37 
10. 
Drug Information .......................................................................................................................... 38 
10.1 
Carboplatin ................................................................................................................................ 38 
10.2 
Pemetrexed ................................................................................................................................ 39 
10.3 
Atezolizumab ............................................................................................................................ 40 
10.4 
Bevacizumab ............................................................................................................................. 42 
11. 
Adverse Events ............................................................................................................................. 46 
11.1 
Definitions................................................................................................................................. 46 
11.2 
Adverse Events Recording ........................................................................................................ 50 
11.3 
Serious Adverse Event (SAEs) Reporting ................................................................................ 51 
12. 
Statistical Considerations .............................................................................................................. 53 
12.1 
Study Design ............................................................................................................................. 53 
12.2 
Endpoints .................................................................................................................................. 53 
12.3 
Sample Size and Accrual .......................................................................................................... 54 
12.4 
Analysis Datasets ...................................................................................................................... 54 
12.5 
Assessment of Safety ................................................................................................................ 55 
12.6 
Assessment of Efficacy ............................................................................................................. 55 
12.7 
Data Analysis Plans .................................................................................................................. 55 
12.8 
Interim Analysis/Criteria for Stopping Study ........................................................................... 55 
13. 
Trial Management ......................................................................................................................... 56 
13.1 
Data and Safety Monitoring Plan (DSMP) ............................................................................... 56 
13.2 
IUSCC Data Safety Monitoring Committee and Protocol Progress Committee ...................... 56 
13.3 
Data Quality Oversight Activities ............................................................................................. 57 
13.4 
Compliance with Trial Registration and Results Posting Requirements .................................. 57 
14. 
Data Handling and Record Keeping ............................................................................................. 58 
14.1 
Data Management ..................................................................................................................... 58 
14.2 
Case Report Forms and Submission ......................................................................................... 58 
14.3 
Record Retention ...................................................................................................................... 58 
14.4 
Confidentiality .......................................................................................................................... 58 
14.5 
Aggregate Reports .................................................................................................................... 59 
14.6 
Study Close-out ......................................................................................................................... 59 
15. 
Ethics............................................................................................................................................. 59 
15.1 
Institutional Review Board (IRB) Approval ............................................................................. 59 
15.2 
Ethical Conduct of the Study .................................................................................................... 59 
15.3 
Informed Consent Process ........................................................................................................ 59 
16. 
References ..................................................................................................................................... 60 
17. 
Appendix I: Anaphylaxis Precautions .......................................................................................... 62 
18. 
Appendix II: Management of Atezolizumab-Specific Adverse Events ........................................ 63 


Big Ten Cancer Research Consortium 
 
 
 Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 8 of 77 
SCHEMA 
 
 
Discontinue treatment 
Patients with metastatic non-squamous non-small cell lung cancer who are 
chemotherapy and immunotherapy-naïve for the treatment of stage IV or recurrent 
disease and are candidates for first-line therapy
Disease assessment every 2 cycles
CR, PR, or SD 
Progression or  
significant toxicity 
Continue treatment  
Discontinue treatment 
Follow for progression and 
survival for at least 1 year  
(± 2 months) from enrollment
Maintenance (Cycle 5+): 
Pemetrexed + Atezolizumab + Bevacizumab 
Progression or  
significant toxicity 
If CR/PR/SD after 4 cycles
Continue treatment every 3 weeks,  
assessment every 2 cycles,  
until disease progression for at least 1 year
Day 1 Cycles 1-4 (Cycle = 21 days) 
Carboplatin AUC 5 
Pemetrexed 500mg/m2 
Atezolizumab 1200mg  
Bevacizumab 15mg/kg 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 9 of 77 
1. 
BACKGROUND AND RATIONALE 
The hypothesis of this study is that the addition of Atezolizumab (an anti-PD-L1 antibody), to the 
combination of Carboplatin plus Pemetrexed plus Bevacizumab, a vascular endothelial growth factor 
(VEGF) inhibitor, for the treatment of patients with stage IV non-squamous, non-small cell lung cancer 
(NSCLC) will improve progression free survival (PFS) compared with a historical control of carboplatin 
plus pemetrexed plus bevacizumab.  
1.1 
Non-Small Cell Lung Cancer 
In 2015, there were about 220,000 new cases of lung cancer expected in the United States, and 
approximately 160,000 deaths. Lung cancer remains the leading cause of cancer death in the United 
States, being responsible for an estimated 27% of all cancer deaths in 2015[1]. The most common type 
of lung cancer is non-squamous non-small-cell lung cancer (NSCLC). At the time of diagnosis most 
patients will have stage IV disease.  The majority of patients treated for earlier stage disease will also 
develop recurrent or metastatic disease [2]. Historically, patients with advanced stage NSCLC have been 
treated with a platinum-based doublet chemotherapy regimen in the first line setting [3]. 
1.2 
Squamous cell and non-squamous cell histology of NSCLC 
The two most common histologies of NSCLC are squamous cell and adenocarcinoma.  Large cell and 
adenocarcinoma are further categorized as non-squamous NSCLC, to distinguish it from squamous cell.  
In recent years multiple studies have demonstrated clear distinctions in biology and subsequently 
therapeutic approaches between stage IV squamous cell and non-squamous cell subtypes. The squamous 
cell subtype is most associated with a smoking history in a dose-dependent manner [4]. Non-squamous 
subtypes, specifically adenocarcinoma, are much more likely than squamous cell lung cancer to harbor 
driver mutations; examples include EGFR, ALK, ROS1, BRAF, MET and KRAS, and many of these 
driver mutations can now be targeted with molecular therapy [5]. There are also distinctions regarding 
therapeutic responses between squamous and non-squamous subtypes of NSCLC. Pemetrexed is an 
antifolate chemotherapy agent which targets thymidylate synthase (TS); as squamous cell cancers 
generally have very high levels of expression of TS, pemetrexed appears less efficacious in this subtype.  
Pemetrexed is only FDA approved to treat patients with non-squamous NSCLC. [6].  In addition, 
Bevacizumab is contraindicated in patients with squamous cell histology because of the increased risk of 
major life-threatening bleeding as demonstrated in a phase II clinical trial of bevacizumab plus 
carboplatin and paclitaxel [7].  Similar to pemetrexed, bevacizumab is also FDA approved to treat only 
patients with non-squamous NSCLC type. 
1.3 
Cisplatin + Pemetrexed 
Up until 2008, the initial treatment of all subtypes of NSCLC consisted of doublet combinations 
including platinum (cisplatin or carboplatin) combined with gemcitabine, vinorelbine, or taxanes 
(paclitaxel or docetaxel). Comparator trials demonstrated similar efficacy among several regimens [3]. A 
study by Scagliotti et al compared cisplatin plus gemcitabine to cisplatin plus pemetrexed in patients 
with advanced NSCLC. Overall survival for cisplatin and pemetrexed was noninferior to cisplatin plus 
gemcitabine; however, a pre-planned subgroup analysis showed a statically superior overall survival for 
the cisplatin/pemetrexed arm in patients with non-squamous NSCLC.  Patients with squamous cell 
histology had numerically better outcomes when randomized to the cisplatin/gemcitabine arm.  This 
phase III study established the important distinction of squamous vs. non-squamous NSCLC when 
making therapeutic decisions. [8].  Furthermore, this study finding resulted in an FDA label change for 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 10 of 77 
pemetrexed to be used in combination with cisplatin in the first-line treatment of advanced and 
metastatic NSCLC for only patients with non-squamous histology.  
1.4 
Maintenance Pemetrexed  
The use of maintenance chemotherapy was not standard until the last several years.  Maintenance 
pemetrexed had also been studied following platinum-based chemotherapy induction for advanced 
NSCLC in patients without disease progression, demonstrating improvement in overall survival and 
progression free survival [9]. The PARAMOUNT trial was a randomized phase III clinical trial 
investigating the effect of maintenance pemetrexed versus placebo after completing induction 
chemotherapy for advanced non-squamous NSCLC with 4 cycles of pemetrexed plus cisplatin. The 
results of this trial showed a significant risk reduction for progression-free survival and overall survival 
favoring maintenance pemetrexed over a placebo group with a hazard ratio (HR) of 0.62 [10]. This trial 
led to the FDA expansion allowing for maintenance pemetrexed after induction chemotherapy for 
patients with advanced non-squamous NSCLC. 
1.5 
Addition of VEGF inhibitor bevacizumab to chemotherapy 
Vascular endothelial growth factor (VEGF) is an endothelial-cell–specific mitogen and has been found 
to be a major regulator of angiogenesis in tumors [11, 12].  Treatment with the VEGF inhibitor, 
bevacizumab, in combination with chemotherapy had shown improved survival when combined with 
standard chemotherapy alone in the treatment of patients with metastatic colon cancer [13].  A phase III 
study investigated the effect of adding Bevacizumab to carboplatin plus paclitaxel in patients with 
advanced non-squamous NSCLC.  Patients treated on the bevacizumab arm experienced improved 
overall survival, progression free survival, and response rate [14].  This study established the 
combination of carboplatin plus paclitaxel plus bevacizumab as a standard treatment for patients with 
advanced non-squamous cell NSCLC.   
1.6 
Carboplatin plus pemetrexed plus bevacizumab 
For patients with advanced non-squamous NSCLC, carboplatin plus pemetrexed had recently been 
established as an option for the initial systemic treatment.  Previously, carboplatin, paclitaxel and 
bevacizumab had already been an established initial treatment[14]. The POINTBREAK study compared 
pemetrexed, carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab to 
paclitaxel, carboplatin, and bevacizumab followed by maintenance bevacizumab. Patients treated on the 
pemetrexed-containing arm experienced prolonged progression free survival but not overall survival 
compared with the paclitaxel containing regimen [15]. This trial established carboplatin, pemetrexed and 
bevacizumab followed by maintenance pemetrexed plus bevacizumab as an acceptable alternative to 
carboplatin, paclitaxel, and bevacizumab followed by maintenance bevacizumab for the treatment of 
patients with advanced non-squamous NSCLC in the first-line setting. 
1.7 
Carboplatin plus pemetrexed plus immunotherapy for NSCLC 
There has been a great deal of interest in recent years in studying how the immune system interacts with 
neoplastic cells. T-cells express a certain regulatory receptor called programmed death 1 receptor (PD-1) 
and this receptor interacts with a ligand (PD-L1 and PD-L2) to downregulate T cell activity [16, 17]. 
Drugs targeting programmed death 1 (PD-1) and its ligand, PD-L1, have demonstrated a manageable 
safety profile and robust efficacy [18]. The KEYNOTE-021 study per Langer et al. analyzed the 
addition of pembrolizumab, an anti- PD-1 monoclonal antibody, to carboplatin plus pemetrexed. [19] 
This randomized phase II trial compared carboplatin plus pemetrexed with maintenance pemetrexed to 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 11 of 77 
carboplatin, pemetrexed and pembrolizumab with maintenance pemetrexed and pembrolizumab in 
patients with advanced, non-squamous cell NSCLC. There was significant improvement in objective 
response in the carboplatin plus pemetrexed plus pembrolizumab group (55%) compared to the 
carboplatin plus pemetrexed alone group (29%).  Progression free survival also favored the 
pembrolizumab group. This trial was the basis for accelerated FDA approval of pembrolizumab 
combined with carboplatin and pemetrexed for previously untreated metastatic non-squamous NSCLC, 
irrespective of PD-L1 level expression in tumor. A phase III trial by Ghandhi et al. reported improved 
OS for patients receiving pembrolizumab plus combination chemotherapy compared with chemotherapy 
alone in patients with metastatic non-squamous NSCLC (1-year OS 69.2% vs. 49.4%).  Survival was 
improved with the addition of pembrolizumab, regardless of PD-L1 status [20]. 
1.8 
VEGF inhibitors combined with PD-L1 inhibitors 
There are no fully-published studies examining the addition of angiogenesis inhibitors with PD-1 or PD-
L1 targeted immunotherapy in patients with lung cancer.  There is a good deal of preclinical data 
suggesting the combination of immunotherapy with antiangiogenic agents may have synergistic effects 
[21]. Proangiogenic factors like VEGF can reduce T-cell infiltration, thereby lessening the immune 
response to cancer. Data from other malignancies reveals the close association with angiogenesis and 
immune response.  In patients with metastatic renal cell carcinoma, measurement of PD-L1 expression 
revealed that a higher level of expression was significantly related to poor response to anti-VEGF 
treatment; this suggests the combination PD-1/PD-L1 blockade could potentially augment therapeutic 
benefit to anti-VEGF therapy [22]. Murine colon adenocarcinoma cancer models evaluating the 
combination of PD-1 and VEGFR2 inhibitors found the two agents induced a synergistic response, with 
significantly inhibited tumor growth; the combination also increased expression of CD4 cell infiltration 
into the tumor bed and elevated levels of tumor necrosis factor [23].  The toxicity profile of carboplatin 
plus pemetrexed plus bevacizumab as well as the combination of carboplatin plus pemetrexed plus 
atezolizumab are well characterized.  Safety data has already been published evaluating the combination 
of the VEGF inhibitor, Ramucirumab, with pembrolizumab in a phase I study of patients with gastric 
adenocarcinoma, NSCLC, or urothelial carcinoma [24]. More recently, a phase II clinical trial in 
metastatic renal cell cancer patients evaluated the combination of the anti-PD-L1 inhibitor atezolizumab 
plus bevacizumab versus and following atezolizumab and sunitinib (a tyrosine kinase inhibitor used in 
first line setting for metastatic renal cell cancer). 101 subjects were in the experimental arm, and safety 
was comparable to the known individual profiles of atezolizumab and bevacizumab; for PD-L1+ 
patients, the PFS hazard ratio was 0.64 for the combination therapy, and this combined therapy is now 
being evaluated in a phase III study [25]. 
1.9 
Carboplatin plus paclitaxel plus atezolizumab or bevacizumab for metastatic NSCLC 
Most recently data from a randomized phase III clinical trial evaluating the role of bevacizumab 
combined with carboplatin plus paclitaxel plus atezolizumab has been reported. This multicenter trial 
randomized patients with advanced non-squamous NSCLC to receive carboplatin plus paclitaxel plus 
atezolizumab versus carboplatin plus paclitaxel plus bevacizumab versus carboplatin plus paclitaxel plus 
atezolizumab plus bevacizumab. Results of this 3-arm phase III trial were recently presented by Reck et 
al at an international meeting. The co-primary objectives were 1. to compare investigator-assessed PFS 
in an ITT population and included the evaluation of T-effector high patients and 2. compare overall 
survival. The carboplatin plus paclitaxel plus bevacizumab arm served as the control. The 4-drug 
regimen of carboplatin plus paclitaxel plus bevacizumab plus atezolizumab resulted in superior PFS 
when compared with the carboplatin plus paclitaxel plus bevacizumab control arm (HR 0.617, 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 12 of 77 
p<0.0001). The 1-year PFS was 37% vs. 18% and median PFS was 11.3 months vs. 6.8 months.  The 
ORR also favored the 4-drug regimen (64%) vs. the control arm (48%).  Preliminary OS also favored 
the 4-drug regimen (HR 0.7, p=0.0262) with a median OS of 19.2 months vs. 14.4 months.  
Furthermore, grade 3/4 toxicities were uncommon with the 4 drug regimen, and comparable to the 
control arm of carboplatin plus paclitaxel plus bevacizumab [26]. 
1.10 
Rationale 
Combination therapy of carboplatin plus pemetrexed plus bevacizumab, or carboplatin plus pemetrexed 
plus pembrolizumab or, carboplatin plus paclitaxel plus atezolizumab plus bevacizumab have 
demonstrated effectiveness in the treatment of patients with non-squamous NSCLC.   The use of 
pemetrexed has several advantages over the use of paclitaxel, namely; pemetrexed can be given as 
maintenance therapy, which is proven to prolong overall survival (paclitaxel can’t be given as 
maintenance due to dose-limiting neurotoxicity); pemetrexed does not require high dose of steroids [that 
may negate the effects of concomitant immunotherapy agents] to prevent major toxicities (paclitaxel 
requires corticosteroids to reduce infusion related reactions); pemetrexed is infused over 10 minutes 
(versus 3 hours for paclitaxel); pemetrexed has a more favorable side effect profile compared with 
paclitaxel. 
 
Based on the landmark trials for treatment of non-squamous NSCLC, and promising recent clinical data 
combining immunotherapy and anti-VEGF therapy, we propose to study the combination of carboplatin 
plus pemetrexed plus atezolizumab plus bevacizumab in chemotherapy and immunotherapy-naïve 
patients with stage IV non-squamous NSCLC.   
2. 
STUDY OBJECTIVES 
2.1 
Objectives 
2.1.1 Primary Objective 
1) To estimate the progression free survival (PFS) of the combination of Carboplatin plus 
Pemetrexed plus Atezolizumab plus Bevacizumab for patients with stage IV non-squamous 
NSCLC who are chemotherapy and immunotherapy naïve.  
 Progression free survival (PFS) defined as the time from the initiation of treatment to the 
time when the criteria for disease progression is met as defined by RECIST v1.1 or death of 
any cause. 
 1-year PFS will be estimated. 
 
2.1.2 Secondary Objectives 
1) To estimate the overall response rate (CR + PR), as well as the disease control rate (CR + PR + 
SD) of carboplatin plus pemetrexed plus atezolizumab plus bevacizumab in immunotherapy and 
chemotherapy-naïve patients with stage IV non-squamous non-small cell lung cancer.  
 Overall Response rate will include confirmed complete response (CR) + confirmed partial 
response (PR), as determined as per RECIST v1.1 criteria and assessed by the local 
investigator or designee. 
 Disease control rate will include complete response (CR], partial response (PR), and stable 
disease (SD), as per RECIST v1.1 criteria. 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 13 of 77 
2) To estimate the overall survival (OS) of carboplatin plus pemetrexed plus atezolizumab plus 
bevacizumab in immunotherapy and chemotherapy-naïve patients with stage IV non-squamous 
non-small cell lung cancer. 
3) To characterize the toxicity of carboplatin plus pemetrexed plus atezolizumab plus bevacizumab 
in immunotherapy and chemotherapy-naïve patients with stage IV non-squamous non-small cell 
lung cancer  
 Toxicity as defined by the NCI Common Terminology Criteria for Adverse Events (NCI 
CTCAE) v5. 
2.1.3 Tertiary, Correlative/Exploratory Objectives 
To characterize the association of tissue and blood markers with efficacy and toxicity.  These MAY 
include genomic, proteomic, methylomic, and immune markers.  This protocol will collect archived 
tissue specimens for future analysis and blood samples at various time points for future analysis.  
These analyses MAY include:  
1) To assess PD-L1 expression levels in the archival tumor samples of subjects and correlate 
with PFS, OS, and treatment toxicity. 
2) To assess associations between cfDNA, DNA, RNA, microRNA, DNA methylation, protein 
expression, immune markers, protein biomarkers, cytokines, and other markers and efficacy 
and toxicity of treatment.   
 
3. 
ELIGIBILITY CRITERIA 
3.1 
Inclusion Criteria 
Subject must meet all the following applicable inclusion criteria to participate in this study: 
 
1. Written informed consent and HIPAA authorization for release of personal health information. 
NOTE:  HIPAA authorization may be included in the informed consent or obtained separately. 
 
2. Age ≥ 18 years at the time of consent. 
 
3. ECOG Performance Status of 0-1 within 21 days prior to registration. 
 
4. Must have life expectancy of > 3 months at time of consent 
 
5. Histological or cytological confirmation of non-squamous NSCLC. 
 
6. Must have known PD-L1 status using the Dako 22C3 antibody (+ vs. -) OR must have at least 5 
unstained slides to perform PD-L1 testing (results not required for eligibility). PD-L1 positive is 
defined as a tumor proportion score (TPS) ≥ 1%. PD-L1 negative is defined as a TPS <1%. If 
tissue is not available, subjects may choose to have a standard of care biopsy to meet eligibility. 
 
7. Patients with known targetable mutations in EGFR or BRAF or known translocations in ALK or 
ROS1 are eligible if they have received FDA approved targeted therapy first. A 1-week washout 
prior to enrollment is strongly encouraged (3 weeks preferred).  
 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 14 of 77 
8. Stage IV disease or recurrent disease 
 
9. Measurable disease according to RECIST v1.1 criteria within 21 days prior to registration with 
either PET/CT scan, CT scan of chest and abdomen, or CT chest including upper abdomen and 
adrenal glands which define stage IV disease. 
 
10. Patients who had disease progression greater than 1 year after completing prior adjuvant therapy 
for stage I – III are eligible as long as no systemic therapy was given for recurrence.  
 
11. No prior immunotherapy or antiangiogenic therapy. 
 
12. Prior platinum therapy or pemetrexed are permissible if previously given in the adjuvant setting 
for stage I-III disease and disease recurrence is > 1 year from completion of therapy. 
 
13. If subject received major surgery or radiation therapy of > 30 Gy, they must have recovered from 
the toxicity and/or complications from the intervention.  
 
14. Demonstrate adequate organ function as defined in the table below; all screening labs to be 
obtained within 21 days prior to registration. 
 
System 
Laboratory Value 
Hematological 
Absolute Neutrophil Count (ANC)
≥ 1.5 K/mm3 
Hemoglobin (Hgb) 
≥ 9 g/dL
Platelets 
≥ 100 K/mm3
Renal 
Serum creatinine: 
Calculated creatinine clearance:
≤1.5 × upper limit of normal (ULN) OR 
≥ 40 cc/min using the Cockcroft-Gault formula 
Hepatic 
Bilirubin 
≤1.5 × upper limit of normal (ULN) 
Aspartate aminotransferase (AST) 
≤ 1.5 × ULN or < 5x ULN if the transferase 
elevation was due to liver metastases 
Alanine aminotransferase (ALT) 
≤ 1.5 × ULN or <5x ULN if the transferase 
elevation was due to liver metastases 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
Activated Partial Thromboplastin Time 
(aPTT) 
≤ 1.5 × ULN (unless subjects is receiving 
anticoagulant therapy, as long as PT or PTT is 
within therapeutic range of intended use of 
anticoagulants) 
 
15. Females of childbearing potential must have a negative serum pregnancy test within 7 days prior 
to registration. NOTE: A woman is considered to be of childbearing potential if she is 
postmenarcheal, has not reached a postmenopausal state (> 12 continuous months of amenorrhea 
with no identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
 
16. For women of childbearing potential:  agreement to remain abstinent (refrain from heterosexual 
intercourse) or use two non-hormonal methods of contraception, including at least one method 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 15 of 77 
with a failure rate of < 1% per year, during the treatment period and for 5 months after the last 
dose of atezolizumab or 120 days after the last dose of any study drug, whichever is later; 
examples of non-hormonal contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices. Must use “estrogen-free” 
hormonal method if this is chosen contraception method. 
A barrier method may be used as the second contraceptive method. The reliability of sexual 
abstinence should be evaluated in relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
or postovulation methods) and withdrawal are not acceptable methods of contraception. 
 
17. Contraception method must begin starting from the time of informed consent until 120 days after 
treatment discontinuation.  
 
18. For men:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below: 
 With female partners of childbearing potential or pregnant female partners, men must remain 
abstinent or use a condom during the treatment period and for 120 days after the last dose of 
study treatment to avoid exposing the embryo.  Men must refrain from donating sperm 
during this same period. 
 The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception. 
 
19. As determined by the enrolling physician or protocol designee, ability of the subject to 
understand and comply with study procedures for the entire length of the study 
 
3.2 
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
 
1. Active infection requiring systemic therapy 
 
2. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother 
is being treated on study). 
 
3. Active secondary cancers. 
 
4. Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases. 
Brain imaging with either MRI or CT with contrast must be performed on all subjects at 
screening to evaluate for the presence of brain metastases. Patients with a history of treated 
CNS lesions are eligible, provided that all of the following criteria are met: 
 Measurable disease, per RECIST v1.1, must be present outside the CNS. 
 The patient has no history of intracranial hemorrhage or spinal cord hemorrhage. 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 16 of 77 
 Metastases are limited to the cerebellum or the supratentorial region (i.e., no metastases to 
the midbrain, pons, medulla, or spinal cord). 
 The patient has not received stereotactic radiotherapy within 14 days prior to initiation of 
study treatment or whole-brain radiotherapy within 21 days prior to initiation of study 
treatment 
 The patient has no ongoing requirement for corticosteroids as therapy for CNS disease and 
off steroid therapy for at least 14 days. Anticonvulsant therapy at a stable dose is permitted. 
 Asymptomatic patients with CNS metastases newly detected at screening are eligible for the 
study after receiving radiotherapy or surgery, with no need to repeat the screening brain scan. 
 
5. Major surgery within 3 weeks of the first dose of trial treatment. 
 
6. Completed palliative radiotherapy within 7 days of the first dose of trial treatment. 
 
7. The patient had a history of uncontrolled hereditary or acquired thrombotic disorder. 
 
8. Patients with a history of gross hemoptysis (defined as bright red blood or ≥1/2 teaspoon) within 
2 months prior to enrollment. 
 
9. The patient had clinically relevant congestive heart failure (CHF; NYHA II-IV) or symptomatic 
or poorly controlled cardiac arrhythmia. 
 
10. The patient had experienced any arterial thrombotic event, including myocardial infarction, 
unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to 
enrollment. 
 
11. The patient had uncontrolled arterial hypertension ≥150 / ≥90 mm Hg despite standard medical 
management. 
 
12. The patient has had a serious or non-healing wound, ulcer, or bone fracture within 28 days prior 
to enrollment. 
 
13. Patients with ≥ 2 + protein on dipstick urinalysis. All patients with ≥ 2 + protein on dipstick 
urinalysis at baseline must undergo a 24-hour urine collection and must demonstrate ≤ 1 g of 
protein in 24 hours to be eligible.  
 
14. Clear cavitation of pulmonary lesions seen on imaging. 
 
15. The patient had significant bleeding disorders, vasculitis, or experienced Grade 3-4 
gastrointestinal (GI) bleeding within 3 months prior to enrollment. 
 
16. History of GI perforation and/or fistulae within 6 months prior to enrollment. 
 
17. Evidence of tumor invading or abutting major blood vessels. 
 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 17 of 77 
18. The patient had a bowel obstruction, history or presence of inflammatory enteropathy or 
extensive intestinal resection (hemicolectomy or extensive small intestine resection with chronic 
diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea. 
 
19. Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu 
vaccines that do not contain live virus are permitted. 
 
20. Previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody 
(mAb). 
 
21. Has active autoimmune disease that has required systemic treatments in the past 2 years, 
including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti-TNF- agents; chronic or occasional use of low-dose steroid therapy can be still be 
considered eligible as long as no greater than the daily equivalent of 5mg oral prednisone.   
 
22. Exceptions to excluding patients with active autoimmune disease include the following: 
 Patients with a history of autoimmune-related hypothyroidism who are on thyroid 
replacement hormone are eligible for the study. 
 Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible 
for the study. 
 Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations are eligible for the study provided all of following conditions are met: 
o Rash must cover < 10% of body surface area 
o Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
o No occurrence of acute exacerbations of the underlying condition requiring psoralen plus 
ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin 
inhibitors, or high potency or oral corticosteroids within the previous 12 months 
 
23. Subjects with asthma that require intermittent use of bronchodilators, inhaled steroids, or local 
steroid injections would not be excluded from the study. Subjects on chronic systemic steroids 
would be excluded from the study. 
 
24. Had prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies  
 
25. Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and 
interleukin 2 [IL-2]) within 4 weeks or five half-lives of the drug (whichever is longer) prior to 
initiation of study treatment 
 
26. Treatment with systemic immunosuppressive medication (including, but not limited to 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF- 
agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic 
immunosuppressive medication during the course of the study, with the following exceptions: 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 18 of 77 
 Patients who received acute, low-dose systemic immunosuppressant medication or a one-
time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids 
for a contrast allergy) are eligible for the study. 
 Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic 
obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic 
hypotension or adrenal insufficiency are eligible for the study. 
 
27. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion 
proteins  
 
28. Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab formulation  
 
29. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
 
30. Has known active Hepatitis B or C. Active Hepatitis B is defined as a known positive HBsAg 
result. Active Hepatitis C is defined by a known positive Hep C Ab result and known 
quantitative HCV RNA results greater than the lower limits of detection of the assay. For 
patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis 
B core antibody [HBcAb] and absence of HBsAg), the patient is only eligible if they are negative 
for HBV DNA. 
 
31. Active tuberculosis 
 
32. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the study, interfere with the subject’s participation for the full duration of 
the study, or is not in the best interest of the subject to participate, in the opinion of the treating 
Investigator. 
 
33. Has known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the trial. 
 
34. Has known interstitial lung disease or history of idiopathic pulmonary fibrosis, organizing 
pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, 
or evidence of active pneumonitis on screening chest computed tomography (CT) scan; history 
of radiation pneumonitis in the radiation field (fibrosis) is permitted. Lymphangitic spread of the 
NSCLC is not exclusionary. 
 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 19 of 77 
4. 
SUBJECT REGISTRATION 
All subjects must be registered through Big Ten Cancer Research Consortium (Big Ten CRC) 
Administrative Headquarters’(AHQ) electronic data capture (EDC) system. A subject is considered 
registered when an ‘On Study’ date is entered into the EDC system. 
 
Subjects must be registered prior to starting protocol therapy. Subjects should begin therapy within 7 
business days of registration. Beginning therapy outside that timeframe will not be considered a 
deviation. 
 
5. 
TREATMENT PLAN 
Patients will be treated in 3 week (21 day) cycles for duration of the study, for both the induction and 
maintenance phases. 
5.1 
Initial therapy: Cycles 1-4 
On Day 1 of each cycle, patients will be treated with Carboplatin AUC 5 IV, Pemetrexed 500mg/m2 IV, 
Atezolizumab at fixed dose of 1200mg IV, and bevacizumab 15mg/kg IV. Treatment will continue for a 
maximum duration of 4 cycles in this phase. 
 
If carboplatin is discontinued prior to completing 4 cycles, the patient may continue receiving the 
remaining study drugs.  
5.2 
Maintenance Therapy: Cycle 5+ 
After 4 cycles, the carboplatin will be stopped and subjects without progression (complete response 
[CR], partial response [PR], or stable disease [SD] as defined by RECIST v1.1 criteria) will continue the 
maintenance therapy at the same dosing and schedule as initial treatment:  
 Patients will receive Pemetrexed 500mg/m2 IV, Atezolizumab at fixed dose of 1200mg IV, and 
bevacizumab 15mg/kg IV every 3 weeks on D1 of each 21 day cycle.  
 
Treatment will continue until disease progression or unacceptable toxicity. Should a single agent be 
discontinued secondary to unacceptable toxicity (as defined below), individual remaining agents from 
the maintenance phase can continue to be given. Drugs will be discontinued based upon attribution of 
toxicity.  However, in the event that attribution of drug to toxicity can not be determined, the order of 
discontinuation will be as follows: 
 1st: Bevacizumab. 2nd: Atezolizumab. 3rd: Pemetrexed 
5.3 
Pre-medication and Hydration 
Premedication and hydration will be administered as per institutional standards.  
 
The administration of vitamin B12 and folic acid will be per institutional standards.  The use of 
corticosteroids to prevent chemotherapy-related nausea/vomiting is discouraged but not disallowed.  The 
use of a 5 HT3 antagonist plus neurokinin 1 antagonist (with or without olanzapine) can be considered 
as prophylaxis to prevent nausea/vomiting.  The use of corticosteroids the day before, the day of, and the 
day after each pemetrexed infusion is left to the discretion of the treating physician and the institutional 
standards. Sites may follow institutional standards for the management of nausea/vomiting not otherwise 
addressed. 
 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 20 of 77 
5.4 
Study Drug Administration: Initial Therapy 
 
Drug 
Dose1 
Route 
Schedule2 
Cycle 
Length 
Carboplatin 
AUC 5 
Intravenously (IV) per 
institutional standards 
Day 1 
21 days 
Pemetrexed 
500 mg/m2 
IV per institutional 
standards 
Day 1 
Atezolizumab 
1200 mg 
fixed dose 
IV over 60 minutes; 
subsequent infusions 
over 30 minutes3
Day 1 
Bevacizumab 
15mg/kg 
IV. 1st infusion=90 min 
2nd infusion=60 min 
3rd + infusions=30 min4
Day 1 
1 Body surface area (BSA) should be recalculated when weight changes by ≥ 10% 
according to the Mosteller formula.  
2 A window of ± 7 days may be applied to all study visits to accommodate observed 
holidays, inclement weather, scheduling conflicts etc. Date and time of each drug 
administration should be clearly documented in subject’s chart and electronic case report 
forms (eCRFs). 
3 For 1st infusion, atezolizumab (1200 mg in a 250 mL 0.9% NaCl IV bag) will be given 
over 60 mins ± 10 minutes. If no reaction occurs, subsequent infusions may be delivered 
over 30 minutes (-5/+ 10 minutes). 
4 The initial dose of bevacizumab will be delivered over 90 ± 10 minutes. If the 90-minute 
infusion is tolerated without infusion-associated adverse events (fever or chills), the second 
infusion may be delivered over 60 ± 10 minutes. If the 60 minute infusion is well tolerated, 
all subsequent infusions may be delivered over 30 minutes (-5/+ 10 minutes). 
5.5 
Study Drug Administration: Maintenance Therapy 
 
Drug 
Dose1 
Route 
Schedule2 
Cycle 
Length 
Pemetrexed 
500 mg/m2 
IV per institutional 
standards 
Day 1 
Every 21 
days 
Atezolizumab 
1200 mg 
fixed dose 
IV over 30 minutes 
(-5/+ 10 minutes) 
Day 1 
Bevacizumab 
15mg/kg 
IV over 30 minutes 
(-5/+ 10 minutes) 
Day 1 
1 Body surface area (BSA) should be recalculated when weight changes by ≥ 10% 
according to the Mosteller formula.  
2 A window of ± 7 days may be applied to all study visits to accommodate observed 
holidays, inclement weather, scheduling conflicts etc. Date and time of each drug 
administration should be clearly documented in subject’s chart and electronic case report 
forms (eCRFs). 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 21 of 77 
5.6 
Concomitant Medications 
5.6.1 Allowed Concomitant Medications 
Patients are permitted to use the following therapies during the study: 
 Oral contraceptives 
 Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable dose or low-
molecular-weight heparin) 
 Inactivated influenza vaccinations 
 Mineralocorticoids (e.g., fludrocortisone) 
 Corticosteroids administered for COPD or asthma 
 Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency.  
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered for the second 
and subsequent atezolizumab infusions only, at the discretion of the investigator. 
 
Prophylactic use of colony-stimulating factors including Granulocyte Colony-Stimulating Factor (G-
CSF), pegylated G-CSF or Granulocyte Macrophage Colony-Stimulating Factor GM CSF is not allowed 
in this study. Therapeutic use of G-CSF is allowed in subjects with Grade 3-4 febrile neutropenia.  
 
In general, investigators should manage a patient’s care with supportive therapies as clinically indicated, 
per local standard practice.  Patients who experience infusion-associated symptoms may be treated 
symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., 
famotidine, cimetidine), or equivalent medications per local standard practice.   
Serious infusion-associated events manifested by dyspnea, hypotension, wheezing, bronchospasm, 
tachycardia, reduced oxygen saturation, or respiratory distress should be managed with supportive 
therapies as clinically indicated (e.g., supplemental oxygen and 2-adrenergic agonists; see “Appendix 
on anaphylaxis precautions”) 
5.6.2 Cautionary Therapy for Atezolizumab-Treated patients 
 
Corticosteroids and Tumor Necrosis Factor- Inhibitors 
Systemic corticosteroids and TNF- inhibitors may attenuate potential beneficial immunologic effects 
of treatment with atezolizumab.  Therefore, in situations in which systemic corticosteroids or TNF- 
inhibitors would be routinely administered, alternatives, including antihistamines, should be 
considered.  If the alternatives are not feasible, systemic corticosteroids and TNF- inhibitors may be 
administered at the discretion of the investigator (except that systemic corticosteroids may not be 
given as premedication to patients with an allergy to contrast agents used for tumor scans). 
Systemic corticosteroids are recommended, at the discretion of the investigator, for the treatment of 
specific adverse events when associated with atezolizumab therapy (refer to the Atezolizumab 
Investigator's Brochure for details). 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 22 of 77 
5.6.3 Prohibited Concomitant Medications 
Use of the following concomitant therapies is prohibited as described below: 
 
Concomitant therapy intended for the treatment of cancer outside of the design parameters of this 
study (including, but not limited to, chemotherapy, hormonal therapy, immunotherapy, 
radiotherapy, and herbal therapy), whether health authorityapproved or experimental, is 
prohibited prior to starting study treatment, and during study treatment, until disease progression is 
documented and the patient has discontinued study treatment 
 
Investigational therapy (other than protocol-mandated study treatment) is prohibited during study 
treatment. 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to initiation of study 
treatment, during treatment with atezolizumab, and for 5 months after the last dose of 
atezolizumab. 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and IL-2) are 
prohibited within 4 weeks or five half-lives of the drug (whichever is longer) prior to initiation of 
study treatment and during study treatment because these agents could potentially increase the risk 
for autoimmune conditions when given in combination with atezolizumab. 
 
Systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, 
azathioprine, methotrexate, and thalidomide) are prohibited during study treatment because these 
agents could potentially alter the efficacy and safety of atezolizumab. 
 
Systemic corticosteroids may not be administered as premedication to patients with an allergy to 
contrast agents used for tumor scans 
5.7 
Atezolizumab Related Assessment of Safety 
5.7.1 
Safety Plan 
The safety plan for patients in this study is based on clinical experience with atezolizumab, 
bevacizumab, pemetrexed, and carboplatin in completed and ongoing studies.  The anticipated important 
safety risks are outlined below 
 
Measures will be taken to ensure the safety of patients participating in this study, including the use of 
stringent inclusion and exclusion criteria and close monitoring of patients during the study.  
Administration of atezolizumab, carboplatin, and pemetrexed, and bevacizumab will be performed in a 
monitored setting in which there is immediate access to trained personnel and adequate equipment and 
medicine to manage potentially serious reactions.  Guidelines for managing anticipated adverse events, 
including criteria for dosage modification and treatment interruption or discontinuation, are provided 
below.  Refer to on safety reporting (e.g., adverse events, pregnancies) for this study. 
 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 23 of 77 
5.7.1.1 Risks associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  Infusion-related reactions and 
immune related hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, 
hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, meningoencephalitis, and myocarditis.  In addition, systemic immune activation 
(described below) is a potential risk when atezolizumab is given in combination with other 
immunomodulating agents. Refer to Appendix and Section 6 of the Atezolizumab Investigator's 
Brochure for a detailed description of anticipated safety risks for atezolizumab.   
 
Systemic immune activation is a rare condition characterized by an excessive immune response.  Given 
the mechanism of action of atezolizumab, systemic immune activation is considered a potential risk 
when atezolizumab is given in combination with other immunomodulating agents.   
 
As detailed in this protocol, there will NOT be combination of other immunomodulating agents with 
Atezolizumab in this clinical trial, however, systemic immune activation should be included in the 
differential diagnosis for patients who, in the absence of an alternative etiology, develop a sepsis-like 
syndrome after administration of atezolizumab, and the initial evaluation of those patients should 
include the following: 
 CBC with peripheral smear 
 PT, PTT, fibrinogen, and D-dimer 
 Ferritin 
 Triglycerides 
 AST, ALT, and total bilirubin 
 LDH 
 Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
5.7.2 
Management of Patients who experience Adverse Events with Atezolizumab 
5.7.2.1 Dose Modifications 
There will be no dose modifications of atezolizumab in this study; management of adverse events are 
outlined below. 
5.7.2.2 Treatment Interruption for Atezolizumab 
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity considered to 
be related to study treatment.  If corticosteroids are initiated for treatment of the toxicity, they must be 
tapered over 1 month to  10 mg/day oral prednisone or equivalent before atezolizumab can be 
resumed.  If atezolizumab is withheld for  105 days from the last dose, the patient will be discontinued 
from atezolizumab.  However, atezolizumab may be withheld for  105 days to allow for patients to 
taper off corticosteroids prior to resuming treatment.  Atezolizumab can be resumed after being withheld 
for  105 days if the Investigator believes that the patient is likely to derive clinical benefit.  
Atezolizumab treatment may be suspended for reasons other than toxicity (e.g., surgical procedures).  
The investigator will determine the acceptable length of treatment interruption. 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 24 of 77 
5.7.2.3 Management Guidelines for Atezolizumab Related Adverse Events 
Guidelines for the management of patients who experience specific adverse events related to 
Atezolizumab are provided in detail in Appendix at end of protocol, “Management of Atezolizumab-
Specific Adverse Events”.   
 
Grade events are detailed in NCI Common Terminology Criteria for Adverse Events (CTCAE) v5. 
6. 
TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v5 will be used to grade adverse 
events.  
 
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests before and 
at regular intervals during their participation in this study as specified in Study Calendar & Evaluations. 
 
Subjects will be evaluated for adverse events (all grades), serious adverse events, and adverse events 
requiring study drug interruption or discontinuation as specified in Study Calendar & Evaluations.  
 
All dose reductions of chemotherapy are considered permanent. Once a dose of chemotherapy is 
reduced, it will not be increased to previous level, even if toxicity has resolved. 
 
Subjects who miss a treatment of chemotherapy and/or atezolizumab for a reason unrelated to toxicity 
need to resume therapy ≤ 14 days of the originally planned treatment. If a delay of more than 14 days 
occurs, the subject will be taken off treatment.  
6.1 
Dose Delays/Dose Modifications 
Unless otherwise noted in the dose modification tables below, treatment may be delayed ≤ 2 weeks from 
the expected day of the next treatment for any reason.  If treatment is delayed ≤ 2 weeks, subjects will 
proceed with the next cycle of treatment at the dose level recommended according to the tables below.  
6.2 
Dose Levels for Dose Reductions 
Dose level 
Carboplatin 
Pemetrexed 
Starting Dose 
AUC 5 
500mg/m2 
Dose level (-1) 
AUC 3.75 
(25% reduction) 
375mg/m2 
Dose level (-2) 
AUC 2.5 
(50% reduction) 
250mg/m2 
 
* No adjustments in fixed dose of atezolizumab or bevacizumab; toxicity, treatment delay or 
discontinuation of therapy handled as outlined below.  


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 25 of 77 
6.3 
Bevacizumab   
Dose modifications for fluctuations from baseline body weight of ≥ 10% are permitted for bevacizumab 
according to standard practice. If AEs that require omitting bevacizumab occur, the dose will remain the 
same once treatment resumes. 
 
Any toxicities associated or possibly associated with bevacizumab treatment should be managed 
according to standard medical practice. Omission of bevacizumab will have no immediate therapeutic 
effect. Bevacizumab has a terminal half-life of 21 days. 
 
Patients should be clinically assessed for toxicity before, during, and after each infusion of 
bevacizumab. If unmanageable toxicity occurs because of bevacizumab at any time during the study, 
treatment with bevacizumab should be permanently discontinued, however the patient may remain on 
study. 
 
Adverse events requiring delays or permanent discontinuation of bevacizumab are listed. 
Specific toxicities and treatment schedule: 
 
Infusion reaction: 
- 
Patients who experience an infusion–associated adverse event may be premedicated for the next 
infusion, but the infusion time may not be decreased for that infusion. If the next infusion is well 
tolerated with premedication, the subsequent infusion time may then be decreased by 30 ± 10 
minutes as long as the patient continues to be premedicated. 
- 
If a patient experiences an infusion associated adverse event with the 60 minute infusion despite 
premedication, all subsequent doses should be delivered over 90 ± 10 minutes. Similarly, if a 
patient experiences an infusion associated adverse event with the 30 minute infusion despite 
premedication, all subsequent doses should be delivered over 60 ± 10 minutes. 
- 
Reduce the infusion rate by 50% for grade 1 or 2; add dexamethasone (or equivalent) and 
acetaminophen to diphenhydramine premedication regimen before each bevacizumab dose 
- 
Permanently discontinue for grade 3 or 4 
Hypertension: 
- 
Interrupt therapy for severe hypertension until controlled with medical management 
- 
Permanently discontinue for severe hypertension that cannot be controlled with antihypertensive 
therapy 
Proteinuria: 
- 
Interrupt therapy for urine protein levels ≥2 g/24 hr; reinitiate treatment at previous fixed dose of 
15 mg/kg when urine protein level returns to <2 g/24 hr 
- 
Permanently discontinue for urine protein level >3 g/24 hr, or if there are 3 separate occurrences 
of protein level > 2g/24hr, or in the setting of nephrotic syndrome 
Arterial thrombotic events:  
- 
Permanently discontinue 
Bleeding, grade 3 or 4:  
- 
Permanently discontinue 
Gastrointestinal perforation: 
- 
Permanently discontinue 
 
 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 26 of 77 
Reversible posterior leukoencephalopathy syndrome (RPLS):  
- 
Permanently discontinue for confirmed diagnosis 
Wound healing complications:  
- 
Withhold treatment prior to surgery; do not reinitiate until the surgical wound is fully healed. If 
wound healing complications develop during treatment, withhold until the wound is fully healed. 
Fistula (any type), grade 4 
- 
permanently discontinue 
Tracheooesophageal fistula (any grade) 
- 
permanently discontinue 
Venous thrombosis, grade 3 
- 
 withhold Bevacizumab until stable on anti-coagulation,  
Recurrent VTE, grade 3 
- 
permanently discontinue 
VTE, grade 4  
- 
permanently discontinue 
Congestive Heart Failure (any grade) 
- 
permanently discontinue 
6.4 
Atezolizumab Dose Modifications 
There will be no dose modifications for Atezolizumab. Adverse events will be managed as described in 
detail in Appendix “Management of Atezolizumab-Specific Adverse Events”. 
 
If a dose of atezolizumab is withheld for toxicity, then subjects may resume dosing with atezolizumab if 
that is appropriate at their next scheduled appointment or when toxicity has improved as described in the 
Appendix “Management of Atezolizumab-Specific Adverse Events”. 
 
Subjects who require corticosteroids to manage atezolizumab-related AEs must be at an equivalent dose 
of ≤ 10 mg per day of prednisone to resume dosing with atezolizumab. Furthermore, an inability to 
reduce the corticosteroid dose for managing a drug-related adverse event to the equivalent of ≤ 10 mg 
prednisone per day within 12 weeks of the last atezolizumab dose should prompt discussion between the 
site investigator and sponsor-investigator regarding the subject’s ability to continue on treatment with 
atezolizumab the study. With site investigator and sponsor-investigator agreement, subjects with a 
laboratory adverse event still at Grade 2 after 12 weeks may continue treatment in the study only if 
asymptomatic and controlled. 
 
In subjects who continue on atezolizumab having experienced a Grade 3, Grade 4, or persistent (> 4 
weeks) Grade 2 atezolizumab-related AE, dosing should be held until the AE resolves to Grade 0-1 or 
baseline. 
 
However, in subjects who experience Grade 3 or 4 pneumonitis, or recurrent persistent (> 4 weeks) 
Grade 2 drug-related pneumonitis after re-challenge from a prior episode of persistent (> 4 weeks) 
Grade 2 drug-related pneumonitis, atezolizumab must be permanently discontinued. 
 
For subjects Hepatotoxicity events of Grade 3-4, patients are to permanently discontinue Atezolizumab, 
with the exception of patients with liver metastasis who began treatment with Grade 2 AST or ALT; if 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 27 of 77 
AST or ALT increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week 
then subjects should be discontinued. 
 
Subjects with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician 
discretion. Permanently discontinue study drug for persistent Grade 2 adverse reactions for which 
treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last 
dose. 
 
6.5 
Pemetrexed and Carboplatin Dose Modifications 
Standard previously established dose modifications will apply to use of chemotherapy agents 
pemetrexed and carboplatin.  
 
For Grade 3 or 4 diarrhea or any diarrhea requiring hospitalization, there will be dose reduction to 75% 
of prior dose (as established above in dose adjustment table), and subsequent episodes will have further 
dose reduction to 50% for both pemetrexed and carboplatin.  
 
Grade 3 or 4 mucositis: Pemetrexed dose should be reduced to 50% of the previous dose (continue the 
carboplatin at prior dose). If pemetrexed has already been dose reduced secondary to prior toxicity, 
further dose reductions will not be allowed unless based on the investigator discretion. 
6.6 
Dose modifications for hematologic toxicities 
 CBC with differential is obtained on Day 1 of each cycle.  
 Day 1 carboplatin, pemetrexed, bevacizumab, and atezolizumab may only be given if the platelets 
count ≥ 100 x 109/L and ANC ≥ 1.5 x 109/L.  
 Filgrastim support per FDA labeled guidelines may be utilized on or after the 2nd cycle if warranted 
by neutropenic fever or neutrophil count causing delay or dose reduction in chemotherapy, per 
standard guidelines.  
 
Hematologic toxicities requiring dose modifications of carboplatin and pemetrexed are as follows: 
 Grade 4 hematologic toxicity: Lasting ≥ 7 days OR 
 Febrile neutropenia Grade 3 or Grade 4: 
o Grade 3 is defined as ANC < 1000/mm3 with a single temperature of > 38.3 degrees C (101° F) 
or a sustained temperature of ≥ 38 degrees C (100.4° degrees F) for > 1 hour. 
o Grade 4 is defined as ANC < 1000/mm3 with a single temperature of > 38.3 degrees C (101° F) 
or a sustained temperature of ≥ 38 degrees C (100.4° F) for more > 1 hour, with life-threatening 
consequences and urgent intervention indicated 
 Grade 3 or Grade 4 thrombocytopenia if associated with: 
o A bleeding event which does not result in hemodynamic instability but requires an elective 
platelet transfusion, or 
o life-threatening bleeding event which results in urgent intervention and admission to an Intensive 
Care Unit 
 
For Day 1 hematologic toxicities occurring for cycles 1-4, the current cycle should be delayed by 1 
week. A CBC with differential should be checked at least once a week if treatment is not given on Day 
1. Study treatment may be resumed after a 1 week delay if the platelet count is ≥ 100 x 109/L and ANC 
is ≥ 1.5 x 109/L. Continuation at the same dose or at a reduced dose is based on investigator discretion 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 28 of 77 
unless the above criteria requiring dose reduction is met. If chemotherapy is delayed more than 1 week, 
dose reductions should occur. 
6.7 
Dose Modifications for Renal Toxicity 
Glomerular filtration rate (GFR) as calculated by the standard Cockcroft and Gault formula must be 
used to calculate creatinine clearance (CrCl) prior to each dose of carboplatin on Day 1 of each cycle. 
Only subjects with a CrCl of ≥ 30 mL/min will be treated. 
 
 If CrCl < 30 mL/min, carboplatin, pemetrexed and atezolizumab should be held;  
 If CrCl < 40 mL/min, pemetrexed should be held  
 If a Grade 3 or Grade 4 toxicity (as below, per CTCAE grading) occurs, carboplatin, and 
atezolizumab should be held. 
 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Creatinine increased > ULN* - 1.5 x ULN
> 1.5 - 3.0 x ULN > 3.0 - 6.0 x ULN 
> 6.0 x ULN 
*ULN, upper limit of normal 
 
If medications are held, a serum chemistry should be checked and CrCl calculated at least once a week. 
Carboplatin may be resumed at one dose level lower (per dose level reductions) once the CrCl returns to 
≥ 30 mL/min or returns to Grade 1 toxicity level. Atezolizumab can be resumed at standard dose.  
 
Pemetrexed may be resumed one dose level lower (per dose level reductions) once the CrCl returns to ≥ 
40 mL/min OR ≤1.5 × ULN 
 If CrCl remains < 30 mL/min or > Grade 1 toxicity for ≥ 3 weeks after last dose of carboplatin, 
atezolizumab, or pemetrexed, these therapies should be discontinued.  
 Patient will have the option of proceeding with single agent bevacizumab at this time. No dose 
adjustments are necessary for the bevacizumab in setting of renal failure.  
6.8 
Dose reductions for Hepatic Toxicity 
 Hepatic function labs should be assessed on Day 1 of each cycle.  
 Toxicity evaluated per CTCAE grading.  
 If any medications are required to be held, hepatic function labs should be repeated once a week. 
Treatment can be resumed once liver function tests return to acceptable levels.  
 For Grade 3 (5.1 - 20 times ULN) or 4 (>20 times ULN) transaminase elevation during treatment, 
after returning to acceptable levels, reduce the pemetrexed dose 1 level reduction, or by 25%.  
 If liver function tests remain elevated in Grade 3-4 range for ≥ 3 weeks after last dose of 
atezolizumab, atezolizumab should be discontinued,  
6.9 
Dose Modifications for sensory peripheral neuropathy toxicity 
Sensory neuropathy assessment will be screened for with history and graded by CTCAE v5.  
 Withhold carboplatin for Grade 3-4 sensory peripheral neuropathy.  
 Resume the carboplatin at reduced dose levels, with AUC 3.75 and AUC 2.5 for first and second 
occurrence, respectively, when sensory peripheral neuropathy improves to Grade 1 or completely 
resolves.  


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 29 of 77 
 Discontinue the carboplatin if there is third occurrence.  
6.10 
Protocol Therapy Discontinuation 
In addition to discontinuation from therapy related to toxicities as outlined in section 6.1, a subject will 
also be discontinued from protocol therapy and followed up per protocol under the circumstances 
outlined below. The reason for discontinuation of protocol therapy will be documented on the electronic 
case report form (eCRF). 
 
Documented disease progression  
 
The treating physician thinks a change of therapy would be in the best interest of the subject 
 
The subject requests to discontinue protocol therapy, whether due to unacceptable toxicity or for 
other reasons 
o If a subject decides to prematurely discontinue protocol therapy (“refuses treatment”), the 
subject should be asked if he or she may still be contacted for further scheduled study 
assessments. The outcome of that discussion should be documented in both the medical records 
and in the eCRF. 
 
A female subject becomes pregnant  
 
If protocol therapy is interrupted for ≥ 14 days for events unrelated to toxicity. See section 6. 
 
6.11 
Protocol Discontinuation 
If a subject decides to withdraw from the study (and not just from protocol therapy) all efforts should be 
made to complete the final study assessments. The site study team should contact the subject by 
telephone or through a clinic visit to determine the reason for the study withdrawal. If the reason for 
withdrawal is an adverse event, it will be recorded on the eCRF. 
 


Big Ten Cancer Research Consortium 
 
 
  
Clinical Study Protocol 
 
 
 
 
     
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 30 of 77 
7. 
STUDY CALENDAR & EVALUATIONS 
Cycle = 21 days
Screen 
Initial Therapy 
Maintenance 
Therapy
Safety 
follow up 
Long-term 
Follow up5 
Cycle 12
Cycle 2-4 2
Cycles 5+
-21 days1 
Day 1 
Day 1 
Day 1 
30 days 
post Tx2,4
Q 3months 
(±14 days)
REQUIRED ASSESSMENTS 
 
Medical history, smoking history, trial awareness7
X
 
Diagnosis and Staging6 
X
 
Physical exam 
X
X
X 
X
X
Vital signs, ECOG Performance status8 
X
X
X 
X
X
AEs & concomitant medications 
X
X
X 
X
30, 904
LABORATORY ASSESSMENTS 
 
Complete Blood Cell Count with diff (CBC)
X
X
X 
X
X
Comprehensive Metabolic Profile (CMP)9
X
X
X 
X
X
PT/INR and aPTT 
X 
 
 
 
 
 
Thyroid Function (TSH, T4, free T3), Amylase, Lipase
X
X
Cycle 3
Q2 cycles
X
Pregnancy test (serum or urine) WOCBP 
-7days10
 
Urinalysis 
X10
 
DISEASE ASSESSMENT3,11 
 
CT of chest11 or CT chest and CT abdomen
X
Q2 cycles11
Q2 cycles11
X11
X5
MRI or CT Brain11 
X
 
TREATMENT EXPOSURE 
 
Carboplatin 
X
X 
Pemetrexed 
X
X 
X
Atezolizumab  
X
X 
X
Bevacizumab  
X
X 
X
CORRELATIVE STUDIES (SPECIMEN COLLECTION)
 
PD-L1 results; Prior genetic analyses 
PD-L112
Genetic12
 
Archival tumor tissue13 
X
 
Blood, serum, plasma, and PBMCs14 
X
Cycle 2
X
BANKING SAMPLES (SPECIMEN COLLECTION)
 
Whole Blood15 
X
 
Serum, Plasma16 
X
 
X
FOLLOW-UP 
 
Survival status, subsequent therapies 
 
X
 


Big Ten Cancer Research Consortium 
 
 
  
Clinical Study Protocol 
 
 
 
 
     
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 31 of 77 
Key to Footnotes  
1If screening (baseline) testing was performed within 10 days of D1 of treatment, these do not need to be repeated.   
2A window of 7 days will be applied to all treatment study visits; for the long-term follow up visits, a 14-day window will apply. 
3Tumor imaging to continue every odd numbered cycle until progression, starting with cycle 3. 
4A safety follow-up visit will occur 30 days (±10 days) after the last dose of treatment. AESIs and SAEs will be collected for 90 days after the end 
of treatment. See Section 11.2. 
5Subjects without documented disease progression will be followed for disease progression every 3 months (±14 days) for 1 year. Once disease 
progression is documented, subjects will enter a survival follow up period every 3 months (±14 days) for 1 year from the time of documented 
progression. Follow up for may be accomplished via email, phone or other means as appropriate. 
6Diagnosis and staging to include pathology report and Tumor Node Metastasis (TNM) staging 
7Medical history to include smoking history and trial awareness question. 
8Vital signs to include blood pressure, weight, and height (screening only) and ECOG performance status 
9CMP to include AST, ALT, total bilirubin, creatinine 
10Pregnancy test: For women of childbearing potential (WOCBP): urine or serum βhCG, within 7 days prior to study registration. If a urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required. Urinalysis: All patients with ≥ 2 + protein on dipstick 
urinalysis at baseline must undergo a 24-hour urine collection and must demonstrate ≤ 1 g of protein in 24 hours. 
11Tumor response assessment will be performed every odd numbered cycle starting with cycle 3; tumor imaging to be done at treatment 
discontinuation at discretion of investigator. CT scan of chest alone for imaging is acceptable only if instructed to include the upper abdomen in 
field, specifically must include the liver and bilateral adrenal glands.  Brain imaging with either MRI or CT with contrast will be performed on all 
subjects at screening to evaluate for the presence of brain metastases. A 21 day window may be applied to screening scans and ±14 day window 
may be applied to all subsequent scans.  
12PD-L1: Prior PD-L1 IHC testing must have been performed using the Dako 22C3 antibody. All other subjects must have at least 5 unstained 
slides available to perform PD-L1 testing. Prior genetic testing: If subjects have prior genetic sequencing analyses results available, those results 
should be submitted at C1D1. 
13Fixed paraffin-embedded blocks/slides will be requested, if available, for future evaluation (up to 20-25 unstained slides preferred). See CLM. 
14Serial blood samples will be collected at Pre-Treatment Cycle 1 Day 1, Cycle 2 Day 1, and progression / follow up period: whole blood; plasma; 
plasma and peripheral blood mononuclear cells (PBMC); and serum. See CLM for additional details including collection, processing, labeling and 
shipping. 
15Whole blood for banking is to be collected at Pre-Treatment Cycle 1 Day 1. See CLM. 
16Serum and plasma for banking is to be collected at Pre-Treatment Cycle 1 Day 1 and at the 30-Day Safety Follow up visit. See CLM. 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 32 of 77 
7.1 
Safety Follow-up Evaluations 
A safety follow-up visit should occur when subjects permanently stop study treatment for whatever 
reason (toxicity, progression, or at discretion of site investigator) and should be performed 30 days (±10 
days) after the last dose of treatment. Subjects who have an ongoing ≥ grade 2 or serious AE (SAE) at 
this visit will continue to be followed until the AE resolves to ≤ Grade 1 or baseline, is deemed clinically 
insignificant, and/or until a new anti-cancer treatment starts, whichever is earlier. AESIs and SAEs will 
be collected for 90 days after the end of treatment. See Section 11.2. 
7.2 
Long Term Follow-up Evaluations 
All subjects will be followed until documented disease progression.  Subjects who discontinue treatment 
for any reason without documented disease progression will be followed for disease progression every 3 
months (±14 days) for 1 year.  
 
Once disease progression is documented, subjects will enter a survival follow up period every 3 months 
(±14 days) for 1 year from the time of documented progression.  Follow up may be accomplished via 
clinic visit, phone call, or other avenues as appropriate. 
 
8. 
BIOSPECIMEN STUDIES AND PROCEDURES 
For archival tumor specimens or blood collected in the protocol, please see the Correlative Laboratory 
Manual (CLM) for additional information regarding collection, labeling and shipping. 
8.1 
Source and Timing of Biospecimen Collections 
8.1.1 PD-L1 results 
Prior PD-L1 IHC testing must have been performed using the Dako 22C3 antibody. All other subjects 
must have at least 5 unstained slides available to perform PD-L1 testing. See CLM for details. 
8.1.2 Prior Genetic Sequencing Results 
If subjects have prior genetic sequencing analyses results available, those results should be submitted at 
C1D1. In particular, markers such as EGFR mutation status, ALK, ROS-1, BRAF, KRAS, HER-2, 
MET, RET, NTRK, tumor mutational burden, PD-L1 will be noted in the database. 
8.1.3 Archival Tumor Tissue 
Mandatory submission of formalin-fixed, paraffin-embedded archival tumor tissue block for biomarker 
evaluation are requested, if available. A new biopsy is not required if archival tissue is not available. 
Tissue should be identified and requested before registration; submission to BTCRC AHQ will occur 
after subject is successfully registered. Excisional, incisional, punch or core needle samples are 
preferred. Fine needle aspirates with sufficient number of cells for testing are allowable if fixed in 
paraffin; alcohol fixation not suitable for PD-L1 IHC. Please see CLM for sample specifications. 
 
PD-L1 analyses using the Dako 22C3 antibody will be performed for all subjects except those who have 
prior Dako 22C3 PD-L1 results.  For those without prior Dako 22C3 results, submission of tissue for 
PD-L1 analysis is required. 
 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 33 of 77 
Additional archival tumor tissue is requested if available. Tissue MAY also be macro-dissected and the 
nucleic acids extracted for genetic analyses such as (but not limited to) whole exome sequencing, Next 
Generation Sequencing, and/or DNA methylation analyses. Any residual nucleic acids remaining after 
analyses will be banked for future research with subject consent. 
8.1.4 Mandatory Whole Blood Collection for Somatic Baseline 
Whole blood samples will be collected prior to C1D1 treatment.  
8.1.5 Mandatory Whole Blood Collection for gene expression/RNA 
Whole blood specimens will be submitted prior to C1D1 treatment, prior to C2D1 treatment, and at 
Safety Follow-Up Visit. 
 
RNA MAY be isolated for gene expression profiling using techniques such as (but not limited to) RNA-
Seq. 
8.1.6 Mandatory Plasma Collection for cfDNA and microRNA Analyses  
Plasma specimens will be submitted prior to C1D1 treatment, prior to C2D1 treatment, and at Safety 
Follow-Up Visit. 
 
miRNA MAY be isolated from plasma samples and reverse transcribed prior to quantitative PCR 
analyses. 
 
cfDNA MAY be isolated from plasma samples and analyzed with appropriate platform such as (but not 
limited to) quantitative PCR, digital PCR, or next-generation sequencing. 
8.1.7 Mandatory Serum Collection for Proteomic Analyses, Lipidomic Analyses, and Cytokine 
Analyses 
Serum specimens will be submitted prior to C1D1 treatment, prior to C2D1 treatment, and at Safety 
Follow-Up Visit. 
 
Proteomic analyses MAY be performed and could include ELISA (or multiplex assay system) with 
specific antibodies and/or LC-MS/MS proteomic analyses.  These samples may also provide data for 
metabolomics guided by functional groups. Pre-treatment serum samples MAY also be used to explore 
the association of proteomic and lipidomic tests at baseline with measures of response. 
 
Cytokine analyses MAY be performed and may include assessment of pre- and post-treatment serum 
cytokine markers of interest, such as (but not limited to) Interferon gamma, Interleukin-10, Interleukin-
18, Interleukin-2, Interleukin-4, Interleukin-6, Interleukin-8, Macrophage Inflammatory Protein-1 beta, 
Tumor Necrosis Factor alpha, Tumor Necrosis Factor beta.  
8.1.8 Mandatory PBMCs & Plasma Collection for Flow Cytometry of PBMCs and Banking of 
Plasma 
Blood will be collected and processed for PBMCs and plasma prior to C1D1 treatment, prior to C2D1 
treatment, and at Safety Follow-Up Visit. 
 
Flow cytometry MAY be performed to analyze expression on human peripheral blood mononuclear cells 
stained with antibodies such as (but not limited to) CTLA-4 and CD28. 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 34 of 77 
 
8.2 
Banking of Leftover Biospecimens 
Subject consent will be obtained to bank any leftover samples collected for study-specific correlative 
research. Hoosier Cancer Research Network (HCRN), as Administrative Headquarters for the Big Ten 
CRC, will manage the banked samples. Samples will be banked indefinitely in the Hoosier Cancer 
Research Network Biorepository and used for future unspecified cancer-related research.  
8.3 
Banking Samples for Future Unspecified Research 
Subject consent will be obtained to collect additional samples for future unspecified Big Ten Cancer 
Research Consortium studies. HCRN will manage the banked samples. Samples will be banked 
indefinitely in the HCRN Biorepository.  
 
This includes: 
 Whole blood: Whole blood will be collected prior to treatment on Cycle 1 Day 1.  
 Pre- and Post-treatment plasma: Whole blood for plasma will be collected prior to treatment on Cycle 
1 Day 1 and at the 30-day Safety Follow-up visit.  
 Pre- and Post-treatment serum: Whole blood for serum will be collected prior to treatment on Cycle 1 
Day 1 and at the 30-day Safety Follow-up visit. 
 
Please refer to the Correlative Laboratory Manual (CLM) for all sample collection, processing, labeling, 
and shipping instructions. 
8.4 
Confidentiality of Biospecimens 
Samples will be identified by a subject’s study number assigned at the time of registration to the trial. 
Any material issued to collaborating researchers will be anonymized and only identified by the subject’s 
study number. 
 
9. 
CRITERIA FOR DISEASE EVALUATION 
Disease response will be evaluated as per the Response Evaluation Criteria in Solid Tumors (RECIST) 
v1.1 [27]. Refer to the RECIST v1.1 publication for complete details on these criteria. 
9.1 
Measurable Disease 
Measurable disease is defined as the presence of at least one measurable lesion. Measurable lesions are 
defined as those that can be accurately measured in at least one dimension (longest diameter to be 
recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical 
exam.  All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
9.1.1 Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in short axis 
when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed. 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 35 of 77 
9.2 
Non-measurable Lesions 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as 
non-measurable. 
 
NOTE:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same subject, these are preferred for selection as target lesions. 
9.3 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of 
all involved organs, should be identified as target lesions and recorded and measured at baseline.  Target 
lesions should be selected on the basis of their size (lesions with the longest diameter), be representative 
of all involved organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters.  If 
lymph nodes are to be included in the sum, then only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
9.4 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 target 
lesions should be identified as non-target lesions and should also be recorded at baseline.  Measurements 
of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of 
each should be noted throughout follow-up. 
9.5 
Evaluation of Target Lesions 
NOTE: In addition to the information below, also see section 4.3.2 in the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 1.1 (Eur J Cancer 
45;2009:228-247) for special notes on the assessment of target lesions.  
 
Complete 
Response (CR) 
Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in 
short axis to <10 mm.
Partial Response 
(PR) 
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters 
Progressive 
Disease (PD) 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 36 of 77 
demonstrate an absolute increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also considered 
progressions).
Stable Disease 
(SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study
9.6 
Evaluation of Non-target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm 
short axis) 
 
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a subject to be 
considered in complete clinical response. 
Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, not a 
single lesion increase.
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the site 
investigator should prevail in such circumstances, and the progression status should be confirmed at a 
later time by the sponsor investigator. 
9.7 
Evaluation of Best Overall Response 
 
Target Lesions 
Non-Target Lesions 
New Lesions
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/ or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Non-evaluable 
PD 
Any 
Yes or No 
PD 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 37 of 77 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression.
 
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 
deterioration”.  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  When the 
evaluation of complete response depends on this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response status. 
9.8 
Definitions for Response Evaluation – RECIST v1.1 
9.8.1 First Documentation of Response 
The time between initiation of therapy and first documentation of PR or CR. 
9.8.2 Confirmation of Response 
To be assigned a status of complete or partial response, changes in tumor measurements must be 
confirmed by repeat assessments performed no less than four weeks after the criteria for response are 
first met. 
9.8.3 Duration of Response 
Duration of overall response—the period measured from the time that measurement criteria are met for 
complete or partial response (whichever status is recorded first) until the date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since treatment started). 
9.8.4 Duration of Overall Complete Response 
The period measured from the time that measurement criteria are met for complete response until the 
first date that recurrent disease is objectively documented. 
9.8.5 Objective Response Rate  
The objective response rate is the proportion of all subjects with confirmed PR or CR according to 
RECIST v1.1, from the start of treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the start of treatment). 
9.8.6 Disease Control Rate 
The disease control rate is the proportion of all subjects with stable disease (SD) for 8 weeks, or partial 
response (PR), or complete response (CR) according to RECIST v1.1, from the start of treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the start of treatment). 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 38 of 77 
9.8.7 Time to Progression 
A measurement from the date of the initiation of treatment to the time when the criteria for disease 
progression is met as defined by RECIST v1.1. Subjects who have not progressed will be right-censored 
at the date of the last disease evaluation. Death due to any cause will be considered as a competing risk. 
9.8.8 Progression Free Survival 
A measurement from the date of registration until the criteria for disease progression is met as defined 
by RECIST v1.1 or death occurs. Subjects who have not progressed will be right-censored at the date of 
the last disease evaluation. 
9.8.9 Overall Survival 
Overall survival is defined by the date of registration to date of death from any cause. 
 
10. 
DRUG INFORMATION 
10.1 
Carboplatin 
Please see product package insert for complete details regarding carboplatin. 
10.1.1 Supplier/How Supplied 
Carboplatin is available as a sterile lyophilized powder in single-dose vials containing 50 mg, 150 mg, 
or 450 mg of carboplatin. Each vial contains equal parts by weight of carboplatin and mannitol.  
 
Commercial supplies of carboplatin will be used in this study and billed to third party payers or the 
subject. 
10.1.2 Preparation  
As per institutional standards. 
10.1.3 Storage and Stability 
Intact vials are stored at room temperature protected from light. The reconstituted solution is stable for 
at least 24 hours. When further diluted in glass or polyvinyl plastic to a concentration of 10mg/mL with 
normal saline or 5% dextrose carboplatin is stable for 8 hours at 25 degrees C. Stability with further 
dilution to 0.5mg/mL has been reported for up to 8 hours. Other stability data indicate that carboplatin 
is stable for up to 24 hours and may be refrigerated; however, the manufacturer recommends that 
reconstituted solutions be discarded after 8 hours due to the lack of preservative in drug formulation.  
10.1.4 Handling and Disposal 
Caution should be exercised in handling and preparing carboplatin injection. To minimize the risk of 
dermal exposure, always wear impervious gloves when handling vials containing carboplatin injection. 
If carboplatin injection contacts the skin, immediately wash the skin thoroughly with soap and water. If 
carboplatin injection contacts mucous membranes, the membranes should be flushed immediately and 
thoroughly with water. 
10.1.5 Incompatibilities 
Aluminum displaces platinum from the carboplatin molecule, resulting in the formation of a black 
precipitate and loss of potency. Carboplatin solutions should not be prepared or administered with 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 39 of 77 
needles, syringes, catheters, or IV administration sets containing aluminum parts that might be in 
contact with the drug. 
10.1.6 Adverse Events 
Incidence rates of adverse events associated with carboplatin are provided in the product package 
insert. Some of the expected adverse events with carboplatin treatment are listed below. 
 Hematologic: Thrombocytopenia (dose limiting), neutropenia, leukopenia, anemia.  
 GI: Nausea and vomiting (frequent but less severe than with cisplatin), treatable with appropriate 
antiemetic prophylaxis. Anorexia, diarrhea, and constipation have also been reported.  
 Dermatologic: Rash, urticaria. Rarer reactions include alopecia, mucositis, and hypersensitivity 
reactions.  
 Hepatic: Abnormal liver function tests, usually reversible with standard doses.  
 Neurologic: Rarely peripheral neuropathy is seen. May be more common in subjects greater than 65 
years of age. May also be cumulative, especially in subjects with prior cisplatin treatment. 
Ototoxicity (rare).  
 Renal: Elevations in serum creatinine, BUN; electrolyte loss (Mg, K, Na, Ca).  
 Miscellaneous: Pain, asthenia, flu-like syndrome. 
10.1.7 Drug Interactions 
Concomitant myelosuppressive drugs or radiation therapy may potentiate the hematologic toxicity of 
carboplatin.  
 
Concomitant nephrotoxic drugs may potentiate the nephrotoxicity of carboplatin, particularly when 
carboplatin is given in high-dose chemotherapy regimens. 
 
10.2 
Pemetrexed 
Please refer to the current package insert for complete prescribing and toxicity information. 
10.2.1 Supplier/How Supplied 
Pemetrexed is supplied as a sterile lyophilized powder for intravenous infusion available in single-dose 
vials. The product is a white to either light yellow or green-yellow lyophilized solid. Pemetrexed is 
supplied in 100mg and 500 mg vials. Each 500-mg vial of pemetrexed contains pemetrexed disodium 
equivalent to 500 mg pemetrexed and 500 mg of mannitol. Each 100-mg vial of pemetrexed disodium 
contains equivalent to 100mg pemetrexed and 106mg of mannitol. Hydrochloric acid and/or sodium 
hydroxide may have been added to adjust pH.  
 
Commercial supplies of pemetrexed will be used in this study and billed to third party payers or the 
subject. 
10.2.2 Preparation  
As per institutional standards. 
10.2.3 Storage and Stability 
Pemetrexed for injection, should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). 
Chemical and physical stability of reconstituted and infusion solutions of pemetrexed were 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 40 of 77 
demonstrated for up to 24 hours following initial reconstitution, when stored refrigerated, 2-8°C (36-
46°F), or at 25°C (77°F), excursions permitted to 15-30°C (59-86°F). When prepared as directed, 
reconstituted and infusion solutions of Pemetrexed contain no antimicrobial preservatives. Discard 
unused portion. Pemetrexed is not light sensitive. 
10.2.4 Handling and Disposal 
Preparation should be performed by trained personnel in accordance with good practices rules, 
especially with respect to asepsis. 
 
After final drug reconciliation, unused pemetrexed vials should be disposed at the site following 
procedures for the disposal of anticancer drugs. 
10.2.5 Incompatibilities and Potential Drug Interactions 
Ibuprofen — Daily ibuprofen doses of 400 mg QID reduce pemetrexed’s clearance by about 20% (and 
increase AUC by 20%) in patients with normal renal function. The effect of greater doses of ibuprofen 
on pemetrexed PK is unknown. Pemetrexed is primarily eliminated unchanged renally as a result of 
glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could 
result in delayed clearance of pemetrexed. Concomitant administration of substances that are also 
tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of pemetrexed. 
Although ibuprofen (400 mg QID) can be administered with pemetrexed in patients with normal renal 
function (creatinine clearance (80 mL/min), caution should be used when administering ibuprofen 
concurrently with pemetrexed to patients with mild to moderate renal insufficiency (creatinine 
clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid 
taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days 
following administration of pemetrexed. In the absence of data regarding potential interaction between 
pemetrexed and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt 
dosing for at least 5 days before, the day of, and 2 days following pemetrexed administration. If 
concomitant administration of an NSAID is necessary, patients should be monitored closely for 
toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. 
10.2.6 Adverse Events 
Renal: creatinine elevation (10%)  
Neurologic: neuropathy-sensory (9%), taste disturbance (8%)  
Hematologic: anemia (33%), neutropenia (29%), leucopenia (18%), thrombocytopenia (10%)  
Gastrointestinal: 
nausea 
(56%), 
vomiting 
(40%), 
anorexia 
(27%), 
constipation 
(21%), 
stomatitis/pharyngitis (14%), diarrhea (12%), dyspepsia/heartburn (5%)  
Dermatology/skin: alopecia (12%), rash/desquamation (7%)  
Other: fatigue, febrile neutropenia, infection, pyrexia, dehydration, increased AST, increased ALT, 
creatinine clearance decrease, renal failure, conjunctivitis, arrhythmia, chest pain, increased GGT, motor 
neuropathy 
10.3 
Atezolizumab 
Please refer to the current package insert for complete prescribing and toxicity information. 
10.3.1 Supplier/How Supplied 
Genentech will provide atezolizumab at no charge to subjects participating in this clinical trial.  
 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 41 of 77 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution, and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 
10.3.2 Preparation  
Please refer to the package insert and local guidelines for atezolizumab preparation. 
 
Preparation 
Visually inspect drug product for particulate matter and discoloration prior to administration, whenever 
solution and container permit. Discard the vial if the solution is cloudy, discolored, or visible particles 
are observed. Do not shake the vial. 
 
Prepare the solution for infusion as follows: 
 Withdraw 20mLof TECENTRIQ from the vial. 
 Dilute into a250mLpolyvinyl chloride (PVC), polyethylene (PE), or polyolefin (PO) infusion 
bag containing 0.9% Sodium Chloride Injection, USP. 
 Dilute with 0.9% Sodium Chloride Injection only. 
 Mix diluted solution by gentle inversion. Do not shake. 
 Discard used or empty vials of TECENTRIQ. 
 
Storage of Infusion Solution 
Administer immediately once prepared. If diluted TECENTRIQ infusion solution is not used 
immediately, store solution either: 
 At room temperature for no more than 6 hours from the time of preparation. This includes room 
temperature storage of the infusion in the infusion bag and time for administration of the 
infusion, or 
 Under refrigeration at 2°Cto 8°C (36°F to 46°F) for no more than 24 hours from time of 
preparation. 
10.3.3 Storage and Stability 
Clinical supplies must be stored in a secure, limited-access location. Store vials under refrigeration at 
2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake. 
 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
10.3.4 Handling and Disposal 
Preparation should be performed by trained personnel in accordance with good practices rules, 
especially with respect to asepsis. 
 
After final drug reconciliation, unused atezolizumab vials should be disposed at the site following 
procedures for the disposal of anticancer drugs. 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 42 of 77 
10.3.5 Dispensing 
Atezolizumab must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. Atezolizumab should be stored in a secure area according to local 
regulations.  It is the responsibility of the site investigator to ensure that study drug is only dispensed to 
subjects.   
10.3.6 Adverse Events 
Please refer to the current version of the Investigator’s Brochure for a complete list of AEs. 
 
Atezolizumab is generally well tolerated and demonstrates a favorable safety profile in comparison to 
chemotherapy. Atezolizumab is an immunomodulatory agent, and based on this mechanism of action, 
immune mediated adverse events are of primary concern. Important identified risks for atezolizumab 
are of an immune mediate nature, including: pneumonitis, colitis, hepatitis, nephritis, endocrinopathies 
that include hypophysitis (including hypopituitarism and secondary adrenal insufficiency), thyroid 
disorder (hypothyroidism, hyperthyroidism), Type I diabetes mellitis, uveitis, myositis, Guillain-Barré 
syndrome, pancreatitis, myocarditis, severe skin reactions including Stevens-Johnson syndrome (SJS) 
and toxic epidermal necrolysis (TEN), some with fatal outcome; and “solid organ transplant rejection 
following atezolizumab treatment in donor organ recipients” 
 
The majority of immune-mediated adverse events were mild to moderate in severity, were manageable 
with appropriate care, and rarely required discontinuation of therapy.  
 
The risk profile for atezolizumab also includes 2 important potential risks – i.e. myasthenic syndrome 
and increased risk of severe complications (such as early severe graft versus host disease and veno-
occlusive disease) of allogeneic transplant in patients with hematologic malignancies who have 
previously been treated with PD-1 inhibitors. 
 
Further details around frequency, reporting, and management of immune-related adverse events (irAEs) 
can be found in the current version of the Investigator’s Brochure.  
 
In addition to the previously noted identified risks, infusion-related reactions are a risk but are not 
considered immune mediated; these are also further described in the current IB. 
 
10.4 
Bevacizumab 
Please refer to the current package insert for additional information regarding this drug. 
10.4.1 Supplier/How Supplied 
Bevacizumab is supplied as US commercial Avastin 400 mg per 16 mL single use vials with either 
clinical or commercial secondary packaging  
 
Genentech will provide bevacizumab at no charge to subjects for their first year of participating in this 
clinical trial. After one year, subjects will receive commercial supplies of bevacizumab which will be 
billed to third party payers or the subject. 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 43 of 77 
10.4.2 Preparation and Administration 
As per institutional standards.  
 Do not administer as an intravenous push or bolus. Administer only as an intravenous (IV) infusion.  
 Do not initiate bevacizumab until at least 28 days following major surgery.  
 Administer bevacizumab after the surgical incision has fully healed.  
 First infusion and subsequent infusions duration as per institutional standards.  
10.4.3 Storage and Stability 
Unopened vials of bevacizumab are stable until the expiration date indicated on the package when 
stored at 2° to 8ºC (36° to 46ºF). Bevacizumab vials should be protected from light. Do not freeze or 
shake. Diluted bevacizumab solutions may be stored at 2° to 8ºC (36° to 46ºF) for up to 8 hours. Store 
in the original carton until time of use. No incompatibilities between bevacizumab and 
polyvinylchloride or polyolefin bags have been observed. 
10.4.4 Handling and Disposal 
Preparation should be performed by trained personnel in accordance with good practices rules, 
especially with respect to asepsis. 
 
After final drug reconciliation, unused bevacizumab vials should be disposed at the site following 
procedures for the disposal of anticancer drugs. 
10.4.5 Adverse Events 
Please refer to the current version of the package insert for a complete list of AEs. 
 
Gastrointestinal Perforations 
Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in bevacizumab 
treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 
2.4% across clinical studies.  
 
The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation 
can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred 
within the first 50 days of initiation of bevacizumab. 
 
Discontinue bevacizumab in subjects with gastrointestinal perforation. 
 
Surgery and Wound Healing Complications 
Bevacizumab impairs wound healing in animal models. In clinical trials, administration of bevacizumab 
was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound 
healing complications, including serious and fatal complications, in patients with mCRC who underwent 
surgery during the course of bevacizumab treatment was 15% and in patients who did not receive 
bevacizumab, was 4%. 
 
Bevacizumab should not be initiated for at least 28 days following surgery and until the surgical wound 
is fully healed. Discontinue bevacizumab in subjects with wound healing complications requiring 
medical intervention. 
 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 44 of 77 
The appropriate interval between the last dose of bevacizumab and elective surgery is unknown; however, 
the half-life of bevacizumab is estimated to be 20 days. Suspend bevacizumab for at least 28 days prior 
to elective surgery. Do not administer bevacizumab until the wound is fully healed. 
 
Necrotizing fasciitis, including fatal cases, has been reported in patients treated with bevacizumab, 
usually secondary to wound healing complications, gastrointestinal perforation, or fistula formation. 
Discontinue bevacizumab therapy in subjects who develop necrotizing fasciitis.  
 
Hemorrhage 
Bevacizumab can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 
1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, 
including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal 
bleeding occurred up to five-fold more frequently in patients receiving bevacizumab compared to patients 
receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among 
patients receiving bevacizumab ranged from 1.2 to 4.6%. 
 
Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell 
histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving 
bevacizumab and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. 
In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed 
radiation and surgery more than 4 weeks prior to the start of bevacizumab were evaluated with serial 
CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 bevacizumab -
treated patients (rate 1.2%, 95% CI 0.06%–5.93%). 
 
Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients 
had Grade 3–4 hemorrhage. 
 
Do not administer bevacizumab to subjects with recent history of hemoptysis of ≥ 1/2 teaspoon of red 
blood. Discontinue bevacizumab in subjects with hemorrhage.  
Non-Gastrointestinal Fistula Formation 
Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheoesophageal, 
bronchopleural, biliary, vaginal, renal, and bladder sites occurs at a higher incidence in bevacizumab -
treated patients compared to controls. The incidence of non-gastrointestinal perforation was ≤ 0.3% in 
clinical studies. Most events occurred within the first 6 months of bevacizumab therapy. 
 
Discontinue bevacizumab in subjects with fistula formation involving an internal organ.  
 
Arterial Thromboembolic Events  
Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient 
ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence 
in patients receiving bevacizumab compared to those in the control arm. Across indications, the incidence 
of Grade ≥ 3 ATE in the bevacizumab containing arms was 2.6% compared to 0.8% in the control arms. 
Among patients receiving bevacizumab in combination with chemotherapy, the risk of developing ATE 
during therapy was increased in patients with a history of arterial thromboembolism, diabetes, or age 
greater than 65 years.  


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 45 of 77 
 
The safety of resumption of bevacizumab therapy after resolution of an ATE has not been studied. 
Discontinue bevacizumab in subjects who experience a severe ATE.  
 
Hypertension 
The incidence of severe hypertension is increased in patients receiving bevacizumab as compared to 
controls. Across clinical studies, the incidence of Grade 3 or 4 hypertension ranged from 5-18%. 
 
Monitor blood pressure every two to three weeks during treatment with bevacizumab. Treat with 
appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood 
pressure at regular intervals in subjects with bevacizumab -induced or -exacerbated hypertension after 
discontinuation of bevacizumab. 
 
Temporarily suspend bevacizumab in subjects with severe hypertension that is not controlled with 
medical management. Discontinue bevacizumab in subjects with hypertensive crisis or hypertensive 
encephalopathy.  
 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) 
RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred 
from 16 hours to 1 year after initiation of bevacizumab. RPLS is a neurological disorder, which can 
present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic 
disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is 
necessary to confirm the diagnosis of RPLS. 
 
Discontinue bevacizumab in subjects developing RPLS. Symptoms usually resolve or improve within 
days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating 
bevacizumab therapy in patients previously experiencing RPLS is not known.  
 
Proteinuria 
The incidence and severity of proteinuria is increased in patients receiving bevacizumab as compared to 
controls. Nephrotic syndrome occurred in < 1% of patients receiving bevacizumab in clinical trials, in 
some instances with fatal outcome. In a published case series, kidney biopsy of six patients with 
proteinuria showed findings consistent with thrombotic microangiopathy. 
 
Subjects with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour 
urine collection. Suspend bevacizumab administration for ≥ 2 grams of proteinuria/24 hours and resume 
when proteinuria is < 2 gm/24 hours. Continue to monitor until 24-hr protein demonstrates < 1 g of 
protein. Discontinue bevacizumab in subjects with nephrotic syndrome. Data from a post-marketing 
safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine 
protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57).  
 
Infusion Reactions 
Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, 
hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, 
Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion 
reactions with the first dose of bevacizumab were uncommon (< 3%) and severe reactions occurred in 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 46 of 77 
0.2% of subjects. 
 
Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy.  
 
Ovarian Failure 
The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving 
bevacizumab in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX 
chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which bevacizumab is not 
approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment 
with bevacizumab.  
 
11. 
ADVERSE EVENTS 
11.1 
Definitions 
11.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence whether or not considered related to the study drug that 
appears to change in intensity during the course of the study. The following are examples of AEs:  
 Unintended or unfavorable sign or symptom 
 A disease temporally associated with participation in the protocol 
 An intercurrent illness or injury that impairs the well-being of the subject 
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE (e.g., 
surgical insertion of central line) should not be recorded as an AE.  
 
Disease progression should not be recorded as an AE, unless it is attributable to the study regimen by 
the site investigator. 
11.1.2 Laboratory Test Abnormalities 
Asymptomatic laboratory abnormalities that do not require treatment will not be collected as adverse 
events. 
 
However, the following laboratory abnormalities should be documented and reported appropriately: 
 any laboratory test result that is clinically significant or meets the definition of an SAE or Drug 
Induced Liver Injury (DILI) 
 any laboratory abnormality that required the participant to have study drug discontinued or 
interrupted 
 any laboratory abnormality that required the subject to receive specific corrective therapy.  
 
Wherever possible, the clinical rather than laboratory term should be used by the reporting investigator 
(e.g., anemia versus low hemoglobin value). 
11.1.3 Serious Adverse Event (SAE) 
An SAE is an adverse event that: 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 47 of 77 
 Results in death. NOTE: Death due to disease progression should not be reported as a SAE, 
unless it is attributable by the site investigator to the study drug(s) 
 Is life-threatening (defined as an event in which the subject was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it were more 
severe) 
 Requires inpatient hospitalization for >24 hours or prolongation of existing hospitalization. 
NOTE: Hospitalization for anticipated or protocol specified procedures such as administration 
of chemotherapy, central line insertion, metastasis interventional therapy, resection of primary 
tumor, or elective surgery, will not be considered serious adverse events. 
 Results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
 Results in a congenital anomaly or birth defect in a neonate/infant born to a mother exposed to 
the investigational medicinal product. 
 Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention (e.g., medical, 
surgical) to prevent one of the other serious outcomes listed in the definition above). Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions not resulting in hospitalization; 
or the development of drug dependency or drug abuse. 
o Potential drug induced liver injury (DILI) is also considered an important medical event.  
o Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the 
study drug is an SAE.  
o Although pregnancy is not always serious by regulatory definition, it must be handled as an 
SAE. 
o Bevacizumab and/or atezolizumab overdose. For purposes of this trial, an overdose will be 
defined as any dose exceeding the prescribed dose for bevacizumab and/or atezolizumab by 
20%.  
o Any venous or arterial event leading to discontinuation of bevacizumab will be considered 
serious and should be reported per SAE guidelines. 
o Cases of RPLS must be reported per SAE guidelines. 
11.1.4 Pregnancy 
If a female subject or a female partner of a male subject becomes pregnant while receiving the study 
drug or within 5 months after the last dose of study drug, an SAE report should be completed and 
submitted to Big Ten CRC AHQ according to the SAE reporting timelines described in 11.3.1. Follow-
up to obtain the outcome of the pregnancy should also occur. Abortion, whether accidental, therapeutic, 
or spontaneous, should always be classified as serious, and expeditiously reported as an SAE. 
Similarly, any congenital anomaly/birth defect in a child born to a female subject exposed to the study 
drug should be reported as an SAE. 
11.1.5 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency from 
information provided in the current IB, package insert, or when it is not included in the informed 
consent document as a potential risk. For example, under this definition, hepatic necrosis would be 
unexpected if the prescribing information or Investigator’s Brochure only referred to elevated hepatic 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 48 of 77 
enzymes or hepatitis. Unexpected also refers to AEs that are mentioned in the IB as occurring with a 
class of drugs or are anticipated from the pharmacological properties of the drug but are not specifically 
mentioned as occurring with the particular drug under investigation.   
11.1.6 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
Unrelated 
The Adverse Event is not related to the drug(s)  
Unlikely 
The Adverse Event is doubtfully related to the drug(s)  
Possible 
The Adverse Event may be related to the drug(s)  
Probable 
The Adverse Event is likely related to the drug(s)  
Definite 
The Adverse Event is clearly related to the drug(s)  
 
To ensure consistency of AE and SAE causality assessments, site investigators should apply the 
following general guideline: 
 
Yes 
There is a plausible temporal relationship between the onset of the AE and administration of 
Atezolizumab, and the AE cannot be readily explained by the subject’s clinical state, inter-current 
illness, or concomitant therapies; and/or the AE follows a known pattern of response to 
Atezolizumab; and/or the AE abates or resolves upon discontinuation of atezolizumab or dose 
reduction and, if applicable, reappears upon re- challenge. 
 
No 
Evidence exists that the AE has an etiology other than the Atezolizumab (e.g., preexisting medical 
condition, underlying disease, inter-current illness, or concomitant medication); and/or the AE has 
no plausible temporal relationship to Atezolizumab administration (e.g., cancer diagnosed 2 days 
after first dose of Atezolizumab. 
 
For subjects receiving combination therapy, causality will be assessed individually for each protocol-
mandated therapy. 
11.1.7 AEs of Special Interest (AESIs) 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to the 
product, for which ongoing monitoring and rapid communication by the local investigator to Big Ten 
CRC AHQ is required. Such an event might require further investigation in order to characterize and 
understand it. Depending on the nature of the event, rapid communication by Big Ten CRC AHQ to 
other parties (e.g., Regulatory Authorities) may also be warranted. 
 
The site will submit a completed SAE Submission Form (see Documents/ Info tab of the EDC) to Big 
Ten CRC AHQ within 3 business days of discovery of the event to safety@hoosiercancer.org. Big Ten 
CRC AHQ will forward AESIs to Genentech within fifteen (15) calendar days of the awareness date. 
 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 49 of 77 
Non-Drug Specific AESIs are: 
Adverse events of special interest for this study include the following: 
 Cases of potential drug-induced liver injury that include an elevated ALT or AST in combination 
with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law: 
o Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin > 2 x ULN 
o Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
 Suspected transmission of an infectious agent by Atezolizumab and Bevacizumab, as defined 
below: 
o Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent.  
A transmission of an infectious agent may be suspected from clinical symptoms or laboratory 
findings that indicate an infection in a patient exposed to a medicinal product.  This term applies 
only when a contamination of the study drug is suspected. 
 
The Atezolizumab Events of Special Interest are:  
 Pneumonitis 
 Colitis 
 Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism, and 
hypophysitis 
 Hepatitis, including AST or ALT > 10 × ULN 
 Systemic lupus erythematosus 
 Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, and 
meningoencephalitis 
 Events suggestive of hypersensitivity, infusion-related reactions, cytokine release syndrome, 
influenza-like illness and systemic inflammatory response syndrome  
 Nephritis 
 Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 Myositis 
 Myopathies, including rhabdomyolysis 
 Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
 Vasculitis 
 Autoimmune hemolytic anemia 
 Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic epidermal 
necrolysis) 
 
The Bevacizumab Adverse Events of Special Interest are:  
 Hypertension ≥ grade 3 
 Proteinuria ≥ grade 3 
 GI perforation, abscesses and fistulae (any grade) 
 Wound healing complications ≥ grade 3 
 Haemorrhage ≥ grade 3 (any grade CNS bleeding; > grade 2 haemoptysis) 
 Arterial thromboembolic events (any grade) 
 Venous thromboembolic events ≥ grade 3 
 Posterior reversible encephalopathy syndrome (PRES - any grade) 
 CHF ≥ grade 3 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 50 of 77 
 Non-GI fistula or abscess ≥ grade 2 
11.2 
Adverse Events Recording 
 AEs will be recorded from time of signed informed consent until 90 days after discontinuation of 
study drug(s) or until a new anti-cancer treatment starts, whichever occurs first. 
 AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).   
 All AEs will be recorded in the subject’s medical record and on the appropriate study specific 
eCRF form within the EDC system. 
 All AEs considered related to study drug(s) will be followed until resolution to ≤ Grade 1 or 
baseline, deemed clinically insignificant, and/or until a new anti-cancer treatment starts, 
whichever occurs first. 
 Asymptomatic laboratory abnormalities that do not require treatment will not be collected as 
adverse events. 
11.2.1 Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. Avoid 
colloquialisms and abbreviations. 
A. Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases). However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, it is 
acceptable to report the information that is currently available. If a diagnosis is subsequently 
established, it should be reported as follow-up information. 
B. Deaths 
All deaths that occur during the protocol-specified AE reporting period, regardless of 
attribution, will be reported to the appropriate parties. When recording a death, the event or 
condition that caused or contributed to the fatal outcome should be reported as the single 
medical concept. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, report “Unexplained Death”. 
C. Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be 
re-assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study. When reporting such events, it is important 
to convey the concept that the preexisting condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”). 
D. Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE. If a subject is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE. For example, if a subject is hospitalized to undergo coronary bypass 
surgery, record the heart condition that necessitated the bypass as the SAE. 
 Hospitalizations for the following reasons do not require reporting: 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 51 of 77 
o Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
o Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study or 
o Hospitalization or prolonged hospitalization for scheduled therapy of the target disease 
of the study 
E. Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for assessing 
adverse event severity. Below Table should be used for assessing severity for adverse events 
that are not specifically listed in the NCI CTCAE. 
 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE 
Grade 
Severity
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; or intervention not indicated
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age‐appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life‐threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self‐care activities of daily living b,c
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a. Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b. Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c. If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event 
d. Grade 4 and 5 events must be reported as serious adverse events
11.3 
Serious Adverse Event (SAEs) Reporting 
11.3.1 Site Requirements for Reporting SAEs to Big Ten CRC Administrative Headquarters 
 SAEs will be reported from time of signed informed consent until 90 days after discontinuation 
of study drug(s) or until a new anti-cancer treatment starts, whichever occurs first.  
 SAEs will be reported on the SAE Submission Form and entered in the SAE tab in the EDC 
system within 1 business day of discovery of the event.   


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 52 of 77 
 SAEs include events related and unrelated to the study drug(s).  
 All SAEs will be recorded in the subject’s medical record and on the appropriate study specific 
eCRF form within the EDC system.   
 All SAEs regardless of relation to study drug will be followed until resolution to ≤ Grade 1 or 
baseline and/or deemed clinically insignificant and/or until a new anti-cancer treatment starts, 
whichever occurs first. 
 All Product Complaints (with or without an AE) shall be forwarded within fifteen (15) calendar 
days of the awareness date. 
 Pregnancy reports: While such reports are not serious AEs or Adverse Drug Reactions (ADRs) 
per se, as defined herein, any reports of pregnancy (including pregnancy occurring in the partner 
of a male study subject), where the fetus may have been exposed to the Product, shall be 
transmitted within thirty (30) calendar days of the awareness date. Pregnancies will be followed 
up until the outcome of the pregnancy is known, whenever possible, based upon due diligence 
taken to obtain the follow-up information. 
 
The site will submit the completed SAE Submission Form (see Documents/ Info tab of the EDC) to Big 
Ten CRC AHQ within 1 business day of discovery of the event.  The form will be sent electronically 
to safety@hoosiercancer.org.  The site investigator is responsible for informing the IRB and/or other 
local regulatory bodies of the SAE as per local requirements. 
 
The original copy of the SAE Submission Form and the email correspondence or fax confirmation 
sheet must be kept within the study file at the study site. 
 
Once the SAE has resolved, sites must submit a follow up SAE Submission Form within a reasonable 
timeframe to Big Ten CRC AHQ electronically to safety@hoosiercancer.org. 
11.3.2 Big Ten CRC AHQ Requirements for Reporting SAEs to Genentech (GNE) 
Big Ten CRC AHQ will report all SAEs to GNE within 1 business day of receipt of the SAE 
Submission Form from a site. Follow-up information will be provided to GNE as it is received from 
site. 
 
Please refer to the Genentech Safety Data Exchange Agreement (SDEA) for contact information. 
11.3.3 Sponsor-Investigator Responsibilities 
Big Ten CRC AHQ will send a SAE summary to the sponsor-investigator within 1 business day of 
receipt of SAE Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness. 
11.3.4 Big Ten CRC AHQ Responsibilities for Reporting SAEs to FDA 
Big Ten CRC AHQ has been designated to manage the Investigational New Drug Application (IND) 
associated with this protocol on behalf of the sponsor-investigator.  Big Ten CRC AHQ will cross-
reference this submission to Genentech’s parent IND at the time of submission.  Additionally, Big Ten 
CRC AHQ will submit a copy of these documents to Genentech at the time of submission to FDA. 
 
Big Ten CRC AHQ will be responsible for all communication with the FDA in accordance with 
21CFR312 which includes but is not limited to the 7 and 15 Day Reports, as well as an Annual 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 53 of 77 
Progress Report. Additionally, Big Ten CRC AHQ will submit a copy of these reports to Genentech at 
the time of submission to FDA. 
11.3.5 IND Safety Reports Unrelated to this Trial 
GNE will provide IND safety reports from external studies that involve the study drug(s) per their 
guidelines.  Big Ten CRC AHQ will forward safety reports to the sponsor-investigator who will review 
these reports and determine if revisions are needed to the protocol or consent. Big Ten CRC AHQ will 
forward these reports to participating sites within 1 business day of receiving the sponsor-
investigator’s review. Based on the sponsor-investigator’s review, applicable changes will be made to 
the protocol and informed consent document (if required).  All IND safety reports will also be made 
available to sites via the EDC system. 
 
Upon receipt from Big Ten CRC AHQ, site investigators (or designees) are responsible for submitting 
these safety reports to their respective IRBs, as per their IRB policies. 
12. 
STATISTICAL CONSIDERATIONS 
Statistical analysis will be performed at the Department of Biostatistics at Indiana University School of 
Medicine. Parameter estimates and relevant summary statistics will be reported for both efficacy and 
safety outcomes. Continuous variables will be summarized by means, medians, minima, maxima and 
standard deviations. Categorical variables will be summarized by frequencies and percentages. Missing 
data will not be imputed. Additional exploratory analysis will be conducted when appropriate. Changes 
from the analysis plan will not require an amendment to the protocol unless it changes a significant 
feature in the protocol; however all changes from the original analysis plan will be documented in the 
final study report. The statistical analysis methods are outline below. 
12.1 
Study Design 
This is a multicenter single arm phase II clinical trial.  
12.2 
Endpoints 
12.2.1 Definition of Primary Endpoint 
Progression free survival (PFS) is defined as the time from the initiation of treatment to the time when 
the criteria for disease progression is met as defined by RECIST v1.1 OR death due to any cause. The 
PFS is subject to right censoring due to loss to follow-up or at the end of study duration. For patients 
who have not progressed and are alive at the last contact, the censoring time is defined as the time from 
the initiation of treatment to the time of the last disease evaluation. 
12.2.2 Definition of Secondary Endpoints 
Secondary objectives include the overall response rate (CR + PR), as well as the disease control rate (CR 
+ PR + SD), toxicity, and overall survival.  
 Response rate is defined as the number of confirmed complete response (CR) + confirmed partial 
response (PR) divided by the total number evaluable for response, as determined as per RECIST 
v1.1 criteria and assessed by the local investigator or designee. 
 Disease Control Rate is defined as the number of confirmed complete response (CR) + 
confirmed partial response (PR) + stable disease (SD) divided by the total number evaluable for 
response, as determined as per RECIST v1.1 criteria. 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 54 of 77 
 Toxicities will be defined by the NCI Common Terminology Criteria for Adverse Events (NCI 
CTCAE) v5. 
 Overall survival will be defined as the time from the initiation of treatment until death from any 
cause. 
12.3 
Sample Size and Accrual  
The study will evaluate whether carboplatin plus pemetrexed plus atezolizumab plus bevacizumab will 
improve the PFS compared to the PFS of carboplatin plus pemetrexed plus bevacizumab as reported in 
the literature. According to the current knowledge as reported in the literature, the median PFS for 
patients treated with carboplatin plus pemetrexed plus bevacizumab is approximately 6 months. We 
hypothesize that carboplatin plus pemetrexed plus atezolizumab plus bevacizumab will improve the 
median PFS to 9.6 months. 
 
The total study duration is 30 months, where the accrual period for the trial is 18 months and each 
patient will have a pre-scheduled follow-up of 12 months except for reason due to death. The test 
statistic is the nonparametric one-sample log-rank test [28]. The sample size was calculated using the 
PASS sample size software, one-sample log-rank tests procedure. The assumptions are uniform accrual 
over time, no loss to follow-up, exponentially distributed PFS times. A sample size of 42 patients would 
detect the hypothesized PFS difference with 83.5% power with 1-sided type I error of 0.05. To ensure 
the power of study, the study would require all accrued patients to complete the 1-year follow-up or until 
death. The expected number of events is 32. Suppose a rate of loss to follow-up of 5%. Then we 
anticipate recruiting 46 patients. If all 46 patients finish their pre-scheduled follow-up, then the power of 
the study is 86.3%. We thus propose a total sample size of 46 patients. The expected number of events is 
35.  
 
Because of the short accrual period (18 months), no interim analysis is planned to avoid the interruption 
of the study flow. The primary analysis will start when the last accrued patient finishes the 1-year 
follow-up.  
12.4 
Analysis Datasets 
 
Population 
Definition 
Enrolled 
This will comprise all subjects who meet the eligibility criteria 
and are registered onto the study.  
Full analysis set 
for efficacy 
The efficacy population will comprise all registered subjects 
who have received at least one dose of the treatment.  
Safety 
The safety population will comprise all subjects who received at 
least one dose of study medication. This population will be used 
for safety analysis. 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 55 of 77 
12.5 
Assessment of Safety 
Patients that have received at least one dose of study medication will be assessed for safety. Toxicities 
according to CTCAE v5 will be summarized by frequencies and rates calculated as the proportion of 
patients in the safety population experiencing SAEs, discontinuations due to AEs, and AEs. 
12.6 
Assessment of Efficacy 
Response Rate, disease control rate, and PFS will be assessed with RECIST v1.1. All registered subjects 
will be evaluable for efficacy.  
12.7 
Data Analysis Plans 
12.7.1 Analysis Plans for Primary Objective 
The hypothesis on PFS will be tested using the nonparametric one-sample log-rank test[28].  PFS will 
estimated with a Kaplan-Meier curve and 1-year PFS will be calculated with a 95% confidence interval.  
12.7.2 Analysis Plans for Secondary Objectives 
Response rate will be summarized as a rate measured as a proportion of patients in the efficacy 
population who achieved CR or PR during the study along with a 95% exact confidence interval.  
Disease control rate will be summarized as the proportion of patients who achieve CR or PR or SD with 
a 95% exact confidence interval.  OS will be estimated with a Kaplan-Meier curve and 1-year OS will 
be calculated with a 95% confidence interval.  
12.7.3 Analysis Plans for Exploratory Objectives 
Tissue samples will be collected at baseline and blood markers will be collected at baseline, after cycle 1 
and at end of study.  Markers will be correlated with clinical outcomes and specific toxicities using 
logistic and Cox regression methods, which will include important covariates such as age, gender, and 
genotypes.  Changes over time for blood markers will be analyzed with paired t-tests. 
12.7.4 Subgroup Analyses 
No pre-specified subgroup analyses are planned. 
12.7.5 Other Planned Analyses 
Subject characteristics, significant protocol violations, concomitant medication, exposure and 
compliance will be described. 
12.8 
Interim Analysis/Criteria for Stopping Study 
Because of the short accrual period (1 year), no interim analysis is planned to avoid the interruption of 
the study flow. 
 
Toxicities will be continuously monitored to determine if, in the first 10 subjects treated with at least one 
dose of study drug and observed for a minimum of 3 months after first dose of study therapy, two or 
more patients experience unacceptable toxicities warranting early closure of the trial, defined as: a) any 
treatment death; or b) any unexpected grade 3 or 4 toxicity lasting more than 2 weeks. If such events are 
observed as described above, the DSMC will discuss and provide recommendations to the sponsor-
investigator whether to terminate the study.  
 
 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 56 of 77 
13. 
TRIAL MANAGEMENT 
13.1 
Data and Safety Monitoring Plan (DSMP) 
The study will be conducted with guidance from the Indiana University Melvin and Bren Simon Cancer 
Center’s (IUSCC) DSMP for High Risk Phase II Trials. 
 
BTCRC AHQ facilitated oversight activities for High Risk Phase II Trials include: 
 Review and processing of all AEs requiring expedited reporting as defined in the protocol 
 Provide trial accrual progress, safety information, and data summary reports to the sponsor-
investigator, including a weekly update of aggregate AE data. For any increase in frequency 
of grade 3 or above adverse events (above the rate reported in the Investigator Brochure or 
package insert), the sponsor investigator will notify Big Ten CRC AHQ who will notify the 
DSMC Chair and Compliance Officer immediately. The notification will include the 
incidence of study adverse events, grades, and attributions, as well as investigator statements 
regarding comparison with risks per the IB/ package insert. 
 Notify of participating sites of adverse events potentially requiring expedited reporting and 
subsequent DSMC recommendations for study modifications. 
 Investigators will conduct continuous review of data and patient safety.  
 BTCRC AHQ will coordinate monthly (Phase II) meetings which will include representation 
from each accruing site.  
o These meetings should include review of data, the number of subjects, and significant 
toxicities as described in the protocol. Big Ten CRC AHQ will maintain meeting minutes 
and attendance for submission to the DSMC upon request. 
 Conduct the trial across all participating sites in accordance with the requirements set forth in the 
IUSCC DSMP. 
 Submit data summary reports to the lead institution Data Safety Monitoring Committee for review as 
per their DSMP 
13.2 
IUSCC Data Safety Monitoring Committee Oversight  
The IUSCC Data and Safety Monitoring Committee (DSMC) is responsible for oversight of subject 
safety, regulatory compliance, and data integrity for this trial. The DSMC will review this study to 
assess toxicity, compliance, data integrity, and accrual per the Institutional DSMP. Trials managed by 
Big Ten CRC AHQ are not routinely audited or monitored by IUSCC; however, the IUSCC DSMC 
retains the right to audit Big Ten CRC AHQ trials on a for cause basis. 
 
The IUSCC DSMC will review study data semi-annually during the active treatment and safety follow-
up portion of the trial per the IUSCC DSMP.   
 
In preparation for the IUSCC DSMC review, Big Ten CRC AHQ will provide the IUSCC DSMC with 
the following: 
 Monthly Summary Reports 
 Reports of the following, if not already included in the Monthly Summary Report: 
o Adverse event summary report (including serious adverse events) 
o Study accrual patterns  
o Protocol deviations 
 Audit and/or monitoring results, if applicable 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 57 of 77 
 Data related to stopping/ dose decision rules described in study design 
 Big Ten CRC AHQ monthly (Phase II) meeting minutes/ attendance 
 
Documentation of DSMC reviews will be provided to the sponsor-investigator and Big Ten CRC AHQ.  
The IUSCC DSMC will notify the sponsor-investigator and other regulatory bodies, as appropriate, for 
issues of immediate concern. The sponsor-investigator will work with Big Ten CRC AHQ to address the 
DSMC’s concerns as appropriate. 
 
At any time during the conduct of the trial, if it is the opinion of the sponsor-investigator that the risks 
(or benefits) to the patient warrant early closure of the study, this recommendation should be made in 
writing to the DSMC Chair and Compliance Officer. Alternatively, the DSMC may initiate suspension 
or early closure of the study at any time based on its review of the investigator reports. 
13.3 
IND Annual Reports 
For trials with an IND held locally by the IU principal investigator or university, the IND Annual Report 
will be prepared and submitted to the Compliance Team. This report will be reviewed by the DSMC at 
the time of FDA submission. 
13.4 
Data Quality Oversight Activities 
Remote validation of the EDC system data will be completed on a continual basis throughout the life 
cycle of the study.  A summary report (QC Report) of these checks together with any queries resulting 
from manual review of the eCRFs will be generated for each site and transmitted to the site and the site 
monitor. Corrections will be made by the study site personnel. 
 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects of the 
protocol are followed.  Additional for-cause visits may occur as necessary. Source documents will be 
reviewed for verification of agreement with data entered into the EDC system.  It is important for the 
site investigator and their relevant personnel to be available for a sufficient amount of time during the 
monitoring visits or audit, if applicable. The site investigator and institution guarantee access to source 
documents by Big Ten CRC AHQ or its designee. 
13.5 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food and 
Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All results of primary and 
secondary objectives must be posted to CT.gov within a year of completion. The sponsor-investigator 
has delegated responsibility to Big Ten CRC AHQ for registering the trial and posting the results on 
clinicaltrials.gov. Information posted will allow subjects to identify potentially appropriate trials for 
their disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and study site contact information. 
 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 58 of 77 
14. 
DATA HANDLING AND RECORD KEEPING 
14.1 
Data Management 
Big Ten CRC AHQ will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web-based clinical research platform compliant with Good Clinical Practices and Federal 
Rules and Regulations. Big Ten CRC AHQ personnel will coordinate and manage data for quality 
control assurance and integrity. All data will be collected and entered into the EDC system by study site 
personnel from participating institutions.   
14.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in the EDC system and correlative results will be 
captured in the EDC system or other secure database(s). If procedures on the study calendar are 
performed for standard of care, at minimum, that data will be captured in the source document. Select 
standard of care data will also be captured in the EDC system, according to study-specific objectives. 
Please see the Data and Safety Oversight Process (DSOP) guidelines for further details.  
 
The completed dataset is housed at Big Ten CRC AHQ and is the sole property of the sponsor-
investigator’s institution. It should not be made available in any form to third parties, except for 
authorized representatives of appropriate Health/Regulatory Authorities, without written permission 
from the sponsor-investigator and Big Ten CRC AHQ. After the initial publication, the complete data 
set will be available to all Big Ten CRC institutions. 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/Big Ten CRC AHQ, the site investigator 
agrees to keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, and 
detailed records of drug disposition.  All source documents are to remain in the subject’s file and 
retained by the site investigator in compliance with local and federal regulations. No records will be 
destroyed until Big Ten CRC AHQ confirms destruction is permitted. 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information.  All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, 
will not be made publicly available. Information collected will be maintained on secure, password 
protected electronic systems. Paper files that contain personal information will be kept in locked and 
secure locations only accessible to the study site personnel.  
 
Subjects will be informed in writing that some organizations including the sponsor-investigator and 
his/her research associates, Big Ten CRC AHQ, Genentech, IRB, or government agencies, like the FDA, 
may inspect their medical records to verify the information collected, and that all personal information 
made available for inspection will be handled in strictest confidence and in accordance with local data 
protection laws. 
 
If the results of the study are published, the subjects’s identity will remain confidential. 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 59 of 77 
14.5 
Aggregate Reports 
The sponsor-investigator (Nasser Hanna) will forward a copy of the Final Study Report to 
Genentech/Roche upon completion of the study. 
14.6 
Study Close-out 
Any study report submitted to the FDA by the sponsor-investigator should be copied to 
Genentech/Roche. This includes all IND annual reports and the Clinical Study Report (final study 
report). Additionally, any literature articles that are a result of the study should be sent to 
Genentech/Roche. Copies of such reports should be mailed to the assigned Clinical Operations contact 
for the study: 
 
Atezolizumab IIS Clinical Operations  
Email: anti-pdl-1-mpd3280a-gsur@gene.com 
 
15. 
ETHICS 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be approved in writing 
by an IRB.  The site investigator must submit written approval by the IRB to Big Ten CRC AHQ before 
he or she can enroll subjects into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements.  In addition, the IRB must approve all advertising used to recruit 
subjects for the study.  The protocol must be re-approved by the IRB as local regulations require.  
 
Progress reports and notifications of adverse events will be provided to the IRB according to local 
regulations and guidelines. 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the Declaration of 
Helsinki. Conduct of the study will be in compliance with ICH Good Clinical Practice, and with all 
applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written information about 
the nature, purpose, possible risks and benefits of the study.  Subjects must also be notified they are free 
to discontinue from the study at any time.  The subject should be given the opportunity to ask questions 
and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any procedure 
specifically for the study.  The site investigator must store the original, signed informed consent form.  
A copy of the signed informed consent form must be given to the subject. 
 
 
 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 60 of 77 
16. 
REFERENCES 
 
1. 
Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2015. CA Cancer J Clin, 2015. 65(1): 
p. 5-29. 
2. 
American Cancer Society. Cancer Facts & Figures 2017. Atlanta: American Cancer Society; 
2017. 
3. 
Schiller, J.H., et al., Comparison of four chemotherapy regimens for advanced non-small-cell 
lung cancer. N Engl J Med, 2002. 346(2): p. 92-8. 
4. 
Derman, B.A., et al., Treatment of advanced squamous cell carcinoma of the lung: a review. 
Translational Lung Cancer Research, 2015. 4(5): p. 524-532. 
5. 
Pao, W. and N. Girard, New driver mutations in non-small-cell lung cancer. The Lancet 
Oncology. 12(2): p. 175-180. 
6. 
Al-Saleh, K., C. Quinton, and P.M. Ellis, Role of pemetrexed in advanced non-small-cell lung 
cancer: meta-analysis of randomized controlled trials, with histology subgroup analysis. Current 
Oncology, 2012. 19(1): p. e9-e15. 
7. 
Johnson, D.H., et al., Randomized phase II trial comparing bevacizumab plus carboplatin and 
paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or 
metastatic non-small-cell lung cancer. J Clin Oncol, 2004. 22(11): p. 2184-91. 
8. 
Scagliotti, G.V., et al., Phase III study comparing cisplatin plus gemcitabine with cisplatin plus 
pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J 
Clin Oncol, 2008. 26(21): p. 3543-51. 
9. 
Ciuleanu, T., et al., Maintenance pemetrexed plus best supportive care versus placebo plus best 
supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. 
Lancet, 2009. 374(9699): p. 1432-40. 
10. 
Paz-Ares, L., et al., Maintenance therapy with pemetrexed plus best supportive care versus 
placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for 
advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, 
randomised controlled trial. Lancet Oncol, 2012. 13(3): p. 247-55. 
11. 
Ferrara, N., The role of vascular endothelial growth factor in pathological angiogenesis. Breast 
Cancer Res Treat, 1995. 36(2): p. 127-37. 
12. 
Folkman, J., What Is the Evidence That Tumors Are Angiogenesis Dependent? JNCI: Journal of 
the National Cancer Institute, 1990. 82(1): p. 4-7. 
13. 
Hurwitz , H., et al., Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic 
Colorectal Cancer. New England Journal of Medicine, 2004. 350(23): p. 2335-2342. 
14. 
Sandler , A., et al., Paclitaxel–Carboplatin Alone or with Bevacizumab for Non–Small-Cell Lung 
Cancer. New England Journal of Medicine, 2006. 355(24): p. 2542-2550. 
15. 
Patel, J.D., et al., PointBreak: a randomized phase III study of pemetrexed plus carboplatin and 
bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus 
carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB 
or IV nonsquamous non-small-cell lung cancer. J Clin Oncol, 2013. 31(34): p. 4349-57. 
16. 
Okazaki, T., et al., PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by 
recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc 
Natl Acad Sci U S A, 2001. 98(24): p. 13866-71. 
17. 
Greenwald, R.J., G.J. Freeman, and A.H. Sharpe, The B7 family revisited. Annu Rev Immunol, 
2005. 23: p. 515-48. 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 61 of 77 
18. 
Garon, E.B., et al., Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J 
Med, 2015. 372(21): p. 2018-28. 
19. 
Langer, C.J., et al., Carboplatin and pemetrexed with or without pembrolizumab for advanced, 
non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label 
KEYNOTE-021 study. Lancet Oncol, 2016. 17(11): p. 1497-1508. 
20. 
Gandhi, L., et al., Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung 
Cancer. New England Journal of Medicine. 378(22): p. 2078-2092. 
21. 
Manegold, C., et al., The Potential of Combined Immunotherapy and Antiangiogenesis for the 
Synergistic Treatment of Advanced NSCLC. J Thorac Oncol, 2017. 12(2): p. 194-207. 
22. 
Shin, S.J., et al., The Association Between PD-L1 Expression and the Clinical Outcomes to 
Vascular Endothelial Growth Factor-Targeted Therapy in Patients With Metastatic Clear Cell 
Renal Cell Carcinoma. Oncologist, 2015. 20(11): p. 1253-60. 
23. 
Yasuda, S., et al., Simultaneous blockade of programmed death 1 and vascular endothelial 
growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clin Exp 
Immunol, 2013. 172(3): p. 500-6. 
24. 
Herbst RS, B.J., Isambert N, et al., A phase 1 study of ramucirumab (R) plus pembrolizumab (P) 
in patients with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, 
nonsmall cell lung cancer (NSCLC), or urothelial carcinoma (UC): phase 1a results [abstract]. 
J Clin Oncol, 2016. 
25. 
Michael B. Atkins, D.F.M., Thomas Powles, Robert J. Motzer, Brian I. Rini, Lawrence Fong, 
Richard Wayne Joseph, Sumanta K. Pal, Mario Sznol, John D. Hainsworth, Walter Michael 
Stadler, Thomas E. Hutson, Alain Ravaud, Sergio Bracarda, Cristina Suarez, Toni K. Choueiri, 
Jiaheng Qiu, Mahrukh A. Huseni, Christina Schiff, Bernard J. Escudier; , IMmotion150: A phase 
II trial in untreated metastatic renal cell carcinoma patients of atezolizumab and bevacizumab vs 
and following atezolizumab or sunitinib. 2017 ASCO Annual Meeting. Abstract 4505. .  . 
26. 
Reck, M., et al., LBA1_PRPrimary PFS and safety analyses of a randomized phase III study of 
carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous 
metastatic nsclc (IMPOWER150). Annals of Oncology, 2017. 28(suppl_11): p. mdx760.002-
mdx760.002. 
27. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
28. 
Kwak MJ, Jung SH. Phase II clinical trials with time-to-event endpoints: Optimal two-stage 
designs with one-sample log-rank test. Statistics in Medicine. 2014;33:2004–2016. 
29. 
Lee DW, Santomasso BD, Locke FL et al. ASTCT Consensus Grading for Cytokine Release 
Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow 
Transplant. 2019 Apr;25(4):625-638. 
30. 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient receiving PD-1-
directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
31. 
Adashek ML, Feldman M. Cytokine release syndrome resulting from anti-programmed death-1 
antibody: raising awareness among community oncologist. J Oncol Practice 2019;15:502-4. 
32. 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of cytokine 
release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin Risk Manag 
2019;15:323-35. 
 
 
 
 
 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 62 of 77 
17. 
APPENDIX I: ANAPHYLAXIS PRECAUTIONS 
 
EQUIPMENT NEEDED 
 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation monitor, and 
thermometer 
 
Oxygen 
 
Epinephrine for intravenous, intramuscular, and endotracheal administration in accordance with 
institutional guidelines 
 
Antihistamines 
 
Corticosteroids 
 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment infusion, the following 
procedures should be performed: 
1. Stop the study treatment infusion. 
2. Call for additional medical assistance. 
3. Ensure that appropriate monitoring is in place, with continuous ECG and pulse oximetry 
monitoring, if possible. 
4. Administer antihistamines, epinephrine, or other medications as required by participant status and 
as directed by the physician in charge. 
5. Continue to observe the participant and document observations. 
6. Draw serum/plasma samples for immunogenicity testing. 
7. Ask participant to return for washout immunogenicity sample if appropriate. 
 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 63 of 77 
18. 
APPENDIX II: MANAGEMENT OF ATEZOLIZUMAB-SPECIFIC ADVERSE EVENTS 
Toxicities associated or possibly associated with atezolizumab treatment should be managed according 
to standard medical practice.  Additional tests, such as autoimmune serology or biopsies, should be used 
to evaluate for a possible immunogenic etiology. 
 
Although most immune-related adverse events observed with immunomodulatory agents have been mild 
and self-limiting, such events should be recognized early and treated promptly to avoid potential major 
complications.  Discontinuation of atezolizumab may not have an immediate therapeutic effect, and in 
severe cases, immune-related toxicities may require acute management with topical corticosteroids, 
systemic corticosteroids, or other immunosuppressive agents.  
 
The investigator should consider the benefitrisk balance a given patient may be experiencing prior 
to further administration of atezolizumab.  In patients who have met the criteria for permanent 
discontinuation, resumption of atezolizumab may be considered if the patient is deriving benefit and has 
fully recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by both the investigator (or an appropriate delegate)  
 
PULMONARY EVENTS 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated with the 
administration of atezolizumab.  Patients will be assessed for pulmonary signs and symptoms throughout 
the study and will also have computed tomography (CT) scans of the chest performed at every tumor 
assessment.   
 
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies such as 
pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, heart failure, chronic 
obstructive pulmonary disease, or pulmonary hypertension.  Management guidelines for pulmonary 
events are provided in Table 1. 
 
Table 1 
Management Guidelines for Pulmonary Events, Including Pneumonitis 
Event 
Management 
Pulmonary event, 
Grade 1  
 Continue atezolizumab and monitor closely. 
 Re-evaluate on serial imaging. 
 Consider patient referral to pulmonary specialist.
Pulmonary event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to pulmonary and infectious disease specialists and consider 
bronchoscopy or BAL. 
 Initiate treatment with 12 mg/kg/day oral prednisone or equivalent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. 
 For recurrent events, treat as a Grade 3 or 4 event.
Pulmonary event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab. c 
 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.


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 64 of 77 
BAL = bronchoscopic alveolar lavage. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.   
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by the investigator.
 
HEPATIC EVENTS 
Immune-related hepatitis has been associated with the administration of atezolizumab.  Eligible patients 
must have adequate liver function, as manifested by measurements of total bilirubin and hepatic 
transaminases, and liver function will be monitored throughout study treatment.  Management guidelines 
for hepatic events are provided in Table 2. 
 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting should have 
liver function tests (LFTs) performed immediately and reviewed before administration of the next dose 
of study drug. 
 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic etiologies 
should be considered and addressed, as appropriate. 
 
Table 2 
Management Guidelines for Hepatic Events 
Event 
Management 
Hepatic event, 
Grade 1 
 Continue atezolizumab. 
 Monitor LFTs until values resolve to within normal limits or to baseline values. 
Hepatic event, 
Grade 2 
All events: 
 Monitor LFTs more frequently until return to baseline values.  
Events of   5 days’ duration: 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Initiate treatment with 12 mg/kg/day oral prednisone or equivalent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. c
Hepatic event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab. c 
 Consider patient referral to gastrointestinal specialist for evaluation and liver 
biopsy to establish etiology of hepatic injury.  
 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.
LFT = liver function tests. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  The 
acceptable length of the extended period of time will be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 65 of 77 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by the investigator (or an appropriate delegate). 
 
GASTROINTESTINAL EVENTS 
Immune-related colitis has been associated with the administration of atezolizumab.  Management 
guidelines for diarrhea or colitis are provided in Table 3. 
 
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 C-reactive protein, platelet 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.  
 
Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
 Continue atezolizumab. 
 Initiate symptomatic treatment. 
 Endoscopy is recommended if symptoms persist for  7 days. 
 Monitor closely. 
Diarrhea or 
colitis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 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.  
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. c
Diarrhea or 
colitis, Grade 3 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 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, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab c
Diarrhea or 
colitis, Grade 4 
 Permanently discontinue atezolizumab. c 
 Refer patient to GI specialist for evaluation and confirmation biopsy. 
 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 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. 
GI  gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  The acceptable 
length of the extended period of time will be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone 
or equivalent before atezolizumab can be resumed.


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 66 of 77 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by the investigator (or an appropriate delegate).  
 
ENDOCRINE EVENTS 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have been associated 
with the administration of atezolizumab.  Management guidelines for endocrine events are provided in 
Table 4. 
 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, constipation, or 
mental status changes should be investigated for the presence of thyroid, pituitary, or adrenal 
endocrinopathies.  The patient should be referred to an endocrinologist if an endocrinopathy is 
suspected.  Thyroid-stimulating hormone (TSH) and free triiodothyronine and thyroxine levels should 
be measured to determine whether thyroid abnormalities are present.  Pituitary hormone levels and 
function tests (e.g., TSH, growth hormone, luteinizing hormone, follicle-stimulating hormone, 
testosterone, prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may help to 
differentiate primary pituitary insufficiency from primary adrenal insufficiency. 
 
Table 4 
Management Guidelines for Endocrine Events 
Event 
Management 
Asymptomatic 
hypothyroidism 
 Continue atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH weekly.
Symptomatic 
hypothyroidism 
 Withhold atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH weekly. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and thyroid function is 
improving. 
Asymptomatic 
hyperthyroidism 
TSH  0.1 mU/L and  0.5 mU/L: 
 Continue atezolizumab. 
 Monitor TSH every 4 weeks. 
TSH  0.1 mU/L: 
 Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism 
 Withhold atezolizumab. 
 Initiate treatment with anti-thyroid drug such as methimazole or carbimazole 
as needed. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and thyroid function is 
improving. 
 Permanently discontinue atezolizumab for life-threatening immune-related 
hyperthyroidism. c
Symptomatic adrenal 
insufficiency, 
Grade 24  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to endocrinologist. 
 Perform appropriate imaging. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 67 of 77 
Event 
Management 
and convert to 12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event resolves to Grade 1 or better and patient is stable on replacement 
therapy, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better or patient is not stable on 
replacement therapy while withholding atezolizumab, permanently 
discontinue atezolizumab. c
Hyperglycemia, 
Grade 1 or 2  
 Continue atezolizumab. 
 Investigate for diabetes. If patient has Type 1 diabetes, treat as a Grade 3 
event. If patient does not have Type 1 diabetes, treat per institutional 
guidelines. 
 Monitor for glucose control.
Hyperglycemia, 
Grade 3 or 4 
 Withhold atezolizumab. 
 Initiate treatment with insulin. 
 Monitor for glucose control. 
 Resume atezolizumab when symptoms resolve and glucose levels are stable.
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 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. 
 Initiate hormone replacement if clinically indicated. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
 For recurrent hypophysitis, treat as a Grade 4 event.
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 
 Permanently discontinue atezolizumab c 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 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. 
 Initiate hormone replacement if clinically indicated.
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  The 
acceptable length of the extended period of time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by the investigator (or an appropriate delegate).  
 
 
 
 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 68 of 77 
OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  Management 
guidelines for ocular events are provided in Table 5. 
 
Table 5 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, Grade 1  
 Continue atezolizumab. 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If symptoms persist, treat as a Grade 2 event.
Ocular event, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab c 
Ocular event, Grade 3 or 4 
 Permanently discontinue atezolizumab. c 
 Refer patient to ophthalmologist. 
 Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.   
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month.
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by the investigator (or an appropriate delegate).  
 
IMMUNE-RELATED MYOCARDITIS 
Immune-related myocarditis has been associated with the administration of atezolizumab.  Immune-
related myocarditis should be suspected in any patient presenting with signs or symptoms suggestive of 
myocarditis, including, but not limited to, dyspnea, chest pain, palpitations, fatigue, decreased exercise 
tolerance, or syncope.  Immune-related myocarditis needs to be distinguished from myocarditis resulting 
from infection (commonly viral, e.g., in a patient who reports a recent history of GI illness), ischemic 
events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, or progression of 
malignancy.   
 
All patients with possible myocarditis should be urgently evaluated by performing cardiac enzyme 
assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as appropriate per 
institutional guidelines.  A cardiologist should be consulted.  An endomyocardial biopsy may be 
considered to enable a definitive diagnosis and appropriate treatment, if clinically indicated. 
 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 69 of 77 
Patients with signs and symptoms of myocarditis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 6. 
 
Table 6 
Management Guidelines for Immune-Related Myocarditis 
Event 
Management 
Immune-related 
myocarditis, Grade 1 
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines.
Immune-related 
myocarditis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset a  
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate. 
 Consider 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. a 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
Immune-related 
myocarditis, Grade 3-4 
 Permanently discontinue atezolizumab. c 
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate. 
 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. a,b 
 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.
ECMO  extracorporeal membrane oxygenation; VAD  ventricular assist device. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time must be determined by the investigator . 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by the investigator (or an appropriate delegate).
 
INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  However, patients 
who experience an infusion-related reaction (IRR) or cytokine-release cyndrome (CRS) with 
atezolizumab may receive premedication with antihistamines, antipyretics and/or analgesics (e.g., 
acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is prohibited in treating atezolizumab-
associated IRRs because of its potential for causing agranulocytosis. 
 
IRRs are known to occur with the administration of monoclonal antibodies and have been reported with 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 70 of 77 
atezolizumab. These reactions, which are thought to be due to release of cytokines and/or other chemical 
mediators, occur within 24 hours of atezolizumab administration and are generally mild to moderate in 
severity. 
 
CRS is defined as a supraphysiologic response following administration of any immune therapy that 
results in activation or engagement of endogenous or infused T cells and/or other immune effector cells. 
Symptoms can be progressive, always include fever at the onset, and may include hypotension, capillary 
leak (hypoxia), and end-organ dysfunction [29]. CRS has been well documented with chimeric antigen 
receptor T-cell therapies and bispecific T-cell engager antibody therapies but has also been reported with 
immunotherapies that target PD-1 or PD-L1 [30, 31], including atezolizumab. 
 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in recognition of the 
challenges in clinically distinguishing between the two, consolidated guidelines for medical 
management of IRRs and CRS are provided in Table 7.   
 
Table 7 
Management Guidelines for Infusion-Related Reactions 
Event 
Management
Grade 1a  
Feverb with or 
without 
constitutional 
symptoms 
 Immediately interrupt infusion. 
 Upon symptom resolution, wait 30 minutes and then restart infusion at half the 
rate being given at the time of event onset. 
 If the infusion is tolerated at the reduced rate for 30 minutes, the infusion rate 
may be increased to the original rate. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment,c including maintenance of IV fluids for 
hydration. 
 In case of rapid decline or prolonged CRS (> 2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per Grade 2. 
 For subsequent infusions, consider administration of oral premedication with 
antihistamines, anti-pyretics, and/or analgesics, and monitor closely for IRRs 
and/or CRS. 
Grade 2a 
Feverb with 
hypotension not 
requiring 
vasopressors 
and/or 
Hypoxia requiring 
low-flow oxygend 
by nasal cannula 
or blow-by 
 Immediately interrupt atezolizumab infusion. 
 Upon symptom resolution, wait for 30 minutes and then restart infusion at half 
the rate being given at the time of event onset. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment.c 
 For hypotension, administer IV fluid bolus as needed. 
 Monitor cardiopulmonary and other organ function closely (in the ICU, if 
appropriate). Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis). If no 
improvement within 24 hours, initiate workup and assess for signs and 
symptoms of HLH or MAS. 
 Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.e 
 Consider hospitalization until complete resolution of symptoms. If no 
improvement within 24 hours, manage as per Grade 3, that is, hospitalize patient 
(monitoring in the ICU is recommended), permanently discontinue 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 71 of 77 
atezolizumab. 
 If symptoms resolve to Grade 1 or better for 3 consecutive days, the next dose of 
atezolizumab may be administered. For subsequent infusions, consider 
administration of oral premedication with antihistamines, anti-pyretics, and/or 
analgesics and monitor closely for IRRs and/or CRS. 
 If symptoms do not resolve to Grade 1 or better for 3 consecutive days, contact 
Medical Monitor. 
Grade 3a 
Feverb with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin)  
and/or 
Hypoxia requiring 
high-flow 
oxygend 
by nasal cannula, 
face mask, non-
rebreather mask, 
or venturi mask 
 Permanently discontinue atezolizumab.f 
 Administer symptomatic treatment.c 
 For hypotension, administer IV fluid bolus and vasopressor as needed. 
 Monitor cardiopulmonary and other organ function closely; monitoring in the 
ICU is recommended. Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis). If no 
improvement within 24 hours, initiate workup and assess for signs and 
symptoms of HLH or MAS. 
 Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.e 
 Hospitalize patient until complete resolution of symptoms. If no improvement 
within 24 hours, manage as per Grade 4, that is, admit patient to ICU and initiate 
hemodynamic monitoring, mechanical ventilation, and/or IV fluids and 
vasopressors as needed; for patients who are refractory to anti-cytokine therapy, 
experimental treatments may be considered at the discretion of the investigator.
Grade 4a 
Fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) 
and/or 
Hypoxia requiring 
oxygen by 
positive pressure 
(e.g., CPAP, 
BiPAP, intubation 
and mechanical 
ventilation) 
 Permanently discontinue atezolizumab.f 
 Administer symptomatic treatment.c 
 Admit patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed. Monitor other organ 
function closely. Manage constitutional symptoms and organ toxicities as per 
institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis). If no 
improvement within 24 hours, initiate workup and assess for signs and 
symptoms of HLH or MAS. 
 Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.e For patients who are refractory to anti-cytokine 
therapy, experimental treatmentsg may be considered at the discretion of the 
investigator. 
  Hospitalize patient until complete resolution of symptoms.
ASTCT= American Society for Transplantation and Cellular Therapy; BiPAP= bi-level positive airway 
pressure; CAR= chimeric antigen receptor; CPAP= continuous positive airway pressure; 
CRS= cytokine-release syndrome; HLH= hemophagocytic lymphohistiocytosis; IRR = infusion-related 
reaction; MAS= macrophage activation syndrome.
Note: The management guidelines have been adapted from NCCN guidelines for management of 
CAR T-cell-related toxicities (Version 2.2019). 
a. Grading system for management guidelines is based on ASTCT consensus grading for CRS. NCI 
CTCAE (version as specified in the protocol) should be used when reporting severity of IRRs, CRS, 
or organ toxicities associated with CRS on the Adverse Event eCRF. Organ toxicities associated 
with CRS should not influence overall CRS grading.


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 72 of 77 
b. Fever is defined as temperature ≥ 38°C not attributable to any other cause. In patients who develop 
CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no longer 
required when subsequently determining event severity (grade). In this case, the grade is driven by 
the presence of hypotension and/or hypoxia. 
c. Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen. For bronchospasm, urticaria, or dyspnea, additional treatment may 
be administered as per institutional practice. 
d. Low flow is defined as oxygen delivered at ≤ 6 L/min, and high flow is defined as oxygen delivered 
at > 6 L/min. 
e. There are case reports where anti-cytokine therapy has been used for treatment of CRS with immune 
checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), but data are limited, and the 
role of such treatment in the setting of antibody-associated CRS has not been established. 
f. Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by the investigator (or an appropriate delegate). For subsequent 
infusions, administer oral premedication with antihistamines, anti-pyretics, and/or analgesics, and 
monitor closely for IRRs and/or CRS. Premedication with corticosteroids and extending the infusion 
time may also be considered after considering the benefit-risk ratio. 
g. Refer to Riegler et al. [32] for information on experimental treatments for CRS.
 
PANCREATIC EVENTS 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab.  The differential diagnosis of 
acute abdominal pain should include pancreatitis.  Appropriate work-up should include an evaluation for 
ductal obstruction, as well as serum amylase and lipase tests.  Management guidelines for pancreatic 
events, including pancreatitis, are provided in Table 8. 
 
Table 8 
Management Guidelines for Pancreatic Events, Including Pancreatitis  
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
Amylase and/or lipase > 1.5-2.0 × ULN: 
 Continue atezolizumab. 
 Monitor amylase and lipase weekly. 
 For prolonged elevation (e.g.,  3 weeks), consider treatment with 10 
mg/day oral prednisone or equivalent. 
Asymptomatic with amylase and/or lipase > 2.0-5.0 × ULN: 
 Treat as a Grade 3 event
Amylase and/or lipase 
elevation, Grade 3 or 4 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to GI specialist. 
 Monitor amylase and lipase every other day. 
 If no improvement, consider treatment with 12 mg/kg/day oral 
prednisone or equivalent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
 For recurrent events, permanently discontinue atezolizumab. c 
Immune-related pancreatitis, 
Grade 2 or 3 
 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to GI specialist. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 73 of 77 
Event 
Management 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
 For recurrent events, permanently discontinue atezolizumab. c 
Immune-related pancreatitis, 
Grade 4 
 Permanently discontinue atezolizumab. c 
 Refer patient to GI specialist. 
 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 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. 
GI  gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by the investigator (or an appropriate delegate). 
 
DERMATOLOGIC EVENTS 
Treatment-emergent rash has been associated with atezolizumab.  The majority of cases of rash were 
mild in severity and self-limited, with or without pruritus.  A dermatologist should evaluate persistent 
and/or severe rash or pruritus.  A biopsy should be considered unless contraindicated.  Management 
guidelines for dermatologic events are provided in Table 9. 
 
Table 9 
Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic event, Grade 1   Continue atezolizumab. 
 Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines).
Dermatologic event, Grade 2   Continue atezolizumab. 
 Consider patient referral to dermatologist. 
 Initiate treatment with topical corticosteroids. 
 Consider treatment with higher-potency topical corticosteroids if 
event does not improve.
Dermatologic event, Grade 3   Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to dermatologist. 
 Initiate treatment with 10 mg/day oral prednisone or equivalent, 
increasing dose to 12 mg/kg/day if event does not improve within 
4872 hours. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 74 of 77 
Event 
Management 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
Dermatologic event, Grade 4 
 Permanently discontinue atezolizumab. c 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time will be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by the investigator (or an appropriate delegate). 
 
NEUROLOGIC DISORDERS 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent atezolizumab.  
Patients may present with signs and symptoms of sensory and/or motor neuropathy.  Diagnostic work-up 
is essential for an accurate characterization to differentiate between alternative etiologies.  Management 
guidelines for neurologic disorders are provided in Table 10. 
 
Table 10 
Management Guidelines for Neurologic Disorders 
Event 
Management
Immune-related neuropathy, 
Grade 1 
 Continue atezolizumab. 
 Investigate etiology.
Immune-related neuropathy, 
Grade 2  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Investigate etiology. 
 Initiate treatment as per institutional guidelines. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
Immune-related neuropathy, 
Grade 3 or 4 
 Permanently discontinue atezolizumab. c  
 Initiate treatment as per institutional guidelines.
Myasthenia gravis and 
Guillain-Barré syndrome (any 
grade) 
 Permanently discontinue atezolizumab. c 
 Refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider initiation of 12 mg/kg/day oral or IV prednisone or 
equivalent.
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by the investigator (or an appropriate delegate). 
 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 75 of 77 
IMMUNE-RELATED MENINGOENCEPHALITIS 
Immune-related meningoencephalitis is an identified risk associated with the administration of 
atezolizumab.  Immune-related meningoencephalitis should be suspected in any patient presenting with 
signs or symptoms suggestive of meningitis or encephalitis, including, but not limited to, headache, neck 
pain, confusion, seizure, motor or sensory dysfunction, and altered or depressed level of consciousness.  
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from potential 
meningoencephalitis resulting from infection (bacterial, viral, or fungal) or progression of malignancy, 
or secondary to a paraneoplastic process.   
 
All patients being considered for meningoencephalitis should be urgently evaluated with a CT scan 
and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema.  If deemed safe by the 
treating physician, a lumbar puncture should be performed and a neurologist should be consulted. 
 
Patients with signs and symptoms of meningoencephalitis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 11. 
 
Table 11 
Management Guidelines for Immune-Related Meningoencephalitis 
Event 
Management 
Immune-related 
meningoencephalitis, all 
grades 
 Permanently discontinue atezolizumab. a 
 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 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.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by the investigator (or an appropriate delegate). 
 
IMMUNE-RELATED NEPHRITIS 
Immune-related nephritis has been associated with the administration of atezolizumab. Eligible patients 
must have adequate renal function, and renal function, including serum creatinine, should be monitored 
throughout study treatment. Patients with abnormal renal function should be evaluated and treated for 
other more common etiologies (including prerenal and postrenal causes, and concomitant medications 
such as non-steroidal anti-inflammatory drugs). Refer the patient to a renal specialist if clinically 
indicated. A renal biopsy may be required to enable a definitive diagnosis and appropriate treatment. 
 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate etiology, should 
be treated according to the guidelines in Table 12. 
 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 76 of 77 
Table 12 
Management Guidelines for Immune-Related Nephritis 
Event 
Management 
Renal event, 
Grade 1 
 Continue atezolizumab 
 Monitor kidney function, including creatinine, closely until values resolve to 
within normal limits or to baseline values.
Renal event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset (a) 
 Refer patient to renal specialist. 
 Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral prednisone. 
 If event resolves to Grade 1 or better, resume atezolizumab. (b) 
 If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. (c)
Renal event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab. 
 Refer patient to renal specialist and consider renal biopsy. 
 Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral prednisone. 
 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.
a. Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent. The acceptable 
length of the extended period of time must be agreed upon by the investigator. 
b. If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral prednisone 
or equivalent before atezolizumab can be resumed. 
c. Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be re-challenged with atezolizumab only after 
approval has been documented by the investigator (or an appropriate delegate). 
 
IMMUNE-RELATED MYOSITIS 
Myositis or inflammatory myopathies are a group of disorders sharing the common feature of 
inflammatory muscle injury; dermatomyositis and polymyositis are amongst the most common 
disorders. Initial diagnosis is based on clinical (muscle weakness, muscle pain, skin rash in 
dermatomyositis), biochemical (serum creatine-kinase increase), and imaging 
(electromyography/MRI) features, and is confirmed with a muscle-biopsy. 
 
Patients with signs and symptoms of myositis, in the absence of an identified alternate etiology, should 
be treated according to the guidelines in Table 13. 
 
Table 13 
Management Guidelines for Immune-Related Myositis 
Event 
Management 
Immune-related 
myositis, Grade 1 
 Continue atezolizumab 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines.
Immune-related 
myositis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset (a) 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or equivalent 
upon improvement. 
 If corticosteroids are initiated and event does not improve within 48 hours after 


Big Ten Cancer Research Consortium 
 
 
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN17-139 
07APR2020 
Confidential 
Page 77 of 77 
Event 
Management 
initiating corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. (b) 
 If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. (c)
Immune-related 
myositis, Grade 3 
 Withhold atezolizumab for up to 12 weeks after event onset. (a) 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
 Respiratory support may be required in more severe cases. 
 Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone or higher-dose bolus if patient is severely compromised (e.g. 
cardiac or respiratory symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 1-2 mg/kg/day oral prednisolone 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, resume atezolizumab. (b) 
 If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. (c) 
 For recurrent events, treat as a Grade 4 event.
Immune-related 
myositis, Grade 4 
 Permanently discontinue atezolizumab. (c) 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. Respiratory support may be required 
in more severe cases. 
 Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone or higher-dose bolus if patient is severely compromised (e.g. 
cardiac or respiratory symptoms, dysphagia, or weakness that severely limiting 
mobility); 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.
d. Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent. The acceptable 
length of the extended period of time must be agreed upon by the investigator. 
e. If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
f. Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be re-challenged with atezolizumab only after 
approval has been documented by the investigator (or an appropriate delegate).