Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: Non-Small Cell Lung Cancer Non-Small-Cell Lung Carcinoma Nonsmall Cell Lung Cancer NSCLC
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 39
Healthy volunteers: no

Brief summary:
This is a research study to test the effectiveness of nab-paclitaxel + carboplatin + MPDL3280A for treatment of non-small-cell lung carcinoma (NSCLC), which is a type of lung cancer. The study aims to determine if chemotherapy combined with immune-based therapy can lead to improvement in tumor response rates over historical response rates with chemotherapy alone.

Detailed description:
Lung cancer is the most common cancer in both men and women worldwide, accounting for 13% of incident cancers. In 2015, it was estimated there would be 221,200 new lung cancers diagnosed in the United States, with 158,040 lung cancer deaths. Approximately 85% of all lung cancers are characterized as non-small cell lung cancer (NSCLC).

Repeated studies have shown neoadjuvant cytotoxic chemotherapy to be safe prior to surgical resection of NSCLC with no difference in extent of surgical procedures performed, operative morbidity and mortality. The debate remains as to whether neoadjuvant or adjuvant chemotherapy is the best approach, with advantages and disadvantages to each.

The investigators propose that new therapies such as immune checkpoint inhibitors that demonstrate promising clinical activity in the advanced disease setting must be incorporated into the neoadjuvant setting, in order to maximize benefit early in a patient's treatment course, and with a suitable surrogate endpoint that can be used to establish a preliminary efficacy signal, prior to initiation of a large confirmatory study.

Arms:
arm 1: Subjects with advanced or recurrent cancers receiving:

* MPDL3280A every 21 days for up to 84 days
* Carboplatin every 21 days for up to 84 days
* Nab-paclitaxel every 7 days for up to 84 days

Interventions: intervention 1: MPDL3280A intervention 2: Carboplatin intervention 3: Nab-paclitaxel
Intervention descriptions: intervention 1: MPDL3280A is a human, Fc optimized, monoclonal antibody directed against the protein ligand programmed cell death-1 ligand 1 (PD-L1), with potential immune checkpoint inhibitory and antineoplastic activities. Atezolizumab binds to PD-L1, blocking its binding to and activation of its receptor programmed death 1 (PD-1) expressed on activated T-cells, which may enhance the T-cell-mediated immune response to neoplasms and reverse T-cell inactivation. MPDL3280A 1200 mg will be administered as a 60 minute IV infusion on first administration, then over 30 minutes subsequently if tolerated. intervention 2: Carboplatin is a second-generation platinum compound with a broad spectrum of antineoplastic properties. Carboplatin contains a platinum atom complexed with two ammonia groups and a cyclobutane-dicarboxyl residue. This agent is activated intracellularly to form reactive platinum complexes that bind to nucleophilic groups, thereby inducing intrastrand and interstrand DNA cross-links, as well as DNA-protein cross-links. These carboplatin-induced DNA and protein effects result in apoptosis and cell growth inhibition. Carboplatin area under the curve (AUC)=6 will be administered as a 30 minute IV infusion immediately after nab-paclitaxel. intervention 3: Nab-paclitaxel is an albumin-stabilized nanoparticle formulation of the natural taxane paclitaxel with antineoplastic activity. Nab-paclitaxel binds to and stabilizes microtubules, preventing their depolymerization and so inhibiting cellular motility, mitosis, and replication. Nab-paclitaxel 100 mg/m2 will be administered as a 30 minute IV infusion.

Protocol document:
Prot_SAP_000.pdf: 
Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB# AAAQ3153 - Version Date: 05SEP2018 
1 
CUMC IRB#:   
AAAQ3153 
Celgene Protocol Identifier 
AX-CL-NSCLC-PI-005652 
Genentech Protocol Identifier ML29820 
Version Date: 
05-SEP-2018 
TITLE:  
A single-arm, phase II study of neoadjuvant MPDL3280A, 
nab-paclitaxel and carboplatin (MAC) in resectable non-small 
cell lung cancer 
Coordinating Center: 
Columbia University Medical Center 
Principal Investigator: 
Catherine Shu 
161 Fort Washington Avenue 
New York, NY 10032 
Telephone: 212-305-3997 
Fax: 212-305-3035 
cas2145@cumc.columbia.edu 
Statistician: 
Codruta Chiuzan, PhD 
722 W 168th St., 6th Floor 
New York NY 10032 
Telephone: 212-305-9701 
Fax: 212-305-9408 
cc3780@cumc.columbia.edu 
Regulatory Sponsor: 
Columbia University Medical Center 
161 Fort Washington Avenue 
212-305-3997 
New York, NY 10032 
Funding Source: 
Genentech-BioOncology 
1 DNA Way Mailstop 258A 
South San Francisco, CA 94080 
(888) 662-6728 
Celgene Corporation 
Attn: Medical Affairs Operations 
Connell Corporate Park  
400 Connell Drive Suite 700 
Berkeley Heights, NJ  07922 
(908) 673-9000 
NCT02716038


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Protocol Signature Page 
 
I confirm that 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 ICH guidelines for good clinical practices, and the applicable federal, state, and local 
laws, rules, and regulations relating to the conduct of the protocol. I have read and understand 
the information in the Investigators’ Brochure (or Manufacturer’s Brochure) regarding the risks 
and potential benefits. I will promptly submit the protocol to the applicable IRB for review and 
approval. Once the protocol has been approved by the IRB, I understand that any modification 
made during the course of the study must first be approved by the IRB, prior to implementation 
except when such modification is made to remove an immediate hazard to the subject. I certify 
that I, and the study staff, have received the requisite training to conduct this research protocol. I 
agree to maintain adequate and accurate records in accordance with Columbia University and 
Herbert Irving Comprehensive Cancer Center policies, Federal, state and local laws and 
regulations. I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
 
 
_________________________________                _______________ 
Signature of Principal Investigator  
               Date 
 
 
 
_________________________________                 
Principal Investigator Name (Print) 
 
 
 
 
_________________________________                 
Name of Institution
Instructions to Principal Investigator: Sign and Date this signature page and print your name. 
Return the original, completed and signed to the Clinical Protocol & Data Management Office. 
Retain a copy in the regulatory binder.  


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Protocol Synopsis  
 
Title 
A single-arm, phase II study of neoadjuvant MPDL3280A, nab-
paclitaxel and carboplatin (MAC) in resectable non-small cell lung 
cancer (NSCLC) 
Short Title 
Neoadjuvant MPDL3280A, nab-paclitaxel and carboplatin in NSCLC 
Protocol Number 
AAAQ3153 
Celgene Protocol 
Identifier 
AX-CL-NSCLC-PI-005652 
Genentech Protocol 
Identifier 
ML29820 
Phase 
Phase II 
Methodology 
Two-stage trial design with a target accrual of 33 patients, with a goal 
of 30 evaluable patients: 
Stage 1: 18 evaluable patients accrued with pre-defined efficacy and 
safety stoppage criteria 
Stage 2: Additional 12 evaluable patients accrued 
Study Duration 
36-48 months 
Study Center(s) 
Multi-center, anticipating enrollment at Columbia University Medical 
Center, and Dana Farber-Harvard Cancer Center (Massachusetts 
General Hospital & Dana Farber Cancer Institute). 
Objectives 
1. To determine the activity of neoadjuvant MAC, as determined 
by major pathologic response rate (MPR), in comparison with an 
historical control rate. 
2. To measure the activity of neoadjuvant MAC by objective 
response, disease free survival, and overall survival 
3. To determine the safety and feasibility of MAC in the 
neoadjuvant setting for stage IB, II, and IIIA NSCLC 
4. To explore the immune effects of MAC as determined by IHC 
analysis of immune and T cell subsets.  
Number of Subjects Stage 1: 18 patients 
Total at study closure: 30 evaluable patients  
Diagnosis and Main 
Inclusion Criteria 
Resectable stage IB-IIIA NSCLC 
Smoking history 
Study Product, 
Dose, Route, 
Regimen 
MPDL3280A, 1200 mg IV Day 1 every 21 days 
Carboplatin, IV, AUC=5 Day 1 every 21 days 
nab-paclitaxel, IV, 100 mg/m2 Day 1, 8 and 15 every 21 days 
Duration of 
administration 
Four 21 day cycles prior to surgery 
Reference therapy 
Historical, this is a single arm study 


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Statistical 
Methodology 
α=0.05, power=0.83 to detect an increase in MPR from 22% (historical 
control) to 44%. The remainder of the analysis is exploratory. 
 
 
 
 
 
 
 
 
 
 Responder refers to a patient with disease control (defined as CR, PR, or SD) 
 
Non-responders have PD as their best response 
 
 
 
 
 
 
 
 
 


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Contents 
Protocol Signature Page ...................................................................................................................3 
Introduction ......................................................................................................................................9 
1. 
Study Objectives ..................................................................................................................9 
1.1 
Primary Objectives.................................................................................................10 
1.2 
Secondary Objectives.............................................................................................10 
2. 
Background ........................................................................................................................11 
2.1 
Rationale for neoadjuvant therapy in resectable NSCLC ......................................11 
2.2 
Rationale for surrogate biomarkers of benefit .......................................................13 
2.3 
Rationale for neoadjuvant immune checkpoint blockade ......................................14 
2.4 
Rationale for neoadjuvant nab-paclitaxel and carboplatin.....................................15 
2.5 
Rationale for neoadjuvant MPDL3280A and nab-paclitaxel + carboplatin ..........15 
2.6 
Rationale for exclusion of never-smokers .............................................................16 
3. 
Investigational Agent .........................................................................................................17 
3.1 
Preclinical Data ......................................................................................................17 
3.2 
Clinical Pharmacokinetics and Immunogenicity ...................................................17 
3.3 
MPDL3280A Dosage.............................................................................................18 
3.4 
Clinical Data to Date ..............................................................................................18 
3.5 
Safety Data to Date ................................................................................................19 
3.6 
Other Agent(s) .......................................................................................................19 
4. 
Study Design ......................................................................................................................20 
4.1 
Study Design ..........................................................................................................20 
4.2 
Primary Endpoints .................................................................................................20 
4.3 
Secondary Endpoints .............................................................................................20 
4.4 
Safety endpoints .....................................................................................................20 
4.5 
Number of Patients ................................................................................................20 
5. 
Subject Selection and Withdrawal .....................................................................................21 
5.1 
Inclusion Criteria ...................................................................................................21 
5.2 
Exclusion Criteria ..................................................................................................22 
5.3 
Inclusion of Women and Minorities ......................................................................25 
5.4 
Subject Recruitment ...............................................................................................25 
5.5 
Early Withdrawal of Subjects ................................................................................25 
6. 
REGISTRATION PROCEDURES ...................................................................................26 
6.1 
CUMC Research Participant Registration .............................................................26 
7. 
Schedule .............................................................................................................................30 
7.1 
Schedule of Assessments and Interventions ..........................................................30 
7.2 
Follow-up Period ...................................................................................................31 


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7.3 
Surgical resection processing .................................................................................32 
8. 
TREATMENT PLAN ........................................................................................................32 
8.1 
Administration .......................................................................................................32 
8.2 
General Concomitant Medication and Supportive Care Guidelines ......................35 
8.3 
Duration of Therapy ...............................................................................................36 
8.4 
Duration of Follow Up ...........................................................................................37 
8.5 
Criteria for Removal from Study ...........................................................................37 
9. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................37 
9.1 
Monitoring .............................................................................................................38 
9.2 
Management of Specific Safety Concerns with MPDL3280A ..............................38 
9.3 
Carboplatin and nab-paclitaxel ..............................................................................46 
9.4 
Potential Overlapping Toxicities ...........................................................................50 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................50 
10.1 
Adverse  events ......................................................................................................50 
10.2 
Definitions..............................................................................................................50 
10.3 
Assessment of Adverse Events ..............................................................................53 
10.4 
Eliciting of Adverse Events ...................................................................................54 
10.5 
Specific Instructions for Recording Adverse Events .............................................54 
10.6 
Recording of Adverse Events ................................................................................57 
10.7 
Reporting of Adverse Events .................................................................................58 
10.8 
Study Close-Out .....................................................................................................62 
10.9 
Additional Reporting Requirements for IND (MPDL3280A) ...............................62 
11. 
PHARMACEUTICAL INFORMATION ..........................................................................64 
11.1 
Description .............................................................................................................64 
11.2 
Treatment Regimen ................................................................................................65 
11.3 
Method for Assigning Subjects to Treatment Groups ...........................................65 
11.4 
Preparation and Administration of Study Drug .....................................................65 
11.5 
Subject Compliance Monitoring ............................................................................68 
11.6 
Prior and Concomitant Therapy .............................................................................68 
11.7 
Packaging ...............................................................................................................69 
11.8 
Blinding of Study Drug ..........................................................................................69 
11.9 
Receiving, Storage, Dispensing and Return ..........................................................69 
12. 
Outcome Measurements.....................................................................................................70 
12.1 
Pathologic Response Rate ......................................................................................70 
12.2 
Tumor Immune Microenvironment .......................................................................71 
12.3 
Exploratory Biomarkers of Response ....................................................................72 
12.4 
Disease Parameters ................................................................................................72 
12.5 
Methods for Evaluation of Measurable Disease ....................................................74 
12.6 
Radiologic Response Criteria ................................................................................76 
12.7 
Disease-Free Survival ............................................................................................77 
12.8 
Response Review ...................................................................................................77 


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12.9 
Safety Stopping Rules ............................................................................................78 
13. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................79 
13.1 
Data Collection ......................................................................................................79 
13.2 
Data Reporting .......................................................................................................79 
13.3 
Data and Safety Monitoring Committee ................................................................79 
13.4 
Quality Control and Quality Assurance .................................................................80 
13.5 
Confidentiality .......................................................................................................81 
13.6 
Source Documents .................................................................................................81 
13.7 
Case Report Forms .................................................................................................81 
13.8 
Records Retention ..................................................................................................82 
13.9 
Ethical Considerations ...........................................................................................82 
14. 
STATISTICAL CONSIDERATIONS...............................................................................83 
14.1 
Study Design/Endpoints.........................................................................................83 
14.2 
Size/Accrual Rate...................................................................................................84 
14.3 
Analysis of Secondary Endpoints ..........................................................................84 
14.4 
Reporting and Exclusions ......................................................................................84 
15. 
Protection of Human Subjects ...........................................................................................85 
16. 
Study Finances ...................................................................................................................85 
16.1 
Conflict of Interest .................................................................................................85 
16.2 
Subject Stipends or Payments ................................................................................85 
17. 
Publication Plan .................................................................................................................85 
18. 
References ..........................................................................................................................86 
19. 
Attachments .......................................................................................................................91 
SAFETY REPORTING FAX COVER SHEET ........................................................................92 
Genentech Supported Research ...........................................................................................92 
 
  
 


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INTRODUCTION 
 
Lung cancer is the most common cancer in both men and women worldwide, accounting for 13% 
of incident cancers.1 In 2015, it was estimated there would be 221,200 new lung cancers 
diagnosed in the United States, with 158,040 lung cancer deaths.2 Approximately 85% of all lung 
cancers are characterized as non-small cell lung cancer (NSCLC).3 Adenocarcinoma histology 
accounts for the majority of NSCLC, while squamous histology comprises a further 25%.4 Other 
histologies, including large cell carcinoma, neuroendocrine tumors, sarcomatoid carcinoma, and 
poorly differentiated tumors collectively comprise only 15% of NSCLC.  
 
The 5 year survival of stage IB-IIIA NSCLC is only 19-43% and systemic recurrence occurs in 
the majority of patients.5 Randomized multi-modality trials have demonstrated a 10-30% 
survival advantage with the use of adjuvant or neoadjuvant chemotherapy over surgery alone. 
The benefits of platinum-based adjuvant chemotherapy were conclusively demonstrated in the 
Lung Adjuvant Cisplatin Evaluation meta-analysis, which incorporated five large clinical trials 
using a variety of treatment regimen.6 In the pooled analysis of 4584 patients with stage I-III 
NSCLC, followed for a median of 5.2 years, adjuvant cisplatin-based chemotherapy improved 
overall survival with a hazard ratio (HR) of 0.89 (95% CI 0.82-0.96). The effect was most 
pronounced for stage II (HR 0.83, 95% CI 0.73-0.95 and III disease (HR 0.83; 95% CI 0.72-
0.94), with a trend toward effect for stage IB and no effect seen for stage IA. These findings 
were confirmed in another meta-analysis of 2660 patients undergoing NSCLC resection alone, 
although these findings translated to just a 4% improvement in 5-year survival to 33% overall.7 
 
Similar to adjuvant chemotherapy, the survival benefits of neoadjuvant platinum-based 
chemotherapy (NCT) (death HR 0.87, 95% CI 0.78-0.96; 5% improvement in 5-year survival) 
were published in a meta-analysis of 15 randomized controlled trials evaluating patients with 
predominantly stage IB-IIIA NSCLC.8 Of note, several of the trials in that analysis were closed 
early once the outcomes of adjuvant therapy trials were published. As a result of this study, 
neoadjuvant platinum-based chemotherapy for surgically resectable NSCLC is a widely accepted 
alternative to adjuvant chemotherapy. 
 
 
1. STUDY OBJECTIVES 
 
This is an open-label, multi-center, single-arm, phase II study of neoadjuvant MPDL3280A. nab-
paclitaxel and carboplatin administered for 4 cycles. The target population includes patients with 
pathologically confirmed stage IB-IIIA NSCLC. This study aims to determine if chemotherapy + 
anti-PD-L1 antibody therapy is safe and feasible in the preoperative setting. We will also explore 
the  efficacy of the combination in the preoperative setting. Eligible patients must have surgically 
resectable tumors. Excluded patients include those who have previously been treated with T-cell 
checkpoint inhibitors, those with auto-immune disease, concurrent treatment with alternative 
anti-cancer therapy or systemic immunosuppressants. Adjuvant treatment with chemotherapy 
and radiation therapy will be determined based on the results of surgery and as determined by the 
treating investigator.  
 


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Patients must be determined to have surgically resectable disease. Excluded patients include 
never-smokers, those who have previously been treated with T-cell checkpoint inhibitors, those 
with auto-immune disease, concurrent treatment with alternative anti-cancer therapy or systemic 
immunosuppressants. 
Patients will receive 2 cycles of MPDL3280A and carboplatin on D1 and nab-paclitaxel D1, D8, 
and D15 both every 21 days followed by a re-imaging CT scan to assess response. Patients with 
an objective response or stable disease by RECIST v1.1 and acceptable toxicity will receive an 
additional 2 cycles followed by standard restaging scans and then surgery. Patients with 
progressive disease by RECIST v1.1 after the first 2 cycles of treatment will proceed directly to 
surgery.  
The study will accrue a maximum of 30 evaluable patients with early stopping rules for 
treatment related toxicities. An interim evaluation after enrollment of 18 patient will be 
performed with pre-defined stoppage criteria for lack of efficacy (MPR in 4 or fewer patients). If 
at any time more than 2 patients experience severe drug-related toxicity (not progression) that 
prohibits or significantly delays planned surgery, the study will be closed. Patients will receive 
standard postoperative therapy as determined by the treating physician, but not as part of this 
study. Following surgery, patients will be followed with standard CT scans of the chest with 
contrast, as well as routine and exploratory blood tests every 3 months, until 6 months after 
surgery or until resolution of all treatment related toxicities to grade ≤1. 
 
Efficacy endpoints that will be assessed include radiologic response by RECIST v1.1, pathologic 
response, nodal downstaging, DFS and OS. Exploratory endpoints will be measured in pre and 
post-therapy blood and surgical specimens, including: immune ligand expression, T-cell 
phenotype in tumor and tumor-infiltrating lymphocytes (TILs). Safety endpoints will also be 
continuously assessed. 
 
 
1.1 Primary Objectives 
 
 To evaluate the activity of neoadjuvant MAC in patients with NSCLC as measured by 
major pathologic response rate (MPR) defined below as > 90% decrease in viable tumor) 
1.2 Secondary Objectives 
 
 To determine the objective response rate, disease free survival, and overall survival of 
subjects with stage IB-IIIA NSCLC treated with neoadjuvant MAC. 
 To evaluate the safety and feasibility of neoadjuvant MAC in subjects with resectable 
stage IB-IIIA NSCLC  
 To detect alterations of tumor immune microenvironment pre-and post-treatment (PD-L1, 
PD-L2, TIM3, LAG3 and T cell subsets (CD3, CD8, Tregs).   
 
 


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2. BACKGROUND 
 
2.1 
Rationale for neoadjuvant therapy in resectable NSCLC 
 
Repeated studies have shown neoadjuvant cytotoxic chemotherapy to be safe prior to surgical 
resection of NSCLC with no difference in extent of surgical procedures performed, operative 
morbidity and mortality.9-12 Objective response rates to neoadjuvant chemotherapy range from 
40-70%, with rates of pathologic complete response of 6-12% with standard chemotherapy 
regimens used in NSCLC.10,13-17 
 
In 2009 Lim et al.18 published an indirect comparison meta-analysis to obtain the relative 
hazards of post-operative to pre-operative administration of chemotherapy on survival. Data 
from 32 randomized trials involving 10,000 participants were included. There were more trials in 
the postoperative group (n=22) compared to the preoperative group (n=10) demonstrating the 
weight of evidence in existence for postoperative chemotherapy. For overall survival, the relative 
hazard ratio of postoperative compared to preoperative chemotherapy was 0.99 (95% CI: 0.81-
1.21, P=0.91). For disease free survival the findings were similar with a relative hazard ratio of 
0.96 (95% CI: 0.77-1.20, P=0.70). 
 
The debate remains as to whether neoadjuvant or adjuvant chemotherapy is the best approach, 
with advantages and disadvantages to each. Adjuvant treatment has the advantage of providing 
clinicians with a pathologic stage to guide postoperative therapy recommendations. While 
upfront surgery guarantees adequate tissue for molecular studies, current targeted therapies (such 
as erlotinib in EGFR-mutant NSCLC) remain investigational in the adjuvant setting and are 
being studied only after completion of standard therapies. The main disadvantage of adjuvant 
chemotherapy is the difficulty of drug delivery postoperatively. For clinical investigation, 
administration of neoadjuvant chemotherapy allows for an in vivo assessment of treatment 
response radiologically and pathologically, and the use of surrogate endpoints such as 
downstaging and pathologic response. The use of neoadjuvant therapy followed by surgery has 
the advantage of allowing administration of 90% of planned cisplatin-based chemotherapy 
compared with 50% of planned treatment in the post-operative setting without any increase in 
surgical risk. This approach provides earlier systemic therapy for the treatment of 
micrometastatic disease and allows for an assessment of treatment efficacy in each individual 
patient. In addition, sterilization of N2 disease with neoadjuvant chemotherapy can obviate the 
need for adjuvant radiation therapy.  Neoadjuvant therapy also allows for an in vivo evaluation 
of new therapeutic approaches, providing critical information for drug development as response 
to therapy can be assessed both radiographically and correlatively in post-treatment pathologic 
specimens.  
 
Clinical trials in resectable lung cancer have traditionally attempted to institute new agents in the 
adjuvant setting. However, significant co-morbidities and incomplete recovery from surgery 
contribute to a high proportion of patients who are unable to tolerate adjuvant therapy. 
Additionally, clinical endpoints take years of follow-up to ascertain.  The BLOT (Bimodality 
Lung Oncology Team) study was a large phase II study that compared neoadjuvant to adjuvant 
carboplatin and paclitaxel in 134 patients with stage IB-IIIA disease. In this study, 51% of 


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patients who received neoadjuvant chemotherapy had an objective response, and 7% had a 
pathologic complete response. In this study, 97% of patients in the neoadjuvant group completed 
chemotherapy versus 31% of patients in the adjuvant group.19 Following this, the phase III 
NATCH trial compared surgery alone versus surgery + preoperative, versus surgery + 
postoperative therapy, with carboplatin and paclitaxel. In this study, 90% of the preoperative 
cohort completed therapy versus 66% of the post chemotherapy group12. 
Taken together, these trial results demonstrate that it is easier to deliver therapy in the 
neoadjuvant setting, with a higher proportion of patients completing neoadjuvant compared to 
adjuvant therapy. In addition, such an approach is an in vivo test of sensitivity to therapy that is 
positively associated with improved outcomes, and has the potential to eradicate micrometastatic 
disease prior to surgery.  
In addition to these benefits, a neoadjuvant approach has practical benefits of yielding results 
over a shorter time period compared to trials carried out in the adjuvant setting. Two reasons for 
the slow progress of adjuvant studies in resectable NSCLC are the technicalities of using 
multimodality therapy in this setting, and the long wait for results with survival endpoints. The 
ANITA study was a phase III study of adjuvant chemotherapy in NSCLCs.20 In this study, 
results were published 12 years after study initiation. Thus, while OS remains the gold standard 
for assessment of benefit of adjuvant therapy, studies that are 12 years long are slow, expensive, 
and may yield results that are out of date by the time they are published. The use of a valid 
surrogate endpoint for OS is thus a high priority in NSCLC. An example of such an endpoint 
includes 3-year disease-free survival (DFS), which correlates with 5-year OS. However, in the 
context of the ANITA study, a 3-year DFS endpoint would have taken 9 years to be reached. 
This issue is borne out in other solid tumors as well, with the reporting of 3-year DFS in adjuvant 
colon cancer taking 8 years to mature.21-23 Thus a surrogate endpoint which can be achieved in a 
shorter timeframe is needed in NSCLC. 
In resectable breast cancer, the use of neoadjuvant chemotherapy creates an efficient and 
effective surrogate endpoint of pathologic complete response (pCR), that correlates with both 
DFS and OS across multiple randomized studies, and is thus used as a surrogate endpoint for 
survival in this disease.24-30 
The degree of pathologic response seen in lung cancer following neoadjuvant chemotherapy, is 
termed a major pathologic response (MPR, ≤10% residual viable tumor cells).31 MPR has been 
found to directly reflect the impact of NCT in NSCLC, with the magnitude of MPR reflecting 
magnitude of improvement in overall survival.32 MPR also associates with disease-free survival. 
Results from prospective studies by Betticher33 and Chaft34 both report that 22% of patients with 
stage I-IIIA NSCLCs treated with NCT achieved a MPR. Historical reports of cisplatin-based 
NCT estimates major pathologic response rates of 10-15%.35 We propose “major pathologic 
response” (MPR), defined as ≤10% residual, viable tumor in the resected tissue sample at the 
time of surgery, as an assessable and reliable surrogate measurement of survival36. As has been 
demonstrated in breast cancer, a broad acceptance of such as surrogate has the potential to 
substantially expedite conclusions from clinical trials and improvements in clinical practice for 
patients.. 


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With the above data in mind, we propose that new therapies such as immune checkpoint 
inhibitors that demonstrate promising clinical activity in the advanced disease setting must be 
incorporated into the neoadjuvant setting, in order to maximize benefit early in a patient’s 
treatment course, and with a suitable surrogate endpoint that can be used to establish a 
preliminary efficacy signal, prior to initiation of a large confirmatory study.  
 
2.2 
Rationale for surrogate biomarkers of benefit 
 
While disease free and overall survivals remain the gold-standard for evaluation of perioperative 
interventions, surrogate endpoints can provide an earlier estimation of the effectiveness of new 
therapies. Hellmann and colleagues (2014) proposed that pathological response after treatment 
for resectable NSCLCs can serve as a surrogate for OS. This proposal was based on the US Food 
and Drug Administration’s (FDA) definition of a surrogate endpoint in the accelerated drug 
approval process, where such an endpoint is defined as one that is ‘reasonably likely to predict 
clinical benefit.’ Neoadjuvant chemotherapy in lung cancer demonstrates that: (a) the extent of 
pathological response strongly correlates with improved overall survival; (b) the pathological 
response is reflective of the effect of neoadjuvant therapy; and (c) the degree of pathological 
response associates with the degree of benefit in overall survival.32   
 
Major pathologic response is defined as treatment effect of more than 90% (MPR, ≤10% residual 
viable tumor cells). Junker, et al.37 described pathological response as predictive of outcomes 
after multimodality therapy, with patients with <10% viable tumor cells remaining experiencing 
the best outcomes. In a more recent publication of 192 patients with NSCLC who received 
neoadjuvant chemotherapy, the long term OS and RFS of the 19% of patients with tumors 
demonstrating ≥90% pathological response were significantly different than those with <90% 
response. 
 
MPR directly reflects the impact of chemotherapy and the magnitude of MPR reflects the 
magnitude of improvement in overall survival. MPR also associates with disease-free survival. 
Results from prospective studies by Betticher33 and Chaft34 both report that 22% of patients with 
stage I-IIIA NSCLCs treated with neoadjuvant chemotherapy achieved a MPR. We propose 
“major pathologic response” (MPR), defined as ≤10% residual, viable tumor in the resected 
tissue sample at the time of surgery, as an assessable and reliable surrogate measurement of 
survival. As had been demonstrated in breast cancer, a broad acceptance of such as surrogate has 
the potential to substantially expedite conclusions from clinical trials and improvements in 
clinical practice for patients. A standardized approach to assessment of percentage of viable 
residual disease after neoadjuvant chemotherapy is as described by Pataer and colleagues31 (see 
Section 12.1).  
 
Complete pathologic response (CPR) refers to the eradication of any detectable cancer within the 
surgically resected lung specimen and lymph nodes. Of 15 trials which reported CPR, the median 
rate is just 4% (range 0-16%) (Hellmann 2014). Few trials have reported corollary survival data 
for NSCLC due to the low frequency of CPR. One retrospective review of 9 patients with CPR 
observed a remarkable 54% overall survival.10 Combined data from 2 phase III trials in Stage Ib-


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II NSCLC revealed 41 patients (8.3% of total) with CPR had a 5-year DFS 80.1% vs 44.8% for 
the non-CPR group (p<0.0001) and 5-year overall survival 80% vs 56% (p<0.01).38 Given the 
low frequency of CPR, it is not likely to be a feasible endpoint for neoadjuvant clinical trials in 
NSCLC. 
 
 
2.3 
Rationale for neoadjuvant immune checkpoint blockade 
 
Immune based therapies which enhance the host anti-tumor immune response are a promising 
therapeutic strategy in NSCLC. Programmed death-1 (PD-1 or CD279), is a transmembrane 
receptor protein that functions as a CD28 co-stimulatory molecule on the surface of T cells.39 
Upon binding to ligands PD-L1 and PD-L2, T-cell activation is inhibited by suppressing CD28 
mediated increases in IL-2, IL-10, IL-13, IFN-gamma, and Bcl-xL.39-43 In human cells, 
constitutive PD-L1 expression is normally limited to macrophages, while it remains inducible in 
other cells. Aberrant expression of PD-L1 by tumor cells enhances apoptosis of nearby activated 
tumor-specific T cells and simultaneously prevents T cells from inducing apoptosis of malignant 
cells in vitro.43,44 
 
In clinical studies, immune checkpoint inhibitors, including those which target CTLA-4, PD-1, 
and PD-L1, can reverse immune tolerance to cancer specific antigens.45,46 Agents targeting the 
PD-1/PD-L1 interaction enhance the host anti-tumor T-cell response. Many of these agents are 
active against NSCLC in the metastatic setting.47-50 In a phase II single-arm, single agent trial of 
nivolumab in 117 patients with advanced squamous NSCLC, the OR was 14.5% by RECIST 
v1.1, and an additional 26% of patients had stable disease.51 In a separate study of 129 patients 
with heavily pre-treated, advanced NSCLC, the response rate was 22% (17% by RECIST v1.0, 
5% with delayed immune-pattern response) and treatment was generally well tolerated.47 
 
Ipilimumab, an anti-CTLA-4 antibody, is the first checkpoint inhibitor to demonstrate a clinical 
benefit in a phase III trial when administered in the perioperative period for any cancer, in this 
case given adjuvant for melanoma.52 Patients with early stage bladder cancer have been treated 
with neoadjuvant ipilimumab in a phase I study.35 Neoadjuvant ipilimumab was found to have a 
tolerable safety profile without an increase in perioperative complications after 1 or 2 doses of 
neoadjuvant therapy. Valuable information on the immunological effects of ipilimumab was 
gleaned from studying the resected bladder tumors in these patients. A recent publication with 
neoadjuvant ipilimumab in patients with surgically operable regionally advanced melanoma 
demonstrated pathologic response in a subset of melanoma patients.53 Patients were treated with 
ipilimumab (10 mg/kg intravenously every 3 weeks ×2 doses) before surgery. Twenty-one 
patients (64%) had stable disease and eight patients (24%) had disease progression. All patients 
had histologically documented residual melanoma at definitive surgery following 2 doses of 
ipilimumab, although 5 patients had only microscopic disease detected. Additionally in advanced 
melanoma treated with combination CTLA-4/PD-1 blockade major responses (80% tumor 
reduction) and complete responses were observed in 30 and 10% of patients.54 
 
 
 


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Unpublished data from WCLC 2013 (Gettinger et al) has also shown case reports of resection 
samples of residual disease after a PD-L1 antibody (MPDL3280A) with only minimal residual 
disease.  
 
All of the above point to the potential for inducing pathologic response with immune checkpoint 
blockade. 
 
2.4 
Rationale for neoadjuvant nab-paclitaxel and carboplatin 
 
nab-paclitaxel + carboplatin is an FDA approved chemotherapy doublet used in the first-line 
treatment of advanced NSCLC. In the advanced setting, the combination of carboplatin, 
administered at an AUC 6 every 3 weeks of a 21 day cycle, combined with nab-paclitaxel 
100mg/m2 weekly vs. standard carboplatin plus solvent based paclitaxel administered every 21 
days has been studied . Administration of nab-PC as a first-line therapy resulted in a significantly 
improved ORR versus sb-PC (33% v 25%; P = .005) thereby achieving the primary end point. 
Nonsignificant improvement was observed in favor of the nab-PC arm for PFS or OS, meeting 
noninferiority criteria. The nab-PC regimen produced less severe neuropathy, neutropenia, 
myalgia, and arthralgia compared with sb-PC.55 
 
The NATCH trial12 evaluated carboplatin + paclitaxel as either adjuvant or neoadjuvant therapy 
for resectable, stage IA-IIIA NSCLC. Three year PFS was higher in the neoadjuvant group 
(48.4%) than either the adjuvant group (44.9%) or the surgery alone group (41.9%) although 
these results were not statistically significant. Treatment was generally well tolerated, with 
similar surgical mortality (5-7%) between groups. In the neoadjuvant arm, the pCR rate was 
10.5%, and the ORR by RECIST was 53.3% including 9% CR. 
 
A neoadjuvant trial for stage IB to IIIA NSCLC evaluated carboplatin, AUC6, every 21 days and 
paclitaxel 80 mg/m weekly and in 20 patients demonstrated a complete pathologic response rate 
of 17%.56 
 
 
2.5 
Rationale for neoadjuvant MPDL3280A and nab-paclitaxel + carboplatin 
 
MPDL3280A targets PD-L1 with good single agent activity against NSCLC in the advanced 
setting . Tumor cell killing by cytotoxic chemotherapy can reasonably be expected to expose the 
immune system to high levels of tumor antigens, and invigorating tumor-specific T-cell 
immunity in this setting by inhibiting PD-L1/PD-1 signaling may result in deeper and more 
durable responses compared with standard chemotherapy alone.57,58 In preclinical experiments, 
traditional chemotherapies have been shown to augment the host anti-cancer immune response as 
well as disrupt immune evasion by cancer cells.59 Evaluating the safety and efficacy of these 
treatment combinations in NSCLC patients will enable future tests of this hypothesis. 
 
Nivolumab, a fully human IgG4 PD-1 antibody, was evaluated in combination with platinum-
based doublet therapy in PD-1−unselected, chemotherapy-naïve NSCLC patients, and interim 
results were presented at ASCO 2014.60 The ORR for patients treated with gemcitabine+ 


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cisplatin, pemetrexed+ cisplatin, and paclitaxel + carboplatin, in addition to 10 mg nivolumab, 
was 33% (n= 12), 47% (n = 15), and 47% (n= 15), respectively. The median duration of response 
ranged from 24 weeks with nivolumab in combination with paclitaxel + carboplatin to 45 weeks 
with nivolumab in combination with gemcitabine + cisplatin. The 1-year OS for patients treated 
with gemcitabine+ cisplatin, pemetrexed + cisplatin, and paclitaxel + carboplatin in addition to 
10 mg nivolumab was 50%, 87%, and 60%, respectively. Grade 3/4 treatment-related adverse 
events were reported in 45% of patients across all treatment arms with the most common 
treatment-related Grade 3/4 adverse events being pneumonitis (7%), fatigue (5%), and acute 
renal failure (5%).60 
 
The combination of MPDL3280A with carboplatin based chemotherapy was specifically 
evaluated in 37 patients with advanced NSCLC in the phase Ib GP28328.61 MPDL3280A was 
added to carboplatin with either paclitaxel, nab-paclitaxel, or pemetrexed. In the nab-paclitaxel 
arm (n=15), the regimen was well-tolerated with the most common AEs attributed to the 
cytotoxic agents being nausea (73%), fatigue (73%), and constipation (27%). Severe toxicity was 
uncommon: grade 3-4 anemia (7%), thrombocytopenia (7%), and no neutropenia nor 
pneumonitis. The ORR was 62% (33-83%) with 6 PRs and 2 CRs. Safety and efficacy were 
comparable across all study arms, and no patient required steroid treatment. Responses were seen 
independent of PD-L1 expression. 
 
 
2.6 
Rationale for exclusion of never-smokers  
 
The rationale to exclude never-smokers is two-fold.  The first reason is to exclude those who are 
most likely to have an actionable oncogene driver mutation identified in their tumor, such as 
EGFR or ALK.  Due to small diagnostic samples and timeline of neoadjuvant therapies, 
molecular results are often not available when neoadjuvant treatment begins.  Excluding never-
smokers will exclude the majority of those who have an EGFR or ALK mutation and may be 
eligible to receive an adjuvant targeted therapy as part of the upcoming cooperative group trials.  
Secondly, preliminary experience in the assessment of benefit from T-cell checkpoint blockade 
in patients with advance disease suggests a better benefit is obtained in smokers.   In analysis of 
data from treatment with nivolumab (anti-PD-1 mAb), the response rate and progression-free 
survival in current or former smokers was significantly greater than never or minimal smokers 
(≤5 pack-years) (response rate 30% vs 0%, p=0.02; HR for PFS 0.41, p=0.003).51  Similar 
findings were observed with pembrolizumab in the large phase I study KEYNOTE-001.62 
Among 495 patients who received treatment, the response rate in smokers was 22.5% as 
compared with 10.3% in never smokers. We therefore have opted to exclude never-smokers from 
this trial. 
 
 


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3. 
INVESTIGATIONAL AGENT 
 
MPDL3280A is a human immunoglobulin (Ig) G1 monoclonal antibody consisting of two heavy 
chains (448 amino acids) and two light chains (214 amino acids) and is produced in Chinese 
hamster ovary cells.  MPDL3280A was engineered to eliminate Fc-effector function via a single 
amino acid substitution (asparagine to alanine) at position 298 on the heavy chain, which results 
in a non-glycosylated antibody that has minimal binding to Fc receptors and prevents Fc-effector 
function at expected concentrations in humans.  MPDL3280A targets human programmed death-
ligand 1 (PD-L1) and inhibits its interaction with its receptor, programmed death-1 (PD-1).  
MPDL3280A also blocks the binding of PD-L1 to B7.1, an interaction that is reported to provide 
additional inhibitory signals to T cells. 
3.1 Preclinical Data 
 
Comprehensive pharmacology, PK, and toxicology evaluations have been undertaken with 
MPDL3280A. 
The safety, pharmacokinetics, and toxicokinetics of MPDL3280A were investigated in mice and 
cynomolgus monkeys to support intravenous (IV) administration and to aid in projecting the 
appropriate starting dose in humans.  Given the similar binding of MPDL3280A for cynomolgus 
monkey and human PD-L1, the cynomolgus monkey was selected as the primary and relevant 
nonclinical model for understanding the safety, pharmacokinetics, and toxicokinetics of 
MPDL3280A.  
Overall, the nonclinical pharmacokinetics and toxicokinetics observed for MPDL3280A 
supported entry into clinical studies, including providing adequate safety factors for the proposed 
Phase I starting doses.  The results of the toxicology program were consistent with the 
anticipated pharmacologic activity of down-modulating the PD-L1/PD-1 pathway and supported 
entry into clinical trials in patients.  
For further details please refer to the investigator brochure for MPDL3280A.  
3.2 Clinical Pharmacokinetics and Immunogenicity 
 
On the basis of available preliminary PK data (0.03−20 mg/kg), MPDL3280A appeared to show 
linear pharmacokinetics at doses ≥ 1 mg/kg. For the 1-mg/kg and 20-mg/kg dose groups, the 
mean apparent clearance (CL) and the mean volume of distribution at steady state (Vss) had a 
range of 3.11 to 4.14 mL/kg and 48.1 to 67.0 mL/kg, respectively, which is consistent with the 
expected profile of an IgG1 antibody in humans.  
 
The development of anti-therapeutic antibodies (ATAs) has been observed in patients in all dose 
cohorts and was associated with changes in pharmacokinetics for some patients in the lower dose 
cohorts (0.3, 1, and 3 mg/kg). The development of detectable ATAs has not had a significant 
impact on pharmacokinetics for doses from 10 to 20 mg/kg. Patients dosed at the 10-, 15-, and 
20-mg/kg dose levels have maintained the expected target trough levels of drug despite the 


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detection of ATAs. To date, no clear relationship between the detection of ATAs and adverse 
events or infusion reactions has been observed. 
 
3.3 MPDL3280A Dosage 
 
The fixed dose of 1200 mg (equivalent to an average body weight−based dose of 15 mg/kg) was 
selected on the basis of both nonclinical studies and available clinical data from Study 
PCD4989g as described below.  
 
The target exposure for MPDL3280A was projected on the basis of nonclinical tissue 
distribution data in tumor-bearing mice, target-receptor occupancy in the tumor, the observed 
MPDL3280A interim pharmacokinetics in humans, and other factors. The target trough 
concentration (Ctrough) was projected to be 6 μg/mL on the basis of several assumptions, 
including the following: 1) 95% tumor-receptor saturation is needed for efficacy and 2) the 
tumor-interstitial concentration to plasma ratio is 0.30 based on tissue distribution data in tumor-
bearing mice.  
 
 
The MPDL3280A dose is also informed by available clinical activity, safety, pharmacokinetics, 
and immunogenicity data. Anti-tumor activity has been observed across doses from 1 mg/kg to 
20 mg/kg. The MTD of MPDL3280A was not reached, and no DLTs have been observed at any 
dose in Study PCD4989g. Currently available PK and ATA data suggest that the 15-mg/kg 
MPDL3280A q3w regimen (or fixed-dose equivalent) for Phase II and Phase III studies would 
be sufficient to both maintain Ctrough ≥6 μg/mL and further safeguard against both interpatient 
variability and the potential effect of ATAs that could lead to subtherapeutic levels of 
MPDL3280A relative to the 10-mg/kg MPDL3280A q3w regimen (or fixed-dose equivalent). 
From inspection of available observed Ctrough data, moving further to the 20-mg/kg 
MPDL3280A q3w regimen does not appear to be warranted to maintain targeted Ctroughlevels 
relative to the proposed 15-mg/kg MPDL3280A q3w level.  
 
Simulations (Bai 2012) do not suggest any clinically meaningful differences in exposure 
following a fixed dose or a dose adjusted for weight. Therefore, a fixed dose of 1200 mg has 
been selected (equivalent to an average body weight−based dose of 15 mg/kg). Selection of an 
every-21-day dosing interval is supported by this preliminary pharmacokinetics evaluation.  
Refer to the MPDL3280A Investigator’s Brochure for details regarding nonclinical and clinical 
pharmacology of MPDL3280A. 
3.4 Clinical Data to Date 
 
Efficacy analyses are currently available for 386 patients with measurable disease at baseline and 
at least 6 months of follow-up in the phase Ib study PCD4989g (unpublished data). Patients with 
multiple tumor types were included in the study, with the largest cohorts consisting of patients 
with NSCLC, RCC, and bladder cancer.  Objective responses with MPDL3280A monotherapy 
were observed in a broad range of malignancies, including NSCLC, RCC, melanoma, bladder 
cancer, colorectal cancer, head and neck cancer, gastric cancer, breast cancer and sarcoma.  
Altogether, there were 47 patients with responses with a median duration of response of 75.7 


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weeks (range:  11.7  to 85.9  weeks, where “  ” denotes censored value).  The majority of 
these responses have been durable, with 72.3% (34/47) of responses ongoing as of the clinical 
cutoff date. Herbst et al.49 reported that 11/53 (21%) patients with advanced NSCLC experienced 
at least a partial response with single agent therapy at a variety of doses. The percentage of 
patients with no disease progression at 24 weeks was 45%.  
Analyses of tumor-infiltrating immune cells for PD-L1 expression on baseline tumor tissue have 
been performed for Study PCD4989g, in which MPDL3280A is being used as single-agent 
therapy in patients with locally advanced or metastatic solid tumors or hematologic 
malignancies.  Preliminary results from Study PCD4989g suggest that PD-L1 expression in 
tumor-infiltrating immune cells is likely to be associated with response to MPDL3280A. 
3.5 Safety Data to Date 
 
Interim safety data for single agent MPDL3280A are available from PCD4989g.  In 412 treated 
patients, 97.1% reported an AE while on study.  Of these AEs, 48.8% were Grade 1 or 2 in 
maximum severity on the basis of National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 4.0 (NCI CTCAE v4.0).  The most frequently observed AEs (occurring 
in  10% of treated patients) included fatigue, nausea, decreased appetite, pyrexia, dyspnea, 
diarrhea, constipation, cough, headache, back pain, vomiting, anemia, arthralgia, rash, insomnia, 
asthenia, abdominal pain, chills, pruritus, and upper respiratory tract infection.  Grade  3 AEs 
were reported by 199 of 412 patients (48.3%).  There were 51 patients (12.4%) who reported 
Grade  3 AEs that were assessed as related to study drug by the investigators.  The most 
frequently reported related Grade  3 AEs included fatigue (5 patients [1.2%]), increased ALT 
and increased AST (each reported in 4 patients [1.0%]); and asthenia, autoimmune hepatitis, and 
hypoxia (each reported in 3 patients [0.7%]).  
Herbst et al.49 reported on 277 patients with incurable cancers who received MPDL3280A alone 
every 3 weeks. Treatment was well tolerated at doses up to 20mg/kg. Systemic inflammatory 
markers IFN-gamma and CD8+/HLA-DR+/Ki-67+ were elevated approximately 2-fold with 
treatment. Fatigue (67%) was the most common adverse event and typically co-occurred with 
pyrexia (~21%) only during the first cycle. Treatment-related grade 3-4 adverse events (AEs) 
were observed in 13% of patients, and just 3 patients (1%) experienced grade 3-4 immune related 
AEs (irAEs). The majority of grade 3+ AEs involved lab abnormalities of uncertain significance: 
AST/ALT elevation (6 events), hyperglycemia (2), hyponatremia (2), hypophosphatemia (2), and 
tumor lysis syndrome (2). There were two cases of cardiac tamponade and no cases of grade 3-5 
pneumonitis. 
3.6 Other Agent(s) 
 
Nab-paclitaxel + carboplatin is an FDA approved chemotherapy doublet used in the first-line 
treatment of advanced NSCLC. In the advanced setting, the combination of carboplatin, 
administered at an AUC 6 every 3 weeks of a 21 day cycle, combined with nab-paclitaxel 
100mg/m2 weekly vs. standard carboplatin plus solvent based paclitaxel administered every 21 
days has been studied. Administration of nab-PC as a first-line therapy resulted in a significantly 
improved ORR versus sb-PC (33% v 25%; P = .005) thereby achieving the primary end point. 


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Nonsignificant improvement was observed in favor of the nab-PC arm for PFS or OS, meeting 
noninferiority criteria. The nab-PC regimen produced less severe neuropathy, neutropenia, 
myalgia, and arthralgia compared with sb-PC.55 
4. STUDY DESIGN 
4.1 
Study Design 
 
This is an open-label multi-center, single-arm, phase II study of neoadjuvant nab-paclitaxel + 
carboplatin + MPDL3280A administered for 4 cycles. The target population includes patients 
with a smoking history and pathologically confirmed clinical stage IB-IIIA NSCLC. The study 
aims to determine if chemotherapy combined with immune checkpoint blockade can lead to 
improvement in major pathologic response rates over historic controls with platinum doublet 
based chemotherapy alone. Such historical rates approach 22%, as recently reviewed by Pataer, 
et al.31 The study will accrue 30 evaluable patients, and will be performed in a two-stage design, 
with an interim assessment for efficacy after 18 patients, and early stopping rules for pre-defined 
toxicities (see Section 12.9). Adjuvant treatment with chemotherapy and radiation therapy will 
be determined based on the results of surgery and at the discretion of the treating investigator.  
 
4.2 
Primary Endpoints 
 
The primary outcome measure is major pathologic response (MPR) in NSCLC samples at the 
time of surgery.  
 
4.3 
Secondary Endpoints 
 
Secondary efficacy endpoints include overall response rate (ORR) per RECIST v1.1, disease free 
survival (DFS) and overall survival (OS). Secondary exploratory goals will include 
characterization of the tumor immune microenvironment by immunohistochemistry and 
immunofluorescence on resected tumor tissue before and after MAC (see Section 12.2). 
 
4.4 
Safety endpoints 
 
Adverse event will be further categorized as immune related adverse events (irAEs). Pre-defined 
stoppage criteria are outlined in Section 12.9, and pertain to the discontinuation of study regimen 
MPDL3280A prior to completion of 4 cycles. The completion of platinum based neoadjuvant 
chemotherapy, in the absence of the study drug, will be left to the provider’s discretion. Delays 
in time to surgery will also be recorded. 
 
4.5 
Number of Patients  
 
The study will accrue 30 evaluable patients as outlined in Section 14. 
 


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5. 
SUBJECT SELECTION AND WITHDRAWAL 
 
5.1 
Inclusion Criteria 
 
 Patients must have pathologically confirmed non-small cell lung cancer, including 
squamous, non-squamous, mixed histology, or large cell.  
 
Stage IB-IIIA  
 
Deemed potentially surgically resectable by a thoracic surgeon 
 
If the FEV1 < 40%, surgical clearance must be obtained from a pulmonologist as 
well as a thoracic surgeon 
 Age  18 years 
 
Radiologically measurable disease, as defined by RECIST v1.1 
 
Ability to understand and the willingness to sign a written informed consent document 
 Females of child-bearing potential (defined as a sexually mature woman who (1) has not 
undergone hysterectomy [the surgical removal of the uterus] or bilateral oophorectomy [the 
surgical removal of both ovaries] or (2) has not been naturally postmenopausal for at least 
24 consecutive months [i.e., has had menses at any time during the preceding 24 
consecutive months]) must: 
 
 
 
Either commit to true abstinence from heterosexual contact (which must be 
reviewed on a monthly basis), or agree to use, and be able to comply with, effective 
contraception (</=1% failure rate annually) without interruption, 28 days prior to 
starting therapy (including dose interruptions), and while on study medication or 
for a period of 90 days following treatment completion. [Periodic abstinence (eg, 
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are 
not acceptable methods of contraception]. 
 
Have a negative serum pregnancy test (β -hCG) result at screening and agree to 
ongoing pregnancy testing during the course of the study, and after the end of study 
therapy.  This applies even if the subject practices true abstinence from heterosexual 
contact. 
 Male subjects must practice true abstinence or agree to use a condom during sexual contact 
with a pregnant female or a female of childbearing potential while participating in the 
study, during dose interruptions and for 6 months following treatment discontinuation, 
even if he has undergone a successful vasectomy. 
 Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 
 Confirmed sufficient tissue and available block for analysis from a core biopsy-
Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin 
blocks (blocks are preferred) or at least 10 unstained slides, with an associated pathology 
report, for central testing of tumor PD-L1 expression 
 


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Note: If any of the below requirements are not met, the patient may still be eligible if 
the tissue is deemed sufficient for analysis by the Sponsor-Investigator (written 
approval required). 
 
Tumor tissue should be of good quality based on total and viable tumor content.  
Fine-needle aspiration, brushing, cell pellet from pleural effusion, and lavage 
samples are not acceptable.  For core-needle biopsy specimens, at least three cores 
should be submitted for evaluation. 
 
Patients who do not have tissue specimens meeting eligibility requirements may 
undergo a biopsy during the screening period.  Acceptable samples include 
core-needle biopsies for deep tumor tissue (minimum of three cores) or 
excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or 
mucosal lesions. 
 Adequate organ and marrow function as defined below:  
 
Lymphocyte count 
 
≥300/mcL 
 
Neutrophil count 
 
≥1,500/mcL 
 
Hemoglobin  
 
≥9.0g/dl 
 
Platelets 
 
≥100,000/mcL 
 
Total bilirubin 
 
≤1.5 x institutional upper limit of normal (ULN) 
 
 
 
 
*Patients with Gilbert’s disease: ≤3 x ULN 
 
AST(SGOT)/ALT(SGPT) 
≤2.5 × ULN 
 
Alkaline phosphatase 
 
≤2.5 x ULN 
 
INR and aPTT  
 
 1.5  ULN  
*Unless the patient is on therapeutic anticoagulation 
 
Serum creatinine 
 
≤1.5 x ULN 
 
OR 
 
 
Creatinine clearance 
 
≥50 mL/min/1.73 m2 by Cockcoft-Gault estimation 
 
 
 
5.2 
Exclusion Criteria 
 
 Any approved anticancer therapy, including chemotherapy, hormonal therapy, 
or radiotherapy, within 5 years prior to initiation of study treatment; however, 
the following are allowed: 
 
Hormone-replacement therapy or oral contraceptives 
 
Herbal therapy  1 week prior to Cycle 1, Day 1 (herbal therapy intended as 
anticancer therapy must be discontinued at least 1 week prior to Cycle 1, Day 1) 
 Malignancies other than the disease under study within 5 years prior to Cycle 1, Day 1, 
with the exception of those with a negligible risk of metastasis or death and with 


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expected curative outcome (such as adequately treated carcinoma in situ of the cervix, 
basal or squamous cell skin cancer, localized prostate cancer treated surgically with 
curative intent, or ductal carcinoma in situ treated surgically with curative intent) or 
undergoing active surveillance per standard-of-care management (e.g., chronic 
lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason score  6, and prostate-
specific antigen [PSA]  10 mg/mL, etc.) 
 Patients who are receiving any other investigational agents concurrently. 
 Patients with no smoking history 
 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to MPDL3280A, carboplatin, or paclitaxel. 
 Patients with active hepatitis B or C infections or a history of HIV infection. 
 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection 
including TB, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with study 
requirements. 
 Known clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis; cirrhosis; fatty liver; and inherited liver disease 
 Known hypersensitivity to Chinese hamster ovary cell products or other recombinant 
human antibodies 
 History or risk of autoimmune disease, including but not limited to systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis 
associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s 
syndrome, Bell’s palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid 
disease, vasculitis, or glomerulonephritis 
 
Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid 
replacement hormone may be eligible. 
 
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may 
be eligible. 
 
Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 
excluded) are permitted provided that they meet the following conditions: 
Patients with psoriasis must have a baseline ophthalmologic exam to rule 
out ocular manifestations 


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Rash must cover less than 10% of body surface area (BSA) 
Disease is well controlled at baseline and only requiring low potency 
topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, 
flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%) 
No acute exacerbations of underlying condition within the last 12 months 
(not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, 
retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral 
steroids) 
 Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited 
to hospitalization for complications of infection, bacteremia, or severe pneumonia 
 
 Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1 
 
 Received IV antibiotics within 2 weeks prior to Cycle 1, Day 1. Patients receiving 
prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic 
obstructive pulmonary disease) are eligible 
 
 Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need 
for a major surgical procedure during the course of the study  
 
 Patients must not have >/= Grade 2 pre-existing peripheral neuropathy (per CTCAE) 
 
 Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 
or anticipation that such a live, attenuated vaccine will be required during the study 
 
 Pregnant women are excluded from this study because MPDL3280A, and other 
members of the immune checkpoint blocking class of agents, have the potential for 
teratogenic or abortifacient effects.  Because there is an unknown but potential risk for 
adverse events in nursing infants secondary to treatment of the mother with 
MPDL3280A, breastfeeding should be discontinued if the mother is treated with 
MPDL3280A. 
 
 History of interstitial lung disease or pneumonitis of any cause 
Immunotherapy-Related Exclusion Criteria: 
 
Prior treatment with antiPD-1, anti-CTLA-4, or antiPD-L1 therapeutic antibody 
or pathway-targeting agents 
 
Treatment with systemic immunosuppressive medications (including but not limited to 
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor 
necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1 


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– 
Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled. 
– 
The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for 
patients with orthostatic hypotension or adrenocortical insufficiency is allowed. 
 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric 
or humanized antibodies or fusion proteins. 
 
Patients with prior allogeneic bone marrow transplantation or prior solid organ 
transplantation. 
 
 
5.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
2 
+ 
3 
= 
5 
Not Hispanic or Latino 
8 
+ 
17 
= 
25 
Ethnic Category: Total of all 
subjects 
(10) 
+ 
(20) 
= 
(30) 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
0 
+ 
0 
= 
0 
Black or African American 
1 
+ 
3 
= 
4 
Native Hawaiian or other Pacific 
Islander 
0 
+ 
0 
= 
0 
White 
9 
+ 
17 
= 
26 
Racial Category: Total of all 
subjects 
(10) 
+ 
(20) 
= 
(30) 
 
5.4 
Subject Recruitment  
Patients will be recruited from the referral population within the investigator and co-
investigators’ clinical practices.  
 
5.5 
Early Withdrawal of Subjects     
 


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5.5.1 When and How to Withdraw Subjects 
 
 If at any time the patient develops progressive disease, he/she will proceed directly to 
surgery as outlined in the study design. 
 If at any time the patient develops unacceptable toxicity, he/she will be removed from 
study. 
 If at any time the patient is found to be ineligible for the protocol as designated in the 
section on Criteria for Patient/Subject Eligibility (i.e., a change in diagnosis), the 
patient will be removed from study. 
 If the patient fails to comply with the defined treatment plan and follow-up 
evaluations, the patient will be removed from the study. 
 If the patient withdraws consent for continued participation, he/she will be removed 
from study. 
 If the study Sponsor or institutional review board (IRB)/independent ethics committee 
(IEC) terminate the study. 
 In the event that a patient discontinues or is withdrawn from the study, the investigator 
will notify the Sponsor and perform all procedures indicated in the End of Study 
protocol. 
 Patients withdrawn from the study for reasons other than toxicity or disease 
progression (e.g. protocol violation or withdrawal of consent) may be replaced at the 
discretion of the medical monitor and investigator. 
 
 
5.5.2 Data Collection and Follow-up for Withdrawn Subjects 
 
If a subject withdraws consent to participate in the study, attempts will be made to obtain consent 
from the subject to record at least survival data up to the protocol-described end of subject 
follow-up period.  In the event that a study subject is lost to follow-up, multiple methods of 
obtaining follow-up data will be utilized including weekly phone calls to the subject or next-of-
kin, certified letters, and review of the institutional electronic medical record as well as public 
death certificate records. Subjects withdrawn because of unacceptable adverse events will be 
followed-until resolution or stabilization of the adverse event. 
 
6. REGISTRATION PROCEDURES 
  
6.1 
CUMC Research Participant Registration  
 
Confirm eligibility as defined in the section entitled Criteria for Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures, along with applicable institutional policies and federal regulations. 
 
Only Investigators/Research personnel properly trained and delegated to consent subjects for this 
protocol will participate in the consenting process. Furthermore, properly delegated/trained 
Physician Investigators (e.g., MD, MD PhD) are required to sign/verify a protocol specific 


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Eligibility Checklist for each subject enrolled on the study, in addition to providing the relevant 
source documentation confirmation subject eligibility. 
 
All participants must be centrally registered through the Central Registration Office 
within Herbert Irving Comprehensive Cancer Center at CUMC prior to initiation of study 
treatment. 
 
Registration hours are available Monday through Friday from 9:00am – 5:00pm EST (excluding 
holidays and weekends). Same day patient registrations (and after hour registrations) will be 
accommodated on a case by case basis provided that the study team has expressed all time 
sensitive registration concerns/cases in a timely manner to the Central Registration Office.  
 
CPDM Central Registration Procedures: 
 
Within 48 hours of obtaining consent (excluding holidays and weekends), a completed/signed 
IRB approved informed consent HIPAA form, and demographics forms must be submitted to the 
CPDM Central Registration Office via an email to CPDMRegistration@cumc.columbia.edu or 
fax to 212.304.6330 with the subject line “AAAQ3153 Pending Subject Registration Request 
(PHI)”.  Upon receipt, applicable subject information as well as a “pending eligibility” status will 
be entered into HICCC’s institutional database.  This status will remain until further source 
documentation is made available to confirm overall patient eligibility. Required materials for all 
pending registration submissions are as follows: 
 
 
Completed/signed IRB approved/stamped Informed Consent Forms, including additional 
study ICFs (e.g., tissue, DNA, etc.), as applicable. 
 
The completed/signed IRB approved HIPAA Authorization form 
 
Completed/signed CPDM ICF checklist 
 
Completed/signed HICCC personal census form 
 
Completed/signed CPDM Demographics Note to File 
In order to confirm eligibility status, Investigators/designees (e.g., study specific Clinical 
Research Coordinator/Research Nurse, etc.) must submit the following documentation to the 
Central Registration Office via email or fax: 
 
 
The completed/signed study specific Eligibility Checklist  (signed by an Physician level 
Investigator) 
 
Copies of source documentation necessary for each item to be verified on the CPDM 
specific Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (e.g., hematology, serum 
chemistry, pregnancy test when applicable, MRI reports, CT/bone scans, etc.) 


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o Copy of pathology and surgical reports 
o Copy of clinic note(s) or other appropriate medical records capturing the consent process 
information, along with providing source documentation of any other items needed for 
screening/eligibility that are not captured in other source document forms (e.g., positive 
investigator statements of unique eligibility items not captured via other direct source 
documentation, concomitant medication lists, etc.) 
o Protocol deviation/waiver approvals (if applicable) 
 
Please note: subject line of email or fax should include the protocol number followed by: 
“Complete Subject Registration Request (PHI)”. 
Upon receipt of the above mentioned documentation, participant eligibility information will be 
verified by a qualified Central Registration Registrar. If any questions arise during the review 
process, queries in the form of emails will be addressed to the applicable study team personnel 
for clarification prior to enrollment. .All applicable finalized registration/eligibility information 
will then be entered into HICCC’s institutional CTMS database by the Central Registration 
Registrar.  Upon completion, an official subject registration notification email will be sent to the 
PI/research team which will include eligibility/enrollment status, as well as subject ID 
information.  Protocol therapy may not be initiated prior to receipt of this notification from the 
Central Registration Office. 
 
All screen fail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration office in a 
manner analogous to the procedures noted above. Applicable source documentation will be 
required within the corresponding submissions. 
 
Central Registration Procedures- Affiliate Institution Research Participant Registration 
Process:  
 
All Affiliate Institutions must register subjects with the coordinating center (CUMC) prior to 
any administration of study drug/intervention/local institution registration.  Please see 
instructions below: 
 
Within 48 hours of obtaining consent (excluding holidays and weekends), the Affiliate 
Institution CRN and/or CRC is required to submit the following documents to the coordinating 
center’s designee at q3153@columbia.edu  (CUMC’s study specific Multicenter Core contact).  
The coordinating center’s designee will review the documents for accurateness, and subsequently 
submit the documents to the CPDM Central Registration Office via email, with a request to 
register the patient “pending eligibility.” The title of the email should read, “AAAQ3153 
Pending Subject Registration Request (PHI)”.  The following documents should be submitted 
with the pending registration request: 
 Redacted Completed/signed IRB approved/stamped Informed Consent Forms, 
including additional study ICFs (i.e. tissue, DNA, etc.) as applicable 
 Redacted Signed HIPAA (or institutional equivalent) 


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 MCT CPDM Demographics Note to File form  
 
The Affiliate Institution’s investigator/research nurse/data manager/coordinator must contact the 
coordinating center’s designee (Multicenter Core contact) via telephone or email to communicate 
the following: 
 Notify of pending registration request  
 Confirm method of registration request submission (email or fax) 
 Communicate expected time-line of registration request submission (i.e., same day, 
next day, within the hour, etc.) 
 
To complete registration, the Affiliate Institution’s investigator/research nurse/data 
manager/coordinator should then submit the following documents to the CUMC study specific 
designee at q3153@columbia.edu: 
 A signed Affiliate Site Eligibility Checklist (signed by the investigator) 
 Copies of redacted source documentation necessary for each item to be verified on 
the CUMC specific Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (i.e., hematology, serum 
chemistry, pregnancy test when applicable, MRI reports, CT/bone scans, etc.) 
o Copy of pathology and surgical reports 
o Copy of clinic note(s) capturing the consent process information, along with 
providing source documentation of any other items needed for 
screening/eligibility that are not captured in other source document forms. (e.g., 
positive investigator statements of unique eligibility items not captured via other 
direct source documentation, concomitant medication lists, etc.) 
 
Please note: subject line of email or fax should include the following: “AAAQ3153 
Complete Subject Registration Request (PHI)”. 
 
Upon receipt of the above mentioned documents, the designated study specific Clinical Research 
Coordinator will review all documents and verify patient eligibility.  If any questions arise 
during the review process, queries in the form of emails will be addressed to the applicable 
affiliate site study team personnel for clarification prior to enrollment.  Upon verification, the 
CUMC study specific designee will then forward all documents to the CPDM Central 
Registration Office for central registration (as described above). The CPDM Central Registration 
Registrar will review all applicable documents and communicate to the CUMC study specific 
designee in order to clarify any items.  The CUMC study specific designee will communicate 
with the applicable site study team personnel for additional clarifications necessary prior to 
enrollment. 
 
Upon receipt of the subject registration notification email, the CUMC study specific designee 
will forward the notification email (which will include the study specific patient ID) to the 
affiliate site’s Principal Investigator, Consenting Professional, and applicable research personnel.  
This notification should be filed in the patient research binder accordingly. Protocol therapy may 
not be initiated prior to receipt of this notification from the coordinating center. 
 


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All screenfail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration office in a 
manner analogous to the procedures noted above. Applicable source documentation will be 
required within the corresponding submissions. 
7. SCHEDULE 
 
7.1 
 
Schedule of Assessments and Interventions 
 
Procedure/Interventiona 
Every 3 week cycles (±2 days)k 
 
Pre-
study 
C1D1 
Repeated with 
each cycle 
C2D1 C3D1 C4D1 
Day of 
Surgery 
C1D8 C1D15 
Informed consent 
X 
 
 
 
 
 
 
 
Archived unstained 
slidesb 
X 
 
 
 
 
 
 
 
Clinical Assessments 
History and Physical 
Exam 
X 
X 
 
 
X 
X 
X 
 
ECOG Performance 
Status 
X 
X 
 
 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
 
 
X 
X 
X 
 
Adverse Events 
 
 
 
 
X 
X 
X 
 
Treatmentc 
MPDL3280A 
 
X 
 
 
X 
X 
X 
 
nab-paclitaxel 
 
X 
X 
X 
X 
X 
X 
 
Carboplatin 
 
X 
 
 
X 
X 
X 
 
Tumor assessments 
Brain MRI 
X 
 
 
 
 
 
 
 
CT Chest w/contrast 
X 
 
 
 
 
Pre-
cycle 
 
Pre-
surgery 
PET/CT (if applicable) 
X 
 
 
 
 
 
 
 
Laboratory assessmentsj 
CBC 
X 
X 
X 
X 
X 
X 
X 
Xi 
Chemistryd 
X 
X 
X 
X 
X 
X 
X 
Xi 
PT/PTT 
X 
X 
 
 
X 
X 
X 
Xi 
TSHe 
X 
 
 
 
X 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
Serum beta-HCGf 
X 
X 
 
 
 
 
 
 
EBV, HIV, HCV, HBV 
X 
 
 
 
 
 
 
 
Research bloodsl 
Xg, h, 
 
 
 
Xh 
Xh 
Xh 
Xh, i 
a. 
Assessments should be performed prior to study drug infusion 
b. At least 10 unstained slides are required. A repeat biopsy may be required if sufficient tissue is 
not available. Fine-needle aspiration, brushing, cell pellets from pleural effusion, and lavage 
samples are NOT adequate for enrollment. Retrieval of archival tumor samples can occur 
outside the screening period. 


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c. 
For MPDL3280A, the initial dose will be delivered over 60 ( ± 15) minutes. If the first infusion 
is well tolerated, all subsequent infusions may be delivered over 30 (± 10) minutes until loss of 
clinical benefit. For carboplatin + nab-paclitaxel, administer nab-paclitaxel over 30 minutes (-
5/+10) followed immediately by carboplatin administered over 15−30 minutes. Administer nab-
paclitaxel alone on Days 8 and 15. 
d. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, 
magnesium, uric acid 
e. 
If TSH is abnormal, check T3 and free T4.  If these are normal, include T3 and fT4 testing for 
subsequent cycles (including follow-up period) 
f. 
Serum pregnancy test must be performed within 14 days prior to C1D1 
g. At screening, research bloods will be drawn for a) germline sequencing as a companion to 
somatic tumor DNA sequencing , b) T-cell subsets, and  c) HLA-typing  (see lab manual) 
h. PBMC isolation, serum and plasma (see lab manual) 
i. 
To be collected pre-operatively (within 2 weeks of surgery) 
j. 
Laboratory assessments to be done within 2 days prior to study drug infusion 
k. Treatment is administered every 7 days (± 2 days) but treatments must be a minimum of 5 days 
apart. 
l. 
Research Blood Samples are not to be collected on days when treatment is being delayed or 
held. 
 
 
7.2 
Follow-up Period 
 
 
Post-surgical follow-up date 
Assessment 
 2-4 weeks 
3 months (±3 weeks) 
Survivalc 
Clinical Assessments 
 
 
History and Physical 
X 
X 
 
ECOG PS 
X 
 
 
Vital signs 
X 
X 
 
EKG 
 
 
 
Concomitant Meds 
Xa 
 
 
Adverse Events 
Xb 
 
 
Collection of Survival 
Status 
 
 
Xc 
Laboratory Assessments 
 
 
CBC, Coag 
X 
 
 
Chemistry 
X 
 
 
TSH 
X 
 
 
PBMC isolation, serum
and plasma 
X 
X 
 
Imaging Assessments 
 
 
CT chest w/contrast 
 
X 
X 


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a. 
Only concomitant medications taken for ongoing adverse events related to study drug are recorded 
at this visit and they should continue to be recorded until resolution of the adverse event related to 
study drug.  
b. 
Only adverse events related to the study drug are recorded at this visit and they should continue to 
be followed until resolution. 
c. 
Survival visits are to occur every 4 to 6 months from the date of the 6 month Follow-up visit. 
Either in-person visits or telephone calls/email correspondence to assess the subject’s status are 
acceptable. 
 
 
7.3 
Surgical resection processing 
 
Resected tumor tissue will be processed for standard pathology evaluation and then remaining 
tumor tissue will be partitioned and processed in the following ways: 
- 
Snap frozen in liquid nitrogen at -80 degrees Celsius for future DNA and RNA 
extraction.  
- 
Processed in the Frattini lab as single-cell suspensions of tumor and infiltrating immune 
cells and then frozen at -80 degrees Celsius for future T-cell assays.  
- 
Processed as formalin-fixed tissue and will be embedded in paraffin for future IHC 
assays.  
Sufficient material must be collected to permit all planned correlative studies including (1) 
frozen material for DNA/RNA extraction, (2) FFPE material for IHC, and (3) digested cellular 
material for single-cell suspensions. Adjudication of sufficient material for (1) and (2) will be 
further certified by review of diff quik or H&E stained slide/touch prep from frozen and FFPE 
material to ensure tumor is present in collected material. Adequacy of material for single-cell 
suspensions will be determined by collection of at least 20 million live cells total.  
 
8. TREATMENT PLAN 
 
8.1 
   Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks for MPDL3280A, nab-paclitaxel, and carboplatin are described in Section 10.  Appropriate 
dose modifications for these agents are described in Section 9.  No investigational or commercial 
agents or therapies other than those described below may be administered with the intent to treat 
the patient's malignancy. Treatment is administered every 7 days (± 2 days) but treatments must 
be a minimum of 5 days apart. 
 
 
REGIMEN DESCRIPTION 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
MPDL3280A 
Steroids are 
1200mg in 
IV over 60 
Day 1 
3 weeks 


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contra-indicated as 
premedications for 
cycle 1, but may 
be administered as 
anti-emetic 
prophylaxis at the 
clinicians 
judgement after C1 
250cc NS 
minutes on 
first 
administration, 
then over 30  
minutes 
subsequently if 
tolerated 
(21 
days) 
Nab-
paclitaxel 
 
Premedications to 
be administered 
per institutional 
guidelines 
100 mg/m2 
reconstituted 
with 20cc NS 
IV over 30 
minutes.  
Days 1, 
8, 15 
Carboplatin 
Premedications to 
be administered 
per institutional 
guidelines 
AUC = 5 
Diluted in 
250mL NS 
IV over 30 
minutes, 
immediately 
after nab-
paclitaxel 
Day 1 
 
 
8.1.1 Investigational Agent 
 
The dose level of MPDL3280A to be tested in this study is 1200 mg (equivalent to an average 
body weightbased dose of 15 mg/kg) administered by IV infusion on day 1 of  every 3 weeks 
(21 [ 2] days).  MPDL3280A will be delivered in infusion bags with IV infusion lines that have 
product contacting surfaces of polyvinyl chloride (PVC) or polyolefin and 0.2 m in-line filters 
(filter membrane of polyethersulfone [PES]).  No incompatibilities have been observed between 
MPDL3280A and PVC or polyolefin infusion materials (bags or infusion lines).  
 
Administration of MPDL3280A will be performed in a setting with emergency medical facilities 
and staff who are trained to monitor for and respond to medical emergencies. 
 
The initial dose of MPDL3280A will be delivered over 60 ( 15) minutes.  If the first infusion is 
tolerated without infusion-associated AEs, the second infusion may be delivered over 30 ( 10) 
minutes.  If the 30-minute infusion is well tolerated, all subsequent infusions may be delivered 
over 30 ( 10) minutes.  For the first infusion, the patient’s vital signs (heart rate, respiratory 
rate, blood pressure, and temperature) should be determined within 60 minutes before, during 
(every 15 [ 5] minutes), and 30 ( 10) minutes after the infusion.  For subsequent infusions, 
vital signs will be collected within 60 minutes before and within 30 minutes after the infusion.  
Vital signs should be collected during the infusion only if clinically indicated.  Patients will be 
informed about the possibility of delayed post-infusion symptoms and instructed to contact their 
study physician if they develop such symptoms. 
 
No steroid premedication will be allowed for the first dose of MPDL3280A.  Premedication may 


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be administered for Cycles  2 at the discretion of the treating physician.  The management of 
IRRs will be according to severity as follows: 
 
1. In the event that a patient experiences a mild (NCI CTCAE Grade 1) IRR, the infusion rate 
should be reduced to half the rate being given at the time of event onset.  Once the event has 
resolved, the investigator should wait for 30 minutes while delivering the infusion at the 
reduced rate.  If tolerated, the infusion rate may then be increased to the original rate. 
 
2. In the event that a patient experiences a moderate IRR (NCI CTCAE Grade 2) or flushing, 
fever, or throat pain, the infusion should be immediately interrupted and the patient should 
receive aggressive symptomatic treatment.  The infusion should be restarted only after the 
symptoms have adequately resolved to baseline grade.  The infusion rate at restart should be 
half of the infusion rate that was in progress at the time of the onset of the IRR. 
 
3. For severe or life-threatening IRRs (NCI CTCAE Grade 3 or 4), the infusion should be 
stopped immediately, and aggressive resuscitation and supportive measures should be 
initiated.  Patients experiencing severe or life-threatening IRRs will not receive further 
infusion and will be further managed as clinically indicated until the event resolves. 
 
For anaphylaxis precautions, standard institutional anaphylaxis procedures will be followed. 
 
 
8.1.2 Nab-paclitaxel 
 
ABRAXANE (nab-paclitaxel) is injected into a vein [intravenous (I.V.) infusion] over 30 
minutes (-5/+10) ). A dose of 100mg/m2 will be administered weekly (days 1, 8, and 15 of each 
cycle). The use of an in-line filter is not recommended.  Following administration of nab-
paclitaxel, the intravenous line should be flushed with sodium chloride 9 mg/ml (0.9%) solution 
for injection, to ensure complete administration of the intended dose, according to local practice. 
No premedication is necessary for administration of this agent. This agent will be given second 
in sequence, after MPDL3280A and before carboplatin. Administration will begin after the post 
MPDL3280A infusion vital signs are collected. 
 
 
 
 
8.1.3 Carboplatin 
 
 
The dose of carboplatin will be calculated as an area under the curve (AUC) equal to 5, as 
calculated by the Calvert formula with GFR estimated by the Cockcroft-Gault formula. 
Carboplatin is infused over 30 minutes (+/- 15). Needles or IVs which contain aluminum will not 
be used in the preparation or administration of carboplatin. This medication will be premedicated 
per institutional guidelines. This agent will be administered after nab-paclitaxel infusion is 
completed. 
 
Administration of carboplatin immediately after the completion of the ABRAXANE® infusion to 
patients with NSCLC did not cause clinically meaningful changes in paclitaxel exposure. The 


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observed mean AUCinf of free carboplatin was approximately 23% higher than the targeted 
value (6 min*mg/mL), but its mean half-life and clearance were consistent with those reported in 
the absence of paclitaxel.  
 
8.1.4 Surgery 
 
Standard surgical procedures and techniques, including but not limited to lobectomy, 
bilobectomy, pneumonectomy, and mediastinal lymph node dissection, will be determined by the 
surgical team in consultation with the investigator and will be based on CT scans obtained within 
4 weeks prior to receiving study treatment. In the event of disease progression at the interim or 
post-treatment CT scans, surgical planning will be based on the updated imaging.  
 
Surgical procedure should be scheduled approximately 4 weeks from last dose of study drug as 
best possible and at the clinical discretion of the treating physician and surgeon. 
 
 
8.2 
  General Concomitant Medication and Supportive Care Guidelines 
 
8.2.1 Concomitant therapy 
 
Concomitant therapy includes any prescription medications or over-the-counter preparations 
used by a patient between the 7 days preceding the screening evaluation and the treatment 
discontinuation visit. 
Concomitant treatment is permitted if the medication is not expected to interfere with the 
evaluation of safety or efficacy of the study regimen. During the study, if the use of any 
concomitant treatment becomes necessary (e.g., for treatment of an adverse event), the treatment 
must be recorded on the eCRF, including the reason for treatment, generic name of the drug, 
dosage, route, and start and stop dates of administration.  
 
 
Because there is a potential for interaction of nab-paclitaxel with other concomitantly 
administered drugs through the cytochrome P450 system (CYP2C8 and CYP3A4), the case 
report form must capture the concurrent use of all other drugs, over-the-counter medications, or 
alternative therapies.  The Principal Investigator should be alerted if the patient is taking any 
agent known to affect or with the potential to affect selected CYP450 isoenzymes. 
 
Patients who use oral contraceptives, hormone-replacement therapy, prophylactic or therapeutic 
anticoagulation therapy (such as low-molecular-weight heparin or warfarin at a stable dose 
level), or other allowed maintenance therapy should continue their use.  Males and females of 
reproductive potential should use highly effective means of contraception.  
8.2.2 Supportive Care 
 
Patients who experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or cimetidine or another H2 receptor 


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antagonist, as per standard practice (for sites outside the United States, equivalent medications 
may be substituted per local 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 
Systemic corticosteroids and TNF inhibitors may attenuate potential beneficial immunologic 
effects of treatment with MPDL3280A but may be administered at the discretion of the treating 
physician.  If feasible, alternatives to corticosteroids should be considered.  Premedication may 
be administered for Cycles  2 at the discretion of the treating physician.  The use of inhaled 
corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic 
hypotension or adrenocortical insufficiency is allowed.  Megestrol administered as appetite 
stimulant is acceptable while the patient is enrolled in the study. 
8.2.3 Excluded Therapy 
 
Any concomitant therapy intended for the treatment of cancer, whether health 
authority-approved or experimental, is prohibited.  This includes but is not limited to 
chemotherapy, hormonal therapy, immunotherapy, radiotherapy, investigational agents, or herbal 
therapy 
It is strongly recommended that traditional herbal medicines not be administered because the 
ingredients of many herbal medicines are not fully studied and their use may result in 
unanticipated drug-drug interactions that may cause, or confound assessment of, toxicity. 
Patients are not allowed to receive immunostimulatory agents, including but not limited to IFN-
, IFN-, or IL-2, during the entire study.  These agents, in combination with MPDL3280A, 
could potentially increase the risk for autoimmune conditions. 
Patients should also not be receiving immunosuppressive medications, including but not limited 
to cyclophosphamide, azathioprine, methotrexate, and thalidomide.  These agents could 
potentially alter the activity and the safety of MPDL3280A.  Systemic corticosteroids and anti-
TNF agents may attenuate potential beneficial immunologic effects of treatment with 
MPDL3280A but may be administered at the discretion of the treating physician.  If feasible, 
alternatives to these agents should be considered. 
In addition, all patients (including those who discontinue the study early) should not receive 
other immunostimulatory agents for 10 weeks after the last dose of MPDL3280A. 
 
8.3 
    Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue for  4 cycles or 
until one of the following criteria applies: 
 
 Disease progression 


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o If the treating physician deems the patient has progressed clinically but does not 
meet RECIST criteria for PD, he/she should discuss with the surgeon and the 
principal investigator.  The patient can be taken to the operating room sooner at 
the treatment team’s discretion. 
 Intercurrent illness that prevents further administration of treatment 
 Unacceptable adverse event(s) 
 Patient decides to withdraw from the study 
 General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 Protocol violation 
In the event that a patient is discontinued on study treatment due to adverse events and is to 
proceed to the operating room sooner than was expected, the patient is to continue to present for 
study visits per study schedule during the interim. At each study visit, assessments per Table 7.1 
are to be completed and documented as they would normally just without administration of study 
drug.  
 
8.4 
    Duration of Follow Up 
 
Patients will initially be followed by study team for 90 days after surgery or removal from study 
or until death, whichever occurs first. Patients removed from study for unacceptable adverse 
events will be followed until resolution or stabilization of the adverse event, and will be 
contacted by phone at least every 1 month until 90 days after withdrawal to obtain data regarding 
long term outcomes. 
 
Patients who complete the initial follow-up stage will then move into the Survival stage. Survival 
visits will occur every 4-6 months beginning at the end of the initial follow-up stage (90 days 
post-surgery). Survival can be assessed via in-person visits or telephone calls/email 
correspondence, until death, lost to follow-up, withdrawal of study consent, or for 3 years after 
date of surgery. Standard-of-care imaging is to be reviewed at each survival time point  for 
evaluation of DFS. 
 
 
8.5 
 Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 8.5 applies.  The 
reason for study removal and the date the patient was removed will be documented in the Case 
Report Form. 
 
Potential reasons for removal include adverse event, disease progression, investigator decision, 
protocol violation, patient noncompliance, and study termination by the Sponsor or IRB/IEC.  
 
 
9. 
DOSING DELAYS/DOSE MODIFICATIONS 
 


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9.1 
Monitoring 
Safety will be evaluated in this study through the monitoring of all serious and non-serious AEs, 
defined and graded according to NCI CTCAE v4.03.  Patients will be assessed for safety 
(including laboratory values) at least every 7 days.  Patients will be followed for safety for 90 
days following the last dose of study treatment or until receipt of another anticancer therapy, 
whichever comes first.   
General safety assessments will include serial interval histories, physical examinations, and 
specific laboratory studies, including serum chemistries and blood counts.  All serious adverse 
events (SAEs) will be reported in an expedited fashion (see Section 10).  In addition, the 
investigators will review and evaluate observed AEs on a regular basis. An continuous safety 
analysis will be conducted for treatment related adverse events.   
 
Patients who have an ongoing AE upon study completion or at discontinuation from the study 
will be followed until the event has resolved to baseline grade, the event is assessed by the 
investigator as stable, new anticancer treatment is initiated, the patient is lost to follow-up, the 
patient withdraws consent, or until it has been determined that study treatment or participation is 
not the cause of the AE. 
 
Subjects are considered evaluable for assessment of treatment-related toxicity if they receive at 
least one dose of therapy. Grading of all toxicities will be according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03. 
 
Immune-related adverse events (irAEs) are defined as AEs of immune nature (i.e., inflammatory) 
in the absence of a clear alternative etiology. Additional AEs that are not immune related may 
also be a potential safety event (see Section 12.7). 
 
9.2 
Management of Specific Safety Concerns with MPDL3280A 
Toxicities associated or possibly associated with MPDL3280A treatment should be managed 
according to standard medical practice.  Additional tests, such as autoimmune serology or 
biopsies, may be used to determine a possible immunogenic etiology. 
Although most immune-related adverse events (irAEs) observed with immunomodulatory agents 
have been mild and self-limiting, such events should be recognized early and treated promptly to 
avoid potential major complications.  Discontinuation of MPDL3280A may not have an 
immediate therapeutic effect and, in severe cases, immune-related toxicities may require acute 
management with topical corticosteroids, systemic corticosteroids, mycophenolate, or TNF 
inhibitors. 
The primary approach to Grade 1 to 2 irAEs is supportive and symptomatic care with continued 
treatment with MPDL3280A; for higher-grade irAEs, MPDL3280A should be withheld and oral 
and/or parenteral steroids administered.  Recurrent Grade 2 irAEs may also mandate withholding 
MPDL3280A or the use of steroids.  Assessment of the benefit-risk balance should be made by 


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the investigator, with consideration of the totality of information as it pertains to the nature of the 
toxicity and the degree of clinical benefit a given patient may be experiencing prior to further 
administration of MPDL3280A.  MPDL3280A should be permanently discontinued in patients 
with life-threatening irAEs. 
9.2.1 Gastrointestinal Toxicity 
Immune-mediated colitis has been associated with the administration of MPDL3280A. Patients 
should be advised to inform the investigator if any diarrhea occurs, even if it is mild. 
If the event is of significant duration or magnitude, or is associated with signs of systemic 
inflammation or acute phase reactants (e.g., increased CRP or platelet count or bandemia), it is 
recommended that sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy with 
three to five specimens for standard paraffin block be performed.  If possible, one or two biopsy 
specimens should be snap frozen and stored.     
Treatment may be restarted following the resolution of colitis.  In addition, if the patient is being 
managed with corticosteroids, treatment should not be restarted until the steroids have been 
tapered down to a prednisone dose  10 mg/day.  Patients who resume treatment should be 
monitored closely for signs of renewed diarrhea.  Table 1 provides a summary of dose 
modification guidelines for gastrointestinal toxicities. 


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Table 1 
Dose Modification Guidelines for Gastrointestinal Toxicity 
Toxicity 
Description 
 
 
Management 
Diarrhea 
Grade 2 (46 stools per 
day over baseline)  5 
days 
Hold MPDL3280A, nab-paclitaxel, and 
carboplatin. Discontinue NSAIDS. 
Investigate for etiology.  Restart 
MPDL3280A with chemotherapy once at 
baseline stool frequency. 
Grade 2 (46 stools per 
day over baseline)  5 
days 
Hold MPDL3280A, nab-paclitaxel, and 
carboplatin. Discontinue NSAIDS.  
Consider a referral to a gastroenterologist. 
Administer anti-diarrheal agent (e.g., 
Imodium). 
Consider oral budesonide, mesalamine, or 
10 mg oral prednisone equivalent per day.   
Restart MPDL3280A once at baseline stool 
frequency.  
Abdominal pain 
 
Blood or mucus in stool 
 
OR 
 
Grade  3 ( 7 stools/day 
over baseline) with 
peritoneal signs, ileus, or 
fever 
Hold MPDL3280A, nab-paclitaxel, and 
carboplatin. Discontinue NSAIDS.  
Rule out bowel perforation.  Consider 
administering prednisone 60 mg/day or 
equivalent.  
Taper steroids over 1 month.  Restart 
MPDL3280A if diarrhea is resolved and 
systemic steroid dose is  10 mg oral 
prednisone equivalent per day. 
Permanently discontinue MPDL3280A for 
life-threatening, immune-related diarrhea 
or colitis. 
NSAID  nonsteroidal anti-inflammatory drug. 
 
9.2.2 Hepatotoxicity 
Immune-mediated hepatitis has been associated with the administration of MPDL3280A. 
While in this study, patients presenting with right upper-quadrant abdominal pain and/or 
unexplained nausea or vomiting should have LFTs performed immediately, and LFTs should be 
reviewed before administration of the next dose of study drug. 
If LFTs increase, neoplastic, concurrent medications, viral hepatitis, and toxic etiologies should 
be considered and addressed, as appropriate.  Imaging of the liver, gall bladder, and biliary tree 
should be performed to rule out neoplastic or other causes of increased LFTs.  Anti-nuclear 


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antibody, perinuclear anti-neutrophil cytoplasmic antibody, anti-liver kidney microsomal, and 
anti-smooth muscle antibody tests should be performed if an autoimmune etiology is considered. 
Patients with LFT abnormalities should be managed according to the guidelines in Table 2. 
Table 2 
Dose Modification Guidelines for Hepatotoxicity 
Toxicity 
Description 
Management 
LFT 
abnormalities 
AST/ALT ( ULN to 
3  ULN) with total 
bilirubin  2  ULN 
Continue with the standard monitoring plan 
(i.e., LFTs every 3 weeks before dosing). 
AST/ALT ( 3  ULN to  
 10  ULN) with total 
bilirubin  2  ULN 
Continue MPDL3280A.   
Monitor LFTs at least weekly.   
Consider referral to a hepatologist. 
AST/ALT  10  ULN 
Hold MPDL3280A.   
Consider administering IV steroids for 
2448 hours (prednisone 60 mg/day 
equivalent) followed by an oral prednisone 
(or equivalent) taper over 24 weeks.  If 
LFT results do not decrease within 48 
hours after initiation of systemic steroids, 
addition of an alternative 
immunosuppressive agent (e.g., 
mycophenolate or TNF antagonist) to the 
corticosteroid regimen may be considered.  
Monitor LFTs every 4872 hours until 
decreasing and then follow weekly.   
Restart MPDL3280A if AST/ALT 
 3  ULN with bilirubin  2  ULN and 
steroid dose is  10 mg oral prednisone 
equivalent per day. 
Permanently discontinue MPDL3280A for 
life-threatening, immune-related hepatic 
events. 
 


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Table 2 
Dose Modification Guidelines for Hepatotoxicity (cont.) 
Toxicity 
Description 
Management 
LFT 
abnormalities  
(cont.) 
AST/ALT  3  ULN 
with bilirubin  2  ULN 
Hold MPDL3280A.   
Consult a hepatologist.   
Consider administering IV steroids for 
2448 hours (prednisone 60 mg/day 
equivalent) followed by oral taper over 
1 month.  If LFTs results do not decrease 
within 48 hours after initiation of systemic 
steroids, addition of an alternative 
immunosuppressive agent (e.g., 
mycophenolate or TNF antagonist) to the 
corticosteroid regimen may be considered.  
Monitor LFTs every 4872 hours until 
decreasing and then follow weekly.  Restart 
MPDL3280A if AST/ALT  3  ULN with 
bilirubin  2  ULN and steroid dose is 
 10 mg oral prednisone equivalent per day. 
IV  intravenous; LFT  liver function test; TNF  tumor necrosis factor alpha; 
ULN  upper limit of normal. 
 
 
9.2.3 Dermatologic Toxicity 
Treatment-emergent rash has been associated with MPDL3280A.  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 
performed unless contraindicated.  Low-grade rash and pruritus irAEs have been treated with 
symptomatic therapy (e.g., antihistamines).  Topical or parenteral corticosteroids may be 
required for more severe symptoms. 
Dermatologic toxicity and rash should be managed according to the guidelines in Table 3. 


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Table 3 
Dose Modification Guidelines for Dermatologic Toxicity 
Toxicity 
Description 
Management 
Dermatologic 
toxicity/rash (e.g., 
maculopapular or 
purpura) 
Grade 1:  Mild 
 10% BSA 
Continue MPDL3280A symptomatic 
therapy with antihistamine PRN. 
Consider topical steroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Grade 2:  Moderate  
10%30% BSA 
Continue MPDL3280A.  Consider 
dermatologist referral. 
Administer topical steroids. 
Consider higher potency topical steroids if 
rash is unresolved. 
Grade 3:  Severe  
 30% BSA 
Hold MPDL3280A.   
Consult dermatologist.  Administer oral 
prednisone 10 mg or equivalent.  If the rash 
is unresolved after 4872 hours, administer 
oral prednisone 60 mg or equivalent. 
Restart MPDL3280A if rash is resolved 
and systemic dose is  10 mg oral 
prednisone equivalent per day. 
Permanently discontinue MPDL3280A for 
life-threatening, immune-related 
dermatologic toxicity. 
BSA  body surface area; PRN  as needed. 
 
 
9.2.4 Endocrine Toxicity 
Hypothyroidism has been associated with the administration of MPDL3280A. Patients with 
unexplained symptoms such as fatigue, myalgias, impotence, mental status changes, or 
constipation should be investigated for the presence of thyroid, pituitary, or adrenal 
endocrinopathies, as well as for hyponatremia or hyperkalemia.  An endocrinologist should be 
consulted if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) and free T4 
levels should be obtained to determine whether thyroid abnormalities are present.  TSH, 
prolactin, and a morning cortisol level will help to differentiate primary adrenal insufficiency 
from primary pituitary insufficiency. 
Hypothyroidism should be managed according to the guidelines in Table . 


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Table 4 
Dose Modification Guidelines for Endocrine Toxicity 
Toxicity 
Description 
Management 
Hypothyroidism 
TSH elevated, asymptomatic 
Continue MPDL3280A.   
Start thyroid-replacement hormone.   
Monitor TSH weekly. 
TSH elevated, symptomatic 
Hold MPDL3280A.   
Consider referral to an 
endocrinologist.    
Restart MPDL3280A when 
symptoms are controlled by thyroid 
replacement and TSH levels are 
decreasing.  
TSH  thyroid-stimulating hormone. 
 
 
9.2.5 Pulmonary Toxicity 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of MPDL3280A and have primarily been observed in patients with 
underlying NSCLC. 
Mild-to-moderate events of pneumonitis have been reported with MPDL3280A.  All pulmonary 
events should be thoroughly evaluated for other commonly reported etiologies such as 
pneumonia/infection, lymphangitic carcinomatosis, pulmonary embolism, heart failure, chronic 
obstructive pulmonary disease (COPD), or pulmonary hypertension and the following should be 
performed: 
 
Measurement of oxygen saturation (i.e., arterial blood gas) 
 
High-resolution CT scan of the chest 
 
Bronchoscopy with bronchoalveolar lavage and biopsy 
 
Pulmonary function tests (with diffusion capacity of the lung for carbon monoxide [DLCO]) 
 
Patients will be assessed for pulmonary signs and symptoms throughout the study.  Patients will 
also have CT scans of the chest at every tumor assessment. 
Pulmonary toxicity should be managed according to the guidelines in Table 5. 


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Table 5 
Dose Modification Guidelines for Pulmonary Toxicity 
Toxicity 
Description 
Management 
Pulmonary toxicity 
GGO or non-infectious 
infiltrate in absence of 
hypoxia, or dyspnea 
Hold treatment with MPDL3280A.   
Re-evaluate after 1 week. 
If no worsening in GGO/infiltrates and 
patient still asymptomatic, resume 
treatment with MPDL3280A. 
If GGO/infiltrates worsen and patient is 
still asymptomatic, continue to hold 
MPDL3280A and refer for 
bronchoscopy.  Consider starting low-
dose oral prednisone 10 mg or 
equivalent.   
Re-evaluate after 1 week.  Resume 
MPDL3280A if GGO/infiltrates 
improving.  
Hypoxia or dyspnea in 
presence of GGO or 
infiltrate without 
alternative etiology 
Hold MPDL3280A.   
Consult a pulmonologist.  Investigate 
for other etiologies and consider 
bronchoscopy.  If bronchoscopy is 
consistent with immune-related 
etiology, start 60 mg prednisone 
equivalent per day followed by taper 
over 2 weeks.  
Restart MPDL3280A if 
symptomatically improved, infiltrates 
are resolved, and steroid use is  10 mg 
prednisone equivalent per day. 
 
Permanently discontinue MPDL3280A 
for life-threatening, immune-related 
pulmonary events. 
GGO  ground glass opacities. 
 
 
9.2.6 Pericardial and Pleural Effusions 
 
Pericardial and pleural involvement with associated effusions is common in patients with cancer 
and has the theoretical potential to be exacerbated by inflammation associated with anti-tumor 
immunity following PD-L1 blockade.  Patients presenting with dyspnea, chest pain, or 
unexplained tachycardia should be evaluated for the presence of a pericardial effusion.  Patients 
with pre-existing pericardial effusion should be followed closely for pericardial fluid volume 
measurements and impact on cardiac function.  When intervention is required for pericardial or 


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pleural effusions, appropriate workup includes cytology, LDH, glucose, cholesterol, protein 
concentrations (with pleural effusions), and cell count.  For patients with a pericardial effusion 
causing end-diastolic right ventricular collapse, treatment may be restarted following the 
placement of a pericardial window, demonstration of hemodynamic stability, and resolution of 
right ventricular dysfunction. 
9.2.7 Potential Pancreatic Toxicity 
 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with administration of other immunomodulatory agents.  The 
differential diagnosis of acute abdominal pain should include pancreatitis.  Appropriate workup 
should include an evaluation for obstruction, as well as serum amylase and lipase tests. 
9.2.8 Potential Eye Toxicity 
 
An ophthalmologist should evaluate visual complaints.  Uveitis or episcleritis may be treated 
with topical corticosteroid eye drops.  MPDL3280A should be permanently discontinued for 
immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. 
Ocular toxicity should be managed according to the guidelines in Table 6. 
Table 6 
Dose Modification Guidelines for Eye Toxicity 
Toxicity 
Description 
Management 
Eye toxicity 
(autoimmune uveitis, 
iritis, or episcleritis) 
Symptomatic 
Hold MPDL3280A.   
Consult ophthalmologist and start 
topical corticosteroid eye drops.   
MPDL3280A may be restarted 
following resolution of the events. 
Permanently discontinue 
MPDL3280A for immune-mediated 
ocular disease that is unresponsive to 
local immunosuppressive therapy. 
 
 
9.3 
Carboplatin and nab-paclitaxel 
 
Dose reductions, holds, and discontinuations for each study drug may be made as outlined below 
and in the respective Package Inserts or according to physician judgment. When a treatment 
cycle is delayed or interrupted because of toxicity resulting from either component of the 
regimen, all study drugs should generally be held and resumed together to remain synchronized. 
However, if it is anticipated that chemotherapy will be delayed by 2 weeks or more, then 
MPDL3280A should be given without the chemotherapy if there is no contraindication; this 
should be discussed with the Medical Monitor prior to re-initiating therapy. Investigators should 
be vigilant and alert to early and overt signs of myelosuppression/infection/febrile neutropenia so 


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that these complications can be promptly and appropriately managed. Patients should be made 
aware of these signs and encouraged to seek medical attention at the earliest opportunity. Dose 
modifications of carboplatin and nab-paclitaxel are allowed as described in the following 
sections:  hematologic, gastrointestinal, neurologic, hepatic, and other toxicities. 
 
 
If a patient experiences adverse events and there are conflicting recommendations, the 
investigator will use the recommended dose adjustment that reduces the dose to the lowest level. 
All adverse events should first be screened for potential immunogenic etiologies induced by 
MPDL3280A, as outlined in 9.2. 
 
9.3.1 Hematologic Toxicity  
 
ANC must be ≥ 1500/mm3 and platelet counts must be ≥ 100,000/mm3 on Day 1 of each cycle. 
Nab-paclitaxel should not be administered on Days 8 or 15 of the cycle until counts recover to an 
ANC ≥ 1500/mm3 and platelets ≥ 50,000 cells/mm3.  If nab-paclitaxel cannot be administered 
on Day 8 or 15 of the cycle, this treatment can be skipped, and the next dose should be given per 
original treatment schedule as long as counts have recovered to permissible levels.  However, if 
ANC and platelets are too low for Day 1 administration, then Day 1 treatment should be 
postponed until count recovery. When dosing resumes, the carboplatin and nab-paclitaxel doses 
should be permanently reduced as outlined in Table 7. Initiation or increased dose of granulocyte 
colony-stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte/macrophage 
colony-stimulating factor, and/or pegfilgrastim) is prohibited. 
 
Table 7: Permanent Dose Reductions for Toxicities and Dosing on the Study 
Adverse Drug Reaction 
Occurrence 
nab-Paclitaxel 
Dose (mg/m2) 
Carboplatin 
Dose (AUC 
mg*min/mL) 
Neutropenic Fever (ANC < 500/mm3 with fever > 
38°C) 
OR 
Delay of next cycle by ≥ 7 days for ANC < 
1500/mm3 
OR 
ANC < 500/mm3 for ≥ 7 days 
First 
75 
4.0 
Second 
50 
3.0 
Third 
Discontinue Treatment* 
Platelet count < 50,000/mm3 
First 
75 
4.5 
Second 
Discontinue Treatment* 
Sensory Neuropathy Grade 3 or 4 
First 
75 
4.5 
Second 
50 
3.0 
Third 
Discontinue Treatment* 
Grade 2 or 3 cutaneous toxicity 
Grade 3 diarrhea 
First 
75 
4.5 
Second 
50 
3.0 


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Grade 3 mucositis 
Any other Grade 3 or 4 nonhematologic toxicity 
Third 
Discontinue Treatment* 
Grade 4 cutaneous toxicity, diarrhea or mucositis 
First 
Discontinue Treatment* 
ANC = Absolute Neutrophil Count; AUC = area under the curve. 
* If an adverse event that requires dose reduction recurs after the dose has been reduced twice, the subject should 
generally have treatment discontinued unless, at the discretion of the investigator, there is evidence of continuing 
benefit to the subject that outweighs the risk of recurrent toxicity. Re-Escalation is not permitted at anytime. 
 
 
9.3.2 Gastrointestinal Toxicity  
 
For Grade 3 or 4 gastrointestinal toxicities, treatment should be delayed until resolution to  
patient’s baseline value. Dose reductions at the start of the subsequent cycle will be based on 
gastrointestinal toxicities from the dose administered in the preceding cycle. Table 8 provides the 
relevant dose adjustments for gastrointestinal toxicities.  
 
Table 8:  Carboplatin and Nab-Paclitaxel Dose Modification Based on Gastrointestinal 
 
Toxicities in the Preceding Cycle  
 
Toxicity 
Next Dose for 
Carboplatin as % of 
previous dose* 
Next Dose for nab-
paclitaxel as % of 
previous dose* 
Diarrhea 
Grade 3 or 4** 
75% 
75% 
Oral Stomatitis/Mucositis 
Grade 3 or 4 
75% 
75% 
Nausea/Vomiting 
Grade 3 or 4 
75% 
75% 
*If deemed appropriate by the treating physician, adjust carboplatin dose to the specified 
percentage of the previous AUC. 
** As per investigator discretion 
AUC = area under the curve (mg x min / mL) 
 
 
Nausea and/or vomiting should be controlled with adequate anti-emetics. If Grade 3 or 4 
nausea/vomiting occurs in spite of anti-emetics, the dose should be reduced by 25% for the next 
course. If tolerated, the dose should be increased back to 100% as soon as possible.  
 
If, on Day 1 of any treatment cycle, the patient has oral mucositis/stomatitis, the treatment should 
be withheld until the oral mucositis/stomatitis is cleared. If the oral mucositis/stomatitis has not 
cleared in 3 weeks, the patient’s chemotherapy will be discontinued. If acute Grade 3 oral 
mucositis occurs at any time, a 75% dose should be given when the oral mucositis is completely 
cleared. This is a permanent dose reduction.  
 
 
 


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9.3.3 Neurological Toxicity (Nab-Paclitaxel Only)  
 
Nab-paclitaxel should be withheld for Grade 3-4 peripheral neuropathy. Nab-paclitaxel and 
carboplatin may be resumed at reduced doses (see table below) when peripheral neuropathy 
recovers to Grade 1 or completely resolves.  
 
Table 9:  Nab-Paclitaxel and Carboplatin Permanent Dose Reductions for Neurological 
Toxicity  
 
Toxicity 
Occurrence 
Next Dose for Carboplatin 
Next Dose for nab-
paclitaxel 
Grade 3 or 4 
sensory 
neuropathy 
First 
Decrease to 4.5 AUC 
Decrease to 75mg/m2 
Second 
Decrease to 3 AUC 
Decrease to 50mg/m2 
Third 
Discontinue treatment 
AUC = area under the curve (mg x min / mL) 
 
 
9.3.4 Hepatic Toxicity (Nab-Paclitaxel Only)  
 
 
For patients who develop Grade ≥ 3 hepatotoxicity during study treatment (ALT and/or AST ≥ 5 
x ULN or total bilirubin ≥ 3 x ULN), study treatment should be interrupted. Hepatic toxicity 
must resolve to Grade ≤ 1 prior to dosing. If nab-paclitaxel is withheld because of hepatic 
toxicity, carboplatin should also be withheld and administered when the nab-paclitaxel is 
resumed. If nab-paclitaxel is withheld, hepatic values must recover to Grade ≤ 1 within 3 weeks 
or the patient’s nab-paclitaxel treatment will be discontinued. No dose reductions for carboplatin 
will be made for hepatic toxicity.  
 
If Grade 3 hepatic toxicity occurs at any time, the nab-paclitaxel dose should be permanently 
reduced to 75% of the starting dose (i.e., to 75 mg/m2). Nab-paclitaxel will be discontinued for 
Grade 4 hepatic toxicity.  
 
The investigator should make all efforts to exclude malignant disease progression as a cause of 
liver enzyme derangement. All study medication should be discontinued if the disease under 
investigation has progressed.  
 
9.3.5 Other Toxicities  
 
For any Grade 3 or 4 toxicity not mentioned above, carboplatin or nab-paclitaxel should be 
withheld until the patient recovers completely or to Grade 1 toxicity. The treatment should then 
be resumed at 75% dose (permanent dose reduction) for Grade 3 toxicities and 50% of dose 
(permanent dose reduction) for Grade 4 toxicities. If recovery to Grade 1 toxicity does not occur 
within 3 weeks, the patient’s chemotherapy will be discontinued. For Grade 1 and 2 toxicities, no 


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dose reduction should be made. For guidelines on the dosing of other study drugs when 
carboplatin or nab-paclitaxel are held, see Section 5.1.5.  
 
9.4 
Potential Overlapping Toxicities  
 
The risk of overlapping toxicities between MPDL3280A, carboplatin, and nab-paclitaxel is 
thought to be minimal. Nevertheless, the attribution and management of certain adverse events 
that have been associated with each agent separately (e.g., hepatotoxicity, skin, and 
gastrointestinal toxicity) may not be unambiguous when the agents are administered together. It 
is theoretically possible that allergic or inflammatory adverse events associated with these 
chemotherapeutic agents (e.g., hepatotoxicity) could be exacerbated by the immunostimulatory 
activity of MPDL3280A.  
Toxicities should initially be managed according to the recommendations above, with dose holds 
and modifications (if applicable) applied to the component of the study regimen judged to be the 
primary cause. For severe (Grade 3) or persistent Grade 1/2 diarrhea, an endoscopic evaluation 
should be considered. Additional tests, such as autoimmune serology or biopsies, may be used to 
determine a possible immunogenic etiology for adverse events listed above. If, in the opinion of 
the investigator, MPDL3280A is a potential inciting factor, the dose of MPDL3280A may be 
held indefinitely. Prompt symptomatic management is appropriate for mild immune-mediated 
adverse events. In severe cases, immune-mediated toxicities may be acutely managed with 
topical corticosteroids, systemic corticosteroids, or TNF-α inhibitors. These cases should be 
discussed with the Medical Monitor. 
 
 
 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
10.1 
Adverse  events  
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious 
adverse events (SAEs) per protocol.  This includes all events of death, and any study specific 
issue of concern. 
 
10.2 
Definitions 
Adverse Event: 
 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, 
regardless of attribution. 
 
 
 
 
 


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This includes the following: 
 
 AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with lung cancer that were not 
present prior to the AE reporting period. 
 Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations). 
 If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
 Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period.  
 
Serious Adverse Event: 
 
An AE should be classified as an SAE if the following criteria are met: 
 It results in death (i.e., the AE actually causes or leads to death). 
 It is life threatening (i.e., the AE, in the view of the investigator, places the subject 
at immediate risk of death. It does not include an AE that, had it occurred in a 
more severe form, might have caused death.). 
 It requires or prolongs inpatient hospitalization, unless:  
o routine treatment  or monitoring of the studied indication, not associated 
with any deterioration in condition (procedures such as central line 
placements, paracentesis, pain control) 
o elective or pre-planned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since the 
start of study drug 
o treatment on an emergency outpatient basis for an event not fulfilling any 
of the definitions of an SAE given above/below and not resulting in 
hospital administrations 
o social reasons and respite care in the absence of any deterioration in the 
patient’s general condition 
 It 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). 
 It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the IMP. 
 It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the subject or may require medical/surgical 
intervention to prevent one of the outcomes listed above). 
 
Important medical events are those that may not be immediately life threatening, but are clearly of 
major clinical significance.   They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above.  For example, drug overdose or abuse, a 


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seizure that did not result in in-patient hospitalization or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious events should be regarded as 
non-serious adverse events.  
 
Unanticipated Problem: 
 
An unanticipated problem is any incident, experience or outcome involving risks to subjects or 
others in any human subjects research that meets all of the following criteria: 
 Unexpected (in terms of nature, severity or frequency) given (a) the research procedures 
that are described in the IRB-approval protocol and informed consent document, and (b) the 
characteristics of the subject population being studied; 
 Related or possibly related to participation in such research (e.g., there is a reasonable 
possibility that the incident, experience or outcome may have been caused by the procedures 
involved in such research); and  
 Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic or social harm) than was previously known or recognized.  
 
Adverse Event Reporting Period 
 
The study period during which all AEs and SAEs must be reported begins after informed consent 
is obtained and ends 30 days following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. After this period, investigators should only 
report SAEs that are attributed to prior study treatment. For this study, the study treatment 
follow-up is defined as 90 days following surgical resection procedure, or 90 days following the 
decision to remove the subject from study treatment, whichever is earliest. 
 
Baseline/Preexisting Condition 
 
A baseline/preexisting condition is one that is present at the start of the study. A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or if the character of 
the condition worsens during the study period. 
 
General Physical Examination Findings 
 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event.  
 
 
 
 
Post-study Adverse Event 


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All unresolved treatment-related adverse events should be followed by the investigator until the 
events are resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  
At the last scheduled visit, the investigator should instruct each subject to report any subsequent 
event(s) that the subject, or the subject’s personal physician, believes might reasonably be related 
to participation in this study.   
 
Abnormal Laboratory Values 
 
A clinical laboratory abnormality should be documented as an adverse event if any one of the 
following conditions is met:  
 The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a degree that requires active management (e.g., change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc.). 
 
Hospitalization, Prolonged Hospitalization or Surgery 
 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 
this protocol.  Any condition responsible for surgery should be documented as an adverse event 
if the condition meets the criteria for an adverse event.  
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
a preexisting condition.  Surgery should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the clinical 
investigator. 
 
10.3 
Assessment of Adverse Events 
 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to MPDL3280A, 
and actions taken. 
 


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To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
 
Yes 
 
There is a plausible temporal relationship between the onset of the AE and administration of the 
study treatment, and the AE cannot be readily explained by the subject’s clinical state, 
intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of response 
to the study drug; and/or the AE abates or resolves upon discontinuation of the study regimen or 
dose reduction and, if applicable, reappears upon re-challenge. 
 
No 
 
Evidence exists that the AE has an etiology other than the study drug (e.g., preexisting medical 
condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has 
no plausible temporal relationship to study drug administration (e.g., cancer diagnosed 2 days 
after first dose of study drugs). 
 
Expected adverse events are those adverse events that are listed or characterized in the Package 
Insert (P.I) or current Investigator Brochure (I.B).  
 
Unexpected adverse events are those not listed in the P.I or current I.B or not identified. This 
includes adverse events for which the specificity or severity is not consistent with the description 
in the P.I. or I.B. For example, under this definition, hepatic necrosis would be unexpected if the 
P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis. 
 
10.4 
Eliciting of Adverse Events 
 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event module of the case report form (CRF).  All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should recorded in the source document, though should be grouped 
under one diagnosis. 
 
10.5 
Specific Instructions for Recording Adverse Events 
 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 
Avoid colloquialisms and abbreviations. 
 
10.5.1 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 


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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. 
 
10.5.2 Deaths 
 
All deaths that occur during the protocol-specified AE reporting period (see Section I), 
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”. 
 
10.5.3 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”). 
 
10.5.4 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: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for preexisting conditions 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study or 
 Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of 
the study. 
10.5.5 Pregnancy 
 
If a female subject becomes pregnant while receiving the study drug or within the follow-up 
period (for female patients within one year after the last dose of MPDL3280A or the partner of a 
male patient within three months of completing therapy), a report should be completed and 
expeditiously submitted to Genentech, Inc. 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 


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anomaly/birth defect in a child born to a female subject exposed to the study regimen should be 
reported as an SAE. 
 
10.5.6 Post-Study Adverse Events 
 
The investigator should expeditiously report any SAE occurring after a subject has completed or 
discontinued study participation if attributed to prior MPDL3280A exposure. If the investigator 
should become aware of the development of cancer or a congenital anomaly in a subsequently 
conceived offspring of a female subject who participated in the study, this should be reported as 
an SAE.  
 
10.5.7 Reconciliation 
 
The Sponsor agrees to conduct reconciliation for the product. Genentech, Celgene, and the 
Sponsor will agree to the reconciliation periodicity and format, but agree at minimum to 
exchange quarterly (no less frequently than monthly) line listings of cases received by the other 
party.  
 
If discrepancies are identified with regards to cases reported to Genentech, the Sponsor and 
Genentech will cooperate in resolving the discrepancies. The responsible individuals for each 
party shall handle the matter on a case-by-case basis until satisfactory resolution.  The sponsor 
shall receive reconciliation guidance documents for Genentech within the ‘Activation Package’. 
 
10.5.8 AEs of Special Interest (AESIs) 
 
AEs of Special Interest are defined as a potential safety problem, identified as a result of safety 
monitoring of the Product. 
  
The MPDL3280A Events of Special Interest are:  
 
 Pneumonitis 
 Colitis 
 Endocrinopathies: Diabetes mellitus, Pancreatitis, Hyperthyroidism, or 
Adrenal Insufficiency 
 Hepatitis 
 Transaminitis: Grade ≥2 (AST or ALT >3x ULN and bilirubin >2x ULN ) 
OR AST/ALT >10x ULN  
 Systemic Lupus Erythematosus 
 Guillain Barre Syndrome, Myasthenia gravis 


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 Meningoencephalitis 
 Nephritis 
 Events suggestive of hypersensitivity, cytokine release, influenza like 
illness, systemic inflammatory response syndrome (SIRS), systemic 
inflammatory activation (SIA), or infusion reaction syndromes 
 Suspected Transmission of an Infectious Agent (STIAMP) by the study 
drug 
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. 
 
 
10.6 
Recording of Adverse Events 
 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event module of the case report form (CRF).  All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should recorded in the source document, though should be grouped 
under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause.  Serious adverse events that are still ongoing 
at the end of the study period must be followed up to determine the final outcome.  Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation should be recorded and reported immediately. 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP website at : 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
For multi-site trials such as this study where a Columbia University Medical Center investigator 
is serving as the principal investigator, each participating investigator is required to abide by the 
reporting requirements set by Columbia University Medical Center. The study must be 
conducted in compliance with FDA regulations, local safety reporting requirements, and 
reporting requirements of the principal investigator.  


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Each investigative site will be responsible to report SAEs that occur at that institution to their 
respective IRB. It is the responsibility of each participating investigator to report serious adverse 
events to the study sponsor as described below.  
 
In addition to the reporting requirements for SAEs, a separate case report form will be made for 
reporting of any grade adverse events attributable to research biopsies. These events will not 
require expedited reporting unless they also meet the requirements for SAE reporting, as detailed 
below.  
 
Copies of all IND safety reports submitted to the FDA and/or institutional IRB by the institution 
under the institution’s IND will be shared with an Acetylon representative so that these reports 
can be evaluated and included in the Investigator Brochure and future Acetylon IND safety 
submissions per regulations. 
 
10.7 
Reporting of Adverse Events 
 
10.7.1 IRB Notification by Sponsor-Investigator 
 
Reports of all Serious events (including follow-up information) that meet the definition of an 
unanticipated problem posing risk to subjects or others must be submitted to the IRB within one 
week (5 business days) following the occurrence of the unanticipated problem or the principal 
investigator’s acquiring knowledge of the unanticipated problem  in accordance with IRB policy. 
Additionally, the sponsor-investigator will submit a summary of all Unanticipated problems that 
occurred since the beginning of the study at the time of continuing review. Copies of each report 
and documentation of IRB notification and receipt will be kept in the Regulatory binder. 
 
10.7.2 Reporting to Drug Manufacturer by Sponsor-Investigator 
 
10.7.2.1 
Investigator Reporting to Genentech 
 
Investigators must report all SAEs to Genentech Safety within the timelines described below.  
The completed MedWatch/case report/equivalent should be submitted immediately upon 
completion via fax to Genentech Drug Safety at: 
Fax: 650-238-6067  
 
Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it 
becomes available. 
SAE reports and AEs of Special Interest, whether related or unrelated to MPDL3280A, will be 
transmitted to Genentech within 24 hours of the Awareness Date. 


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Additional reporting requirements to Genentech include the following: 
 
Any reports of pregnancy following the start of administration with the MPDL3280A and 
within the follow-up period (for female patients within one year after the last dose of 
MPDL3280A or the partner of a male patient within three months of completing therapy) 
will be transmitted to Genentech Drug Safety within 24 hours of the Awareness Date.  
 
All non-serious MPDL3280A AEs originating from the study will be forwarded Genentech 
quarterly. 
 
In addition to SAEs, pregnancy reports and AESIs, the following Special Situations Reports 
should be collected and transmitted to Genentech even in the absence of an Adverse Event 
within thirty (30) calendar days: 
 
 Data related to product usage during pregnancy or breastfeeding 
 Data related to overdose, abuse, misuse, inadvertent/erroneous administration, medication 
error or occupational exposure, with or without association with an AE/SAE unless otherwise 
specified in the protocol 
 Lack of therapeutic efficacy 
 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (item 5) of the 
MedWatch 3500A form: 
 
Protocol description (and number, if assigned) 
 
Description of event, severity, treatment, and outcome if known 
 
Supportive laboratory results and diagnostics 
 
Investigator’s assessment of the relationship of the AE to each investigational product and 
suspect medication 
 
Follow-Up Information 
Additional information may be added to a previously submitted report by any of the following 
methods: 
 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
 
Adding supplemental summary information and submitting it as follow-up with the original 
MedWatch 3500A form  
 
Summarizing new information and submitting it with a cover letter including patient 
identifiers (i.e., date of birth, initial, patient number), protocol description and number, if 
assigned, brief AE description, and notation that additional or follow-up information is 
being submitted.  (The patient identifiers are important so that the new information is added 
to the correct initial report.) 


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Occasionally Genentech / Roche may contact the reporter for additional information, 
clarification, or current status of the patient for whom and AE was reported.  For questions 
regarding SAE reporting, you may contact the Genentech Drug Safety representative noted 
above or the Medical Science Liaison assigned to the study.  Relevant follow-up information 
should be submitted to Genentech / Roche Drug Safety as soon as it becomes available and/or 
upon request. 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm 
10.7.2.2 
Expedited Investigator Reporting to Celgene 
 
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events of being related to ABRAXANE® based on the Investigator Brochure.  In the United 
States, all suspected unexpected serious adverse reactions (SUSARs) will be reported in an 
expedited manner in accordance with 21 CFR 312.32. 
 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene in 
writing using a Celgene SAE form or MEDWATCH 3500A form or equivalent of any SAE 
within 24 hours of being aware of the event.  The written report must be completed and supplied 
to Celgene by facsimile within 24 hours.  The initial report must be as complete as possible, 
including an assessment of the causal relationship between the event and the investigational 
product(s).  Information not available at the time of the initial report (e.g., an end date for the 
adverse event or laboratory values received after the report) must be documented on a follow-up 
report.  A final report to document resolution of the SAE is required.  The Celgene tracking 
number (AX-CL-NSCLC-PI-005652 and the institutional protocol number should be included on 
SAE reports (or on the fax cover letter) sent to Celgene.  A copy of the fax transmission 
confirmation of the SAE report to Celgene should be attached to the SAE and retained with the 
patient records. 
 
Pregnancies 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on IP, or within 28 days, are 
considered immediately reportable events.  IP is to be discontinued immediately. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, using the Pregnancy Initial Report Form, 
or approved equivalent form. The female subject may be referred to an obstetrician-gynecologist 
(not necessarily one with reproductive toxicity experience) or another appropriate healthcare 
professional for further evaluation. 
 
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.  
 


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If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the 
Investigator should report the abnormal outcome as an AE.  If the abnormal outcome meets any 
of the serious criteria, it must be reported as an SAE to Celgene Drug Safety immediately by 
facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form, or approved equivalent form. 
 
Male Subjects 
 
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking IP should notify the Investigator, and the pregnant female partner should be 
advised to call their healthcare provider immediately. Male patients treated with nab-paclitaxel 
are advised not to father a child during and up to 6 months after treatment. 
 
Overdose 
 
On a per dose basis, an overdose is defined as the following amount over the protocol-specified 
dose of carboplatin, nab-paclitaxel, or MPDL3280A assigned to a given patient, regardless of 
any associated adverse events or sequelae. 
 
IV 10% over the protocol-specified dose  
 
 
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency.   
 
On an infusion rate basis, an overdose is defined as any rate faster than the protocol-specified 
rate.  For nab-paclitaxel, an infusion completed in less than 25 minutes may increase Cmax by 
approximately 20%, therefore a nab-paclitaxel infusion completed in less than 25 minutes will 
meet the infusion rate criterion for an overdose. 
 
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the case report form.    
 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax: (908) 673-9115 


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E-mail: drugsafety@celgene.com 
10.8 
Study Close-Out 
 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. 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.  
 
10.9 
Additional Reporting Requirements for IND (MPDL3280A) 
 
The sponsor is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, are collected and reported to the FDA, appropriate IRB(s), Celgene, and 
Genentech, Inc. in accordance with CFR 312.32 (IND Safety Reports).  
 
For Investigator-Initiated IND Studies, some additional reporting requirements for the FDA 
apply in accordance with the guidance set forth in 21 CFR § 600.80. 
 
Events meeting the following criteria need to be submitted to the FDA as expedited IND Safety 
Reports according to the following guidance and timelines: 
7 Calendar Day Telephone or Fax Report 
 
The IND sponsor is required to notify the FDA of any fatal or life-threatening AE that is 
unexpected and assessed by the IND sponsor to be possibly related to the use of MPDL3280A.  
An unexpected AE is one that is not already described in the MPDL3280A Investigator’s 
Brochure.  Such reports are to be telephoned or faxed to the FDA and Genentech within 7 
calendar days of first learning of the event. 
15 Calendar Day Written Report 
 
The IND sponsor is also required to notify the FDA and all participating investigators, in a 
written IND Safety Report, of any serious, unexpected AE that is considered reasonably or 
possibly related to the use of MPDL3280A.  An unexpected AE is one that is not already 
described in the MPDL3280A Investigator’s Brochure.  
Written IND Safety reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32.  All safety reports previously filed by the investigator with the IND 
concerning similar events should be analyzed and the significance of the new report in light of 
the previous, similar reports commented on. 
Written IND safety reports with analysis of similar events are to be submitted to the FDA, 
Genentech, and all participating investigators within 15 calendar days of first learning of the 
event.  The FDA prefers these reports on a MedWatch 3500A form, but alternative formats are 
acceptable (e.g., summary letter).  


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Contact Information for IND Safety Reports 
FDA fax number for IND safety reports: 
Fax:  (800) FDA-0178 
 
All written IND safety reports submitted to the FDA by the investigator must also be 
submitted to the following: 
Genentech Drug Safety: 
Fax: (650) 225-4682 OR (650) 225-4630 
Site’s IRB: 
Columbia University Medical Center IRB 
154 Haven Avenue, 1st Floor New York, NY 10032 
Ph 212-305-5883 
Fax 212-305-1316 
Email irboffice@columbia.edu 
 
 
For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel:  (888) 835-2555 
Fax:  (650) 225-4682 or (650) 225-4630 
 
IND Annual Reports 
 
Copies to Genentech: 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. Copies of such reports should be submitted to Genentech Drug Safety: 
 
Fax: (650) 225-4682 or (650) 225-4630 
 
10.9.1 DSMC Reporting by the Sponsor Investigator 
 
Serious adverse events not constituting unanticipated problems are to be reported to the HICCC 
DSMC. Reporting should occur within 24 hours of knowledge of the SAE occurring at our 
institution or affiliate sites. CUMC will notify the HICCC DSMC within 24 hours of knowledge 
of the SAE once informed by the affiliate site. 
 
Participating investigators must report each serious adverse event to the Columbia University 
Medical Center Overall Principal Investigator within 24 hours of learning of the occurrence using 
the SAE Report Form. In the event that the participating investigator does not become aware of 
the serious adverse event immediately (e.g., participant sought treatment elsewhere), the 
participating investigator is to report the event within 24 hours after learning of it and document 
the time of his or her first awareness of the adverse event. 


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11. 
PHARMACEUTICAL INFORMATION 
 
Study Drugs  
11.1 
Description 
 
MPDL3280A is a human immunoglobulin (Ig) G1 monoclonal antibody consisting of two heavy 
chains (448 amino acids) and two light chains (214 amino acids) and is produced in Chinese 
hamster ovary cells.  MPDL3280A was engineered to eliminate Fc-effector function via a single 
amino acid substitution (asparagine to alanine) at position 298 on the heavy chain, which results 
in a non-glycosylated antibody that has minimal binding to Fc receptors and prevents Fc-effector 
function at expected concentrations in humans.  MPDL3280A targets human programmed death-
ligand 1 (PD-L1) and inhibits its interaction with its receptor, programmed death-1 (PD-1).  
MPDL3280A also blocks the binding of PD-L1 to B7.1, an interaction that is reported to provide 
additional inhibitory signals to T cells. It is administered as an intravenous formulation. 
nab-Paclitaxel (ABRAXANE® for Injectable Suspension [Abraxis BioScience, LLC, a wholly 
owned subsidiary of Celgene Corporation, Summit, New Jersey, United States; hereafter referred 
to as “Celgene”], ABI-007) is a proprietary solvent-free, protein-stabilized formulation of 
paclitaxel comprised of paclitaxel in a noncrystalline amorphous state and human albumin with a 
mean particle size of approximately 130 nanometers. nab-Paclitaxel has been developed to 
improve the therapeutic index of paclitaxel, also reducing the toxicities associated with Taxol 
and the CrEL and ethanol vehicle.  This may be achieved in part by taking advantage of 
endogenous transport pathways to deliver higher doses of paclitaxel to the tumor. Because nab-
paclitaxel does not contain a solvent vehicle, micellar entrapment observed with Taxol does not 
occur.63-65 nab-Paclitaxel displays linear pharmacokinetic (PK) characteristics. The novel 
albumin-bound particle formulation of paclitaxel in nab-paclitaxel conferred the ability to 
achieve a higher maximum tolerated dose (MTD) based on every 3-weeks dosing: 300 mg/m2 
for nab-paclitaxel (Study DM97-123) versus 175 mg/m2 for Taxol.66 The use of albumin-bound 
paclitaxel also enables nab-paclitaxel to be given in a shorter, more convenient infusion time of 
30 - 40 minutes compared with 3 hours to 24 hours with Taxol.  Due to its distinct 
pharmacological and PK properties and therapeutic index, nab-paclitaxel has been approved by 
regulatory authorities worldwide in over 40 countries/regions as a new product, rather than as a 
generic formulation of Taxol.    
 
For further details of pharmacokinetics, absorption, and excretion of drugs, please refer to 
manufacturer insert. 
 
 
 


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11.2 
Treatment Regimen 
 
Four (4) cycles of 21 days each will be administered as follows: 
 MPDL3280A fixed dose of 1200 mg IV on day 1 of every 21 days  
 Nab-paclitaxel 100 mg/m2 IV on days 1, 8 and 15  
 Carboplatin AUC = 5 IV on day 1  
11.3 
Method for Assigning Subjects to Treatment Groups 
 
All patients enrolled in this study will receive the same study treatment protocol. 
11.4 
Preparation and Administration of Study Drug 
 
Carboplatin and nab-paclitaxel are prepared according to the recommendations from the 
manufacturers’ label. Carboplatin is obtained through standard commercial pharmacies. Nab-
paclitaxel is supplied by Celgene. MPDL3280A is supplied by Genentech. 
 
11.4.1 Nab-paclitaxel (ABRAXANE®) 
 
ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable 
suspension) (albumin-bound) is paclitaxel formulated as albumin-bound nanoparticles with a 
mean particle size of approximately 130 nanometers.  Paclitaxel exists in the 
particles in a non-crystalline, amorphous state.  ABRAXANE® is supplied as a white to yellow, 
sterile, lyophilized powder for reconstitution with 20 mL of 0.9% Sodium Chloride Injection, 
USP prior to intravenous infusion. 
 
nab-Paclitaxel may be given without steroid and anti-histamine premedication, which is required 
for Taxol to prevent solvent-related HSRs (Taxol US prescribing information).  Cremophor EL 
has been shown to leach plasticizers, specifically di(2-ethylhexyl)phthalate (DEHP), from 
polyvinyl chloride (PVC) bags and polyethylene-lined tubing.67-72  Although no controlled 
epidemiologic toxicity studies have been conducted in humans exposed to DEHP, severe effects 
(eg, carcinogenicity, cardiopulmonary toxicity, hepatotoxicity, and nephrotoxicity) have been 
observed in experimental models.  The Taxol prescribing information instructs users to prepare, 
store, and administer solutions in glass, polypropylene, or polyolefin containers; non-PVC-
containing infusion sets (eg, those with polyethylene lining) should be used (Taxol US 
prescribing information).  By comparison, standard tubing and intravenous (IV) bags may be 
used for the IV administration of nab-paclitaxel.63,66 
 
ABRAXANE® is injected into a vein [intravenous (I.V.) infusion] over 30 minutes.  The use of 
an in-line filter is not recommended.  Following administration, the intravenous line should be 
flushed with sodium chloride 9 mg/ml (0.9%) solution for injection to ensure complete 
administration of the complete dose, according to local practice. 


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11.4.2 Carboplatin 
 
Carboplatin should be administered by IV infusion, immediately after the completion of nab-
paclitaxel administration, over 15–30 minutes to achieve an initial target AUC of 6 mg/mL/min 
(Calvert formula dosing) and with standard anti-emetics per local practice guidelines. 
 
The carboplatin dose of AUC 5 will be calculated using the Calvert formula (Calvert et al. 1989): 
 
Total dose (mg) = (target AUC) × (glomerular filtration rate [GFR] +25) 
 
NOTE: The GFR used in the Calvert formula to calculate AUC-based dosing should 
 
not exceed 125 mL/min. 
 
For the purposes of this protocol, the GFR is considered to be equivalent to the creatinine 
clearance (CrCl). The CrCl is calculated by institutional guidelines or by the method of 
Cockcroft and Gault (1976) using the following formula: 
 
 
(140 – age) (wt)  
CrCl =  
--------------------     (× 0.85 if female) 
      72 × Scr 
 
Where: CrCl = creatinine clearance in mL/min age= patient's age in years wt = patient’s weight 
in kg Scr = serum creatinine in mg/dL 
 
NOTE: For patients with an abnormally low serum creatinine level, estimate GFR using a 
minimum creatinine level of 0.8 mg/dL or cap the estimated GFR at 125 mL/min. 
If a patient’s GFR is estimated based on serum creatinine measurements by the isotope dilution 
mass spectroscopy method, the FDA recommends that physicians consider capping the dose of 
carboplatin for desired exposure (AUC) to avoid potential toxicity due to overdosing. Based on 
the Calvert formula described in the carboplatin label, the maximum doses can be calculated as 
follows: 
 
Maximum carboplatin dose (mg) = target AUC (mg •min/mL) × (GFR+ 25 mL/min) 
 
The maximum dose is based on a GFR estimate that is capped at 150 mL/min for patients with 
normal renal function. No higher estimated GFR values should be used. 
 
For a target AUC= 6, the maximum dose is 6 × 150 = 900 mg.  
For a target AUC= 5, the maximum dose is 5 × 150 = 750 mg.  
For a target AUC= 4, the maximum dose is 4 × 150 = 600 mg. 
 
Refer to the FDA’s communication regarding carboplatin dosing using the following URL for 
more details: 
http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm22897
4.htm. 


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11.4.3 MPDL3280A (Atezolizumab) 
 
The MPDL3280A drug product is provided in a single-use, 20-cc USP/Ph. Eur. Type 1 glass vial 
as a colorless-to-slightly-yellow, sterile, preservative-free clear liquid solution intended for IV 
administration.  The vial is designed to deliver 20 mL (1200 mg) of MPDL3280A solution but 
may contain more than the stated volume to enable delivery of the entire 20 mL volume.  The 
MPDL3280A drug product is formulated as 60 mg/mL MPDL3280A in 20 mM histidine acetate, 
120 mM sucrose, 0.04% polysorbate 20, pH 5.8. 
MPDL3280A must be refrigerated at 2°C  8°C (36°F  46°F) upon receipt until use.  
MPDL3280A vials should not be used beyond the expiration date provided by the manufacturer.  
No preservative is used in the MPDL3280A drug product; therefore, each vial is intended for 
single use only.  Discard any unused portion of drug left in a vial.  Vial contents should not be 
frozen or shaken and should be protected from direct sunlight. 
For further details, see the MPDL3280A Investigator’s Brochure. 
The dose level of MPDL3280A to be tested in this study is 1200 mg (equivalent to an average 
body weightbased dose of 15 mg/kg) administered by IV infusion every 3 weeks (21 [ 2] 
days).  MPDL3280A will be delivered in infusion bags with IV infusion lines that have product 
contacting surfaces of polyvinyl chloride (PVC) or polyolefin and 0.2 m in-line filters (filter 
membrane of polyethersulfone [PES]).  No incompatibilities have been observed between 
MPDL3280A and PVC or polyolefin infusion materials (bags or infusion lines).  
Administration of MPDL3280A will be performed in a setting with emergency medical facilities 
and staff who are trained to monitor for and respond to medical emergencies. 
The initial dose of MPDL3280A will be delivered over 60 ( 15) minutes.  If the first infusion is 
tolerated without infusion-associated AEs, the second infusion may be delivered over 30 ( 10) 
minutes.  If the 30-minute infusion is well tolerated, all subsequent infusions may be delivered 
over 30 ( 10) minutes.  For the first infusion, the patient’s vital signs (heart rate, respiratory 
rate, blood pressure, and temperature) should be determined within 60 minutes before, during 
(every 15 [ 5] minutes), and 30 ( 10) minutes after the infusion.  For subsequent infusions, 
vital signs will be collected within 60 minutes before and within 30 minutes after the infusion.  
Vital signs should be collected during the infusion only if clinically indicated.  Patients will be 
informed about the possibility of delayed post-infusion symptoms and instructed to contact their 
study physician if they develop such symptoms. 
 
No steroid premedication will be allowed for the first dose of MPDL3280A.  Premedication may 
be administered for Cycles  2 at the discretion of the treating physician.  The management of 
IRRs will be according to severity as follows: 
 
In the event that a patient experiences a mild (NCI CTCAE Grade 1) IRR, the infusion rate 
should be reduced to half the rate being given at the time of event onset.  Once the event has 


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resolved, the investigator should wait for 30 minutes while delivering the infusion at the 
reduced rate.  If tolerated, the infusion rate may then be increased to the original rate. 
 
In the event that a patient experiences a moderate IRR (NCI CTCAE Grade 2) or flushing, 
fever, or throat pain, the infusion should be immediately interrupted and the patient should 
receive aggressive symptomatic treatment.  The infusion should be restarted only after the 
symptoms have adequately resolved to baseline grade.  The infusion rate at restart should be 
half of the infusion rate that was in progress at the time of the onset of the IRR. 
 
For severe or life-threatening IRRs (NCI CTCAE Grade 3 or 4), the infusion should be 
stopped immediately, and aggressive resuscitation and supportive measures should be 
initiated.  Patients experiencing severe or life-threatening IRRs will not receive further 
infusion and will be further managed as clinically indicated until the event resolves. 
 
11.5 
Subject Compliance Monitoring 
 
Compliance will be monitored by office visit documentation. 
11.6 
Prior and Concomitant Therapy 
 
All history pertaining to prior and/or concomitant medical therapy will be collected at the time of 
study enrollment.  
Patients who experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or cimetidine or another H2 receptor 
antagonist, as per standard practice (for sites outside the United States, equivalent medications 
may be substituted per local 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). 
Systemic corticosteroids and TNF inhibitors may attenuate potential beneficial immunologic 
effects of treatment with MPDL3280A but may be administered at the discretion of the treating 
physician.  If feasible, alternatives to corticosteroids should be considered.  Premedication may 
be administered for Cycles  2 at the discretion of the treating physician.  The use of inhaled 
corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic 
hypotension or adrenocortical insufficiency is allowed.  Megestrol administered as appetite 
stimulant is acceptable while the patient is enrolled in the study.   
Patients who use oral contraceptives, hormone-replacement therapy, prophylactic or therapeutic 
anticoagulation therapy (such as low-molecular-weight heparin or warfarin at a stable dose 
level), or other allowed maintenance therapy should continue their use.  Males and females of 
reproductive potential should use highly effective means of contraception. 
Any concomitant therapy intended for the treatment of cancer, whether health 
authority-approved or experimental, is prohibited.  This includes but is not limited to 


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chemotherapy, hormonal therapy, immunotherapy, radiotherapy, investigational agents, or herbal 
therapy. It is strongly recommended that traditional herbal medicines not be administered 
because the ingredients of many herbal medicines are not fully studied and their use may result 
in unanticipated drug-drug interactions that may cause, or confound assessment of, toxicity. The 
use of a RANKL inhibitor (denosumab) should be discontinued during the study; this agent 
could potentially alter the activity and the safety of MPDL3280A. Initiation or increased dose of 
granulocyte colony-stimulating factors (e.g., granulocyte colony-stimulating factor, 
granulocyte/macrophage colony-stimulating factor, and/or pegfilgrastim) is prohibited.  
 
Patients are not allowed to receive immunostimulatory agents, including but not limited to IFN-
, IFN-, or IL-2, during the entire study.  These agents, in combination with MPDL3280A, 
could potentially increase the risk for autoimmune conditions. 
Patients should also not be receiving immunosuppressive medications, including but not limited 
to cyclophosphamide, azathioprine, methotrexate, and thalidomide.  These agents could 
potentially alter the activity and the safety of MPDL3280A.  Systemic corticosteroids and anti-
TNF agents may attenuate potential beneficial immunologic effects of treatment with 
MPDL3280A but may be administered at the discretion of the treating physician. This includes 
the administration of rescue therapies for treatment related toxicity.  If feasible, alternatives to 
these agents should be considered. 
In addition, all patients (including those who discontinue the study early) should not receive 
other immunostimulatory agents for 10 weeks after the last dose of MPDL3280A. 
Concomitant use of yellow fever vaccine is contraindicated in subjects receiving carboplatin.  
Subjects receiving carboplatin must not receive Yellow Fever vaccine. 
11.7 
Packaging 
 
As per sponsor packaging instructions. 
 
11.8 
Blinding of Study Drug 
 
This drug is not blinded. 
11.9 
Receiving, Storage, Dispensing and Return 
11.9.1 
Receipt of Drug Supplies 
 
The study drug MPDL3280A will be shipped to the investigative site by Genentech, and will be 
stored and prepared within the investigational pharmacy. 
 
ABRAXANE® will be supplied by Celgene Corporation and labeled appropriately as 
investigational material for this study.  Labels will bear Celgene’s name and address, the 
protocol number, product name, dosage form and strength, medication identification/kit number, 


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lot number, expiry date, dosing instructions, storage conditions, the quantity of IP contained, and 
required caution statements and/or regulatory statements as applicable.  No supplies will be 
shipped to any site until regulatory approval has been obtained.  Investigational sites will be 
supplied with ABRAXANE® upon identification and screening of a potential trial subject. 
 
Upon identification of a potential subject, sites must fax a completed Drug Request Form to 
Celgene Corporation.  Allow at least 5 working days for drug shipment.  There are no shipments 
on Fridays or holidays.  For re-supply of drug, please complete and fax the Drug Request Form 
as well as the Drug Accountability Log to Celgene Corporation at 908-673-2779.  
Upon receipt of the of the study treatment supplies, an inventory will be performed and a drug 
receipt log filled out and signed by the person accepting the shipment.  The designated study 
staff must count and verify that the shipment contains all the items noted in the shipment 
inventory.  Any damaged or unusable study drug in a given shipment (active drug or comparator) 
will be documented in the study files.  The investigator must notify agent manufacturer of any 
damaged or unusable study treatments that were supplied to the investigator’s site. 
 
11.9.2 
Storage 
 
Storage conditions are described in the MPDL3280A Investigators’ Brochure as well as the 
Manufacturer’s Package Insert for carboplatin and nab-paclitaxel. 
 
11.9.3 
Dispensing of Study Drug 
 
Regular study drug reconciliation will be performed to document drug administration.  This 
reconciliation will be logged on the drug reconciliation form, and signed and dated by the study 
team. 
 
11.9.4 
Return or Destruction of Study Drug 
 
At the completion of the study, there will be a final reconciliation of drug shipped, drug 
consumed, and drug remaining.  This reconciliation will be logged on the drug reconciliation 
form, signed and dated.  Any discrepancies noted will be investigated, resolved, and documented 
prior to return or destruction of the study drug. Remaining study drug will be returned to the 
Sponsor. 
 
12. 
 
OUTCOME MEASUREMENTS 
 
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  
Patients do not need labs repeated prior to treatment on C1D1 unless there is a change in clinical 
status.  Scans and x-rays must be done <4 weeks prior to the start of therapy.   
 
12.1 
Pathologic Response Rate 
 


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The primary outcome of interest in this study is the rate of major pathologic response. All 
patients included in the study will be assessed for response to treatment, even if there are major 
protocol treatment deviations or if they are ineligible.  Each patient will be assigned one of the 
following categories for the primary outcome:   
 
1) complete pathologic response: no pathologically detectable viable tumor   
2) major pathologic response: <10% residual viable tumor (see diagram below) 
3) partial pathologic response: ≤50% residual viable tumor 
4) inadequate response: >50% residual viable tumor  
5) early death from malignant disease 
6) early death from toxicity 
7) unknown (not assessable, insufficient data) 
 
All of the patients who met the eligibility criteria (with the exception of those who received no 
study medication) will be included in the main analysis of the response rate.  Patients in response 
categories 4-7 should be considered to have a treatment failure (disease progression).  Thus, an 
incorrect treatment schedule or drug administration does not result in exclusion from the analysis 
of the response rate.   
 
 
 
Diagram 1  
Quantifying Pathologic Response 
Methods for quantifying pathologic response have been previously described (Hellmann 2014). 
Pathologic response will be calculated as the percentage of viable tumor within a tumor cross 
section, and then averaged across multiple tumor cross sections.  
 
12.2 
Tumor Immune Microenvironment 
 
The balance of stimulatory and inhibitory checkpoints that determine T-cell activation or 
inhibition will be evaluated by immunohistochemistry/immunofluorescence on tumor tissue to 
evaluate for the presence of PD-1 and PD-L1, PD-L2 on tumor cells, presence of co-stimulatory 


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(OX40, ICOS, CD137) and co-inhibitory (CTLA4, LAG3, TIM3) markers on pre-treatment 
tissue and post-treatment specimen.   
 
Immunohistochemistry/immunofluorescence will be performed to assess for co-localization of 
CD3+ and CD8+ TILs in pre-treatment biopsies and post treatment resection samples and/or 
PBMCs, serum and plasma. Slides will be stained for CD3 and CD8 and undergo automated 
quantification. In addition surgical samples from tumor resection will be used to create single 
cell suspensions, which will be used for tumor separation and isolation of tumor-infiltrating 
lymphocytes (TILs); tumor and immune cells will be analyzed using multiparametric flow 
cytometry (CD3, CD4, CD8, FoxP3, Ki67, ICOS, PD-1, LAG-3, TIM-3, and CTLA-4).treat 
 
12.3 
Exploratory Biomarkers of Response 
 
An exploratory objective of this study is to identify potential biomarkers of response to the study 
treatment. Such blood and tissue biomarkers may provide evidence for the biological activity of 
MPDL3280A, and may inform selection of patients most likely to benefit from treatment with 
MPDL3280A.  
 
Biomarker analysis may include, but is not limited to, blood based markers such as peripheral 
blood lymphocyte neoantigen activity, pre- and post-treatment tissue flow cytometry, tissue 
immune signature as detected by Nanostring microarray, tumor whole exome sequencing and 
total mutational and neoantigen burden. See Table 10. 
 
Table 10:  Methods 
Tumor 
Non-synonymous mutation burden 
Exome and RNAseq analysis 73-83 
Mutational smoking signature 
Exome and RNAseq analysis 73-83 
Neoantigen prediction 
In silico neoantigen prediction 45 
MHC, PD-L1, PD-L2, LAG3, IDO, Tim3, Ki-67 
IHC/IF 84 
CD3, CD4, CD8, PD-1, FOXP3, TIA-1 
IHC/IF 84 
PBMCs, serum and plasma 
Neoantigen validation in vitro (quantitative) 
Intracellular cytokine staining 85 
Neoantigen validation in vitro (qualitiative) 
Multimer assays 46 
Tumor and PBMCs, serum and plasma 
T cell receptor clonality 
TCR sequencing 86 
Blood 
Germline sequencing 
Exome analysis 73-83 
HLA typing 
HLA sequence-based typing 87 
 
 
 
 
12.4 
     Disease Parameters 
 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for 


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nodal lesions) 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). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
 
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. Cystic lesions thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 


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12.5 
   Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g., for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.   


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Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
 
Endoscopy/Laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers: Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.   
 
Cytology/Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
 
 Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
 
 No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
 
 FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 


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scarring.  The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
12.6 
      Radiologic Response Criteria 
 
12.6.1 Radiologic Response Rate 
 
 
In addition to a baseline scan, scans should be obtained after cycle 2 (not less than 5 weeks after 
initiation of treatment) and after cycle 4. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
Definitions: 
 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with MAC. 
 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
 
 
12.6.2 Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 


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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 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. 
 
Responder: For this study, a patient will be defined as a responder if they exhibit disease control 
(having shown CR, PR or SD radiographically) after receiving the first 2 cycles of treatment. 
 
Non-Responder: For this study, a patient will be defined as a non-responder if they show PD as 
their best response following the first 2 cycles of treatment. 
 
12.6.3   
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). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase. Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
 
12.7 
Disease-Free Survival 
 
DFS is defined as the duration of time from date of surgery to time of recurrence or death, 
whichever occurs first. 
 
12.8 
Response Review 
 
Not applicable. 
 


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12.9 
Safety Stopping Rules  
The study may be discontinued if the study is terminated by the data and safety monitoring 
committee, the Food and Drug Administration (FDA), or other regulatory authorities. 
Any unforeseen deaths or serious adverse events may, after a discussion between the principal 
investigator and investigators at other sites, prompt an interruption to study accrual pending a 
full investigation into the circumstances surrounding the event. 
 
Early safety stopping rules will be defined as a 10% rate of occurrence of qualifying safety 
events or those which prohibit or delay surgical intervention. Therefore, if at any time ≥ 3 of 30 
patients experience a safety event that prohibits surgery or delays medical operability more than 
37 days beyond the preplanned surgical date (day 0), the regimen will be deemed unsafe, and the 
study stopped. 
 
Subjects are considered evaluable for assessment of treatment related toxicity if they receive at 
least one dose of therapy. Grading of all toxicities will be according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03. 
 
A toxicity defined as a safety event for this study will be any Grade 3 or higher of the following:  
 Any ≥ Grade 3 colitis  
 Any Grade 4 immune-related AE (irAE)  
 Any Grade 3 irAE that does not downgrade to ≤ Grade 2 within 1 week after onset of the 
event despite maximal supportive care including systemic corticosteroids or downgrade to ≤ 
Grade 1 or baseline within 14 days  
 Liver transaminase elevation higher than 8 × upper limit of normal (ULN) or total bilirubin 
higher than 5 × ULN 
 Any ≥ Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the initiation 
of maximal supportive care.  
 Additional AES that are not immune related may also be a potential safety event including 
any grade 3 or higher toxicities that do not downgrade to ≤ Grade 2 within 1 week after onset 
of the event despite maximal supportive care or downgrade to ≤ Grade 1 or baseline within 
14 days  
 
The definition excludes the following conditions:  
 Grade 3 endocrinopathy that is managed with or without systemic corticosteroid therapy 
and/or hormone replacement therapy and the subject is asymptomatic or minimally 
symptomatic 
 Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., inflammatory 
reaction at sites of disease, lymph nodes, etc)  
 Dosing may continue despite concurrent vitiligo and alopecia of any grade 
 
 
 


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13. 
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10.0 
(Adverse Events: List and Reporting Requirements).  The Data Safety Monitoring Plan is 
described in Section 12.2. 
 
13.1 
Data Collection 
 
The Herbert Irving Comprehensive Cancer Center has an electronic clinical trials and data 
management system (CTMS) that will be used for data collection. CRFs for the study will be 
built into the CTMS for data entry. The system has full auditing capabilities which is web-based 
and housed on a server in a fully HIPAA compliant server room with restricted access and video 
camera monitoring.  All users must login with their own application username and password.  
Users off campus must first access the Virtual Private Network with their assigned campus 
username and password and then use their application credentials.  Users are only able to see 
study information if they are indicated as study personnel in our electronic IRB system. Users are 
limited to access based on the role assigned in their corresponding protocol.  Subject data is 
entered directly into the system, which (in the case of Columbia subjects) confirms the correct 
identity of patients via an interface with the electronic medical patient index.  Staff with the 
appropriate IRB defined roles can run reports within the system for reporting purposes. 
 
13.2 
Data Reporting 
 
Case Report Forms will be completed for each subject enrolled into the clinical study through the 
CTMS. It is the investigator’s responsibility for ensuring that all clinical and laboratory data 
entered on the corresponding CRFs are complete, accurate and authentic. 
 
13.3 
Data and Safety Monitoring Committee 
 
The NCI-approved Data Safety and Monitoring Committee (DSMC) of the Herbert Irving 
Comprehensive Cancer Center (HICCC) will monitor every subject who receives treatment on 
this protocol for toxicity. This protocol will adhere to the policies of the currently approved 
HICCC Data and Safety Monitoring Plan (DSMP), which is in accordance with NCI and 
CUMC-IRB policy and guidelines.  The committee is chair is appointed by the HICCC Director. 
The committee consists of HICCC faculty and staff with expertise in oncology, research 
pharmacy, research nursing, and data management. The DSMC convenes twice a month to 
review patient safety and the conduct of the trial. The PI will submit data and safety monitoring 
reports to the DSMC at a frequency to be determined by the DSMC based on risk to the subjects. 
 
At the time of renewal, the study team will submit the most recent DSMC approval letter for 
safety review to the CUMC IRB. Any modifications that are required by the DSMC to ensure 
patient safety will be submitted to the IRB. All protocol deviations, violations, and eligibility 
waivers will be submitted to and approved by the DSMC prior to being reported to the IRB. All 
study data reviewed and discussed during these meetings will be kept confidential.  
 


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For multicenter research, the principal investigator will assure that there is a mechanism in place 
to distribute the report to all participating investigators for submission to their local IRB.  The 
report will document that a review of data and outcomes across all centers took place on a given 
date.  It will summarize the DSMC’s review of the cumulative toxicities reported from all 
participating sites without specific disclosure by treatment arm.  It will also inform site 
investigators of the study the DSMC’s conclusion with respect to progress or need for 
modification of the protocol.   
 
13.4 
Quality Control and Quality Assurance 
 
Independent monitoring of the clinical study for protocol and GCP compliance will be conducted 
periodically by the CPDM Compliance Core on behalf of the HICCC DSMC.  Additionally, the 
Compliance Oversight Committee of the IRB at Columbia University Medical Center may audit 
the study at any time per institutional policies and procedures. The investigator-sponsor and 
Columbia University Medical Center will permit direct access of the study monitors and 
appropriate regulatory authorities to the study data and to the corresponding source data and 
documents to verify the accuracy of this data. 
 
A risk-based approach will be used by the Compliance Core to determine the frequency, number 
of subject charts, and data elements to be monitored. The Compliance Coordinator will review the 
study status and summarize enrollment, toxicities, SAEs/UPs, dose escalation, statistical endpoints 
(e.g., stopping rules), etc. for the full DSMC membership at the regularly scheduled meetings.   
 
Internal On-site Monitoring: 
 
 
Initial, recurrent, and close-out on-site monitoring visits will also be conducted at 
remote clinical sites, as appropriate/feasible. Other sites will have monitoring performed 
remotely (see below for further details). 
 
 
The study Monitoring Visit Log will be completed and signed by the monitor and the 
PI/CRNP/CRN and/or CRC and will be filed in the regulatory binder. 
 
 
The Compliance Coordinator will communicate with the site coordinator/Site 
Principle Investigator to schedule the monitoring visit and arrange for access to study materials 
and documentation. 
 
 
The assigned Compliance Coordinator will monitor IIT trials within 1 month after the 
first subject is enrolled and throughout the life of the study to ensure that the study is being 
conducted in accordance with the protocol, GCP, applicable federal and local regulations, and 
per all applicable SOPs. The Compliance Coordinator is responsible to notify the PI and 
CRNP/CRN/CRC of upcoming monitor visits and convey what information and documentation 
will be required for the visit(s).  The Compliance Coordinator is responsible for verifying that 
informed consent is properly obtained, eligibility is met (via the central registration process), 
and all study procedures are conducted according to the study protocol. The Compliance 
Coordinator will also verify that the data reported in the CRF’s accurately reflect source 


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documents, that all toxicities have been reported to date, and that all 
SAE’s/UPs/deviations/violations have been reported according to local IRB and HICCC DSMC 
requirements. The Compliance Coordinator will issue queries and ensure resolution in a timely 
and efficient manner.  The Compliance Coordinator will also monitor for applicable regulatory 
compliance and research pharmacy compliance (if applicable) and communicate any 
deficiencies as appropriate. 
13.5 Confidentiality 
 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
 
What protected health information (PHI) will be collected from subjects in this study 
 
Who will have access to that information and why 
 
Who will use or disclose that information 
 
The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (e.g., that the subject is alive) 
at the end of their scheduled study period. 
The subject binders will be maintained with in the CPDM offices, a secured floor within the 
Herbert Irving Pavilion and only the investigator  and study staff will have access to the file. 
13.6 Source Documents 
 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are 
contained in source documents   Examples of these original documents, and data records include: 
hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
13.7 Case Report Forms 
 
The study case report form (CRF) is the primary data collection instrument for the study.  All data 
requested on the CRF must be recorded.  All missing data must be explained.  If a space on the 
CRF is left blank because the procedure was not done or the question was not asked, write “N/D”.  
If the item is not applicable to the individual case, write “N/A”.  


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13.8 Records Retention 
 
Records relating to a specific research activity, including research records collected by 
investigators, must be maintained for at least three years after completion of the research (45 
CFR 46.115(b); 21 CFR 56.115(b); 21 CFR 312.62). This minimum retention period applies 
whether or not any subjects were enrolled in the study. 
If the research is FDA regulated, records should be retained for at least two years after approval 
of the investigational agent by FDA; if it is not approved, records should be retained at least two 
years after the study is terminated and FDA is notified (note the additional requirement below for 
clinical research studies);  
Clinical records, including consent forms that document clinical intervention or clinical 
diagnostic procedure research-related procedures, must be retained in medical records by the 
institution for at least seven years, per CUMC and NYP policy which is based on state law. 
 
13.9 
Ethical Considerations 
 
Compliance with Laws and Regulations 
 
Patients who comply with the requirements of the protocol, are tolerating study treatment, and 
may be receiving benefit will be offered dosing beyond Cycle 1 at the investigator’s discretion 
after a careful assessment and thorough discussion of the potential risks and benefits of 
continued treatment with the patient.  Such patients may have the option to receive MPDL3280A 
treatment as long as they continue to experience clinical benefit in the opinion of the investigator 
until the earlier of unacceptable toxicity, symptomatic deterioration attributed to disease 
progression, or any of the other reasons for treatment discontinuation listed in Section 8.5.  
 
Informed Consent 
 
The informed consent document must be signed by the subject or the subject’s legally authorized 
representative before his or her participation in the study.  The case history for each subject shall 
document that informed consent was obtained prior to participation in the study.  A copy of the 
informed consent document must be provided to the subject or the subject's legally authorized 
representative.  If applicable, it will be provided in a certified translation of the local language. 
Signed consent forms must remain in each subject’s study file and must be available for 
verification by study monitors at any time. 
 
Institutional Review Board or Ethics Committee Approval 
 
This protocol, the informed consent document, and relevant supporting information must be 
submitted to the IRB for review and must be approved before the study is initiated.  The study 
will be conducted in accordance with FDA, applicable national and local health authorities, and 
IRB requirements. 
 
 
 


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The Principal Investigator is responsible for keeping the IRB apprised of the progress of the 
study and of any changes made to the protocol as deemed appropriate, but in any case, the IRB 
must be updated at least once a year.  The Principal Investigator must also keep the IRB 
informed of any significant AEs. 
 
Investigators are required to promptly notify their respective IRB of all adverse drug reactions 
that are both serious and unexpected.  This generally refers to SAEs that are not already 
identified in the Investigator’s Brochure and that are considered possibly or probably related to 
the molecule or study drug by the investigator.  Some IRBs may have other specific AE 
requirements to which investigators are expected to adhere.  Investigators must immediately 
forward to their IRB any written safety report or update provided by Genentech (e.g., IND safety 
report, Investigator’s Brochure, safety amendments and updates, etc.). 
 
Confidentiality 
 
Patient medical information obtained by this study is confidential and may be disclosed to third 
parties only as permitted by the ICF (or separate authorization to use and disclose personal health 
information) signed by the patient or unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare for treatment purposes. 
Data generated by this study must be available for inspection upon request by representatives of 
the FDA and other regulatory agencies, national and local health authorities, Genentech and 
Celgene representatives and collaborators, and the IRB/Ethics Committee (EC) for each study 
site, if appropriate. 
 
14. 
 
STATISTICAL CONSIDERATIONS 
 
14.1 
      Study Design/Endpoints 
 
A two-stage design will be used to evaluate the neoadjuvant combination of MPDL3280A + nab-
paclitaxel and carboplatin (MAC) in patients with resectable stage IB, II and IIIA NSCLC. The 
primary goal is to determine whether the rate of major pathologic response (MPR, < 10% 
residual viable tumor cells at surgery) may be increased from 22% to 44% by adding 
chemotherapy to an anti-PD-L1 antibody alone. Initially, 18 patients will be enrolled in the first 
stage and treated with the study drug combination. Protocol accrual will be terminated after the 
first stage if only 4 or fewer patients were to achieve MPR at surgery. 
 
Otherwise, the protocol will proceed to the second stage for a total of 30 patients. If the overall 
number of MPR were 11 or more, the study drug combination will be considered to have 
improved neoadjuvant efficacy. The two-stage design provides 83% power for detecting an MPR 
rate of 44% under the alternative hypothesis. If the underlying rate were truly only 22%, the 
probability of early termination at the first stage is 64% while the overall rate of a false positive 
trial is 5% (alpha level). 
  
As the trial will be the first time chemotherapy and an anti-PD-L1 antibody will be administered 


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together preoperatively in NSCLC patients, safety will be monitored on a continual basis. The 
protocol will be stopped early as soon as 3 patients were to experience serious or prolonged 
treatment related and immune-related adverse events as defined in section 12.9, as well as 
extended treatment related delay to surgery defined as >37 days from preplanned Day 0 (>30 
days from preplanned day 0 plus 7 extra days to allow for OR scheduling and other clinical 
constraints). The probability of observing treatment related safety events in 3 or more out of 30 
patients is 85% if the true rate were 15%. In contrast, the probability is only 19% if the 
underlying rate were 5% in the protocol population. 
 
The association between MPR response and post-treatment IHC values will be further explored 
using logistic regression after adjusting for pre-treatment IHC values. In addition, the differences 
between MPR responders and MPR non-responders with respect to IHC post-treatment values 
adjusted for baseline IHC values will be assessed using an analysis of covariance model or a rank 
based analysis of covariance model.  
14.2 
 
Size/Accrual Rate 
 
A total sample size of 30 evaluable patients will be accrued in the first and second stages, with a 
projected accrual rate of 2 patients per month per site. 
 
14.3 
     Analysis of Secondary Endpoints 
 
Adverse events will be scored according to NCI CTCAE v4.03, and their frequency and nature 
will be tabulated by categories. The rates of adverse events, pathologic response and objective 
response (RECIST v1.1) will be reported with 95% confidence intervals based on the exact 
binomial distribution. DFS and OS will be estimated using the Kaplan-Meier method. Markers of 
immune reactivity measured in lung tumor specimens, draining lymph nodes, and peripheral 
blood will be evaluated pre- and post-treatment. Baseline levels and post-treatment changes will 
be summarized using descriptive statistics and graphical methods. 
 
14.4 
 
Reporting and Exclusions 
 
14.4.1  Evaluation of toxicity   
 
All patients will be evaluable for toxicity if they have received at least one dose of protocol 
therapy. 
 
14.4.2  Evaluation of response   
 
Patients will be evaluable for objective response if they have received at least one cycle of 
protocol therapy and undergone response assessment or if they exhibit objective progression 
prior to the end of cycle 1. All patients will be evaluated for pathologic response status according 
to section 12.1 whether they undergo resection or not. 
 


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15. 
PROTECTION OF HUMAN SUBJECTS  
This study is to be conducted in accordance with applicable government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study conduct.  The decision of the IRB concerning the conduct of the study will be made in 
writing to the investigator and a copy of this decision will be obtained before commencement of 
this study.  
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the IRB-approved consent form, must be 
obtained before that subject is submitted to any study procedure.  This consent form must be 
signed by the subject or legally acceptable surrogate, as outlined in the IRB approved protocol, 
and the investigator-designated research professional obtaining the consent.  
16. STUDY FINANCES 
16.1 Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by the Columbia University Conflict of Interest Committee with a Committee-
sanctioned conflict management plan that has been reviewed and approved prior to participation 
in this study.  All CUMC investigators will follow the University conflict of interest policy. 
16.2 Subject Stipends or Payments 
 
No stipend. 
17. PUBLICATION PLAN 
 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor.  Any 
investigator involved with this study is obligated to provide the sponsor with complete test 
results and all data derived from the study. The study drug manufacturers reserve the right to 
review all manuscripts prior to submission for publication. 
 
 


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18. REFERENCES 
 
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Howlader N, Noone AM, Krapcho M. SEER Cancer Statistics Review, 1975-2011. 
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Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: 
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Gilligan D, Nicolson M, Smith I, et al. Preoperative chemotherapy in patients with 
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Martini N, Kris MG, Gralla RJ, et al. The effects of preoperative chemotherapy on the 
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Martini N, Kris MG, Flehinger BJ, et al. Preoperative chemotherapy for stage IIIa 
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Kris MG, Pisters KM, Ginsberg RJ, et al. Effectiveness and toxicity of preoperative 
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Bear HD, Anderson S, Smith RE, et al. Sequential preoperative or postoperative 
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van der Hage JA, van de Velde CJ, Julien JP, Tubiana-Hulin M, Vandervelden C, 
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CTLA-4 blockade in melanoma. N Engl J Med 2014;371:2189-99. 
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Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape 
determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348:124-8. 
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Gettinger SN, Horn L, Gandhi L, et al. Overall Survival and Long-Term Safety of 
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initial therapy in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 
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PD-L1 antibody MPDL3280A in cancer patients. Nature 2014;515:563-7. 
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Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and 
carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a 
randomized, double-blind, multicenter phase II study. J Clin Oncol 2012;30:2046-54. 
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placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, 
double-blind, phase 3 trial. Lancet Oncol 2015;16:522-30. 
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Tarhini AA, Edington H, Butterfield LH, et al. Immune monitoring of the circulation 
and the tumor microenvironment in patients with regionally advanced melanoma receiving 
neoadjuvant ipilimumab. PLoS One 2014;9:e87705. 
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Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced 
melanoma. N Engl J Med 2013;369:122-33. 
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Combination With Carboplatin Versus Solvent-Based Paclitaxel Plus Carboplatin as First-Line 
Therapy in Patients With Advanced Non–Small-Cell Lung Cancer: Final Results of a Phase III 
Trial. Journal of Clinical Oncology 2012;30:2055-62. 
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Ahmed S, Birnbaum AE, Safran HP, et al. Pathologic response after neoadjuvant 
carboplatin and weekly paclitaxel for early-stage lung cancer: a Brown University oncology 
group phase II study. J Thorac Oncol 2011;6:1432-4. 
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Merritt RE, Mahtabifard A, Yamada RE, Crystal RG, Korst RJ. Cisplatin augments 
cytotoxic T-lymphocyte-mediated antitumor immunity in poorly immunogenic murine lung 
cancer. J Thorac Cardiovasc Surg 2003;126:1609-17. 
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contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 
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Emens LA, Middleton G. The interplay of immunotherapy and chemotherapy: 
harnessing potential synergies. Cancer Immunol Res 2015;3:436-43. 
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Antonia S, Brahmer JR, Gettinger SN, et al. Nivolumab (anti-PD-1; BMS-936558, 
ONO-4538) in combination with platinum-based doublet chemotherapy (PT-DC) in advanced 
non-small cell lung cancer (NSCLC). J Clin Oncol 2014;32:suppl; abstr 8113. 
61. 
Liu S, Powderly JD, Camidge DR. Safety and efficacy of MPDL3280A in 
combination with platinum-based doublet chemotherapy in patients with advanced non-small cell 


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lung cancer. N Engl J Med 2015;372:2018-28. 
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a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res 
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19. ATTACHMENTS 
 
 Consent Form 
 Genentech Safety Reporting Fax Cover Sheet  
 Guidelines for Affiliate Institutions in Multicenter Studies 
 
 
 
 
 
 
 
 


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SAFETY REPORTING FAX COVER SHEET 
Genentech Supported Research 
 
 
Submit AEs/SAEs/ AESIs/ Pregnancy reports to 
AE / SAE FAX No: (650) 225-4682Alternate Fax No: (650) 225-4630  
 
Genentech Study Number 
ML29820 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[ ] - [ ] - [ ] 
 
 
SAE or Safety Reporting questions, contact Genentech Drug Safety: (888) 835-2555 
 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET 
 
 
 


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20. GUIDELINES FOR AFFILIATE INSTITUTIONS IN MULTICENTER STUDIES 
 
1. Multi-site Communication: 
 
The CPDM office at CUMC provides administration, data management, and organizational 
support for the affiliate sites in the conduct of a multicenter clinical trial.  The CPDM office will 
coordinate regularly scheduled conference calls with affiliate sites.  
 
The following issues will be discussed as appropriate:  
 
 Enrollment information  
 Cohort updates (i.e. DLTs) 
 Adverse events (i.e. new adverse events and updates on unresolved adverse events and 
new safety information) 
 Protocol violations 
 Other issues affecting the conduct of the study 
 
2. New Protocol Distribution, IRB Submission, Modifications and Annual Renewals 
 
 Protocol specific documents are distributed to affiliate sites once CUMC IRB approval 
has been obtained.  
 The affiliate site must submit a draft of site specific revisions to protocol and/or consent 
form documents for review and approval by the sponsor-investigator prior to submission 
to the local IRB. Draft documents should be sent to the study specific email address. The 
site will be provided confirmation that they are approved to submit to their local IRB.  
 Protocol amendments must be approved by the affiliate site’s local IRB within 90 days of 
distribution to the site by the sponsor-investigator.  
 
3. Regulatory Documents: 
 
3.1 Prior to Site Initiation: 
 
Sponsor-Investigator will ensure that proper requests are made of sites and that the following 
documentation is collected prior to the initiation of an affiliate site.   
 
 CV of PI, Sub-I’s and other research staff listed on FDA 1572 (signed and dated copy 
within 2 years) 
 Medical Licenses of PI and Sub-I’s (current copy) 
 Human subjects training certificates for PI and Sub-I’s 
 CLIA/Laboratory  Certifications for Local Laboratories listed on FDA 1572 
 Local Laboratory Director’s CV and License 
 Local Laboratory Reference Ranges  
 IRB roster or statement of compliance 
 FDA Form 1572, if applicable (wet ink originals required) 


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 Financial Disclosure forms for all members listed on FDA 1572 (wet ink originals 
required) 
 
3.2 Ongoing Regulatory Documentation:  Sponsor-Investigator will ensure that proper 
requests are made of sites and that the following documentation is collected throughout 
the course of the study. 
 
 IRB approval letters for all protocol modifications and all renewals 
 IRB-approved consent forms 
 Current IRB roster, if statement of compliance is not provided as part of site initiation  
 FDA Form 1572, if applicable as updates are required 
 Updated investigator and site information where relevant (e.g., CV, medical licensure 
and Financial Disclosure for new sub-investigator, local laboratory information) 
 
Regulatory documents may be sent to Q3153@columbia.edu or to the following address if wet 
ink originals are required: 
 
Clinical Protocol & Data Management Office 
161 Fort Washington Ave. 
Herbert Irving Pavilion 
Mezzanine Level, M-203 
New York, NY 10032 
 
4. Protocol Deviation/Subject Waiver request for Affiliate Sites: 
 
The Affiliate site MUST submit a prospective deviation request to the CUMC lead PI for review 
and submission to the HICCC DSMC and CUMC IRB. Approvals must be obtained from all 
entities prior to implementation at the Affiliate site.  If a prospective protocol deviation request is 
submitted for review (from an Affiliate site), the PI/site memo(s), HICCC DSMC approval(s) and 
correspondence and CUMC IRB eligibility deviation approval letter(s)/correspondence should be 
forwarded to the Affiliate site for documentation. The Affiliate site is also required to obtain 
prospective local IRB approval as per institutional policies/procedures prior to implementing the 
proposed deviation. All documents and determinations must be clearly documented in the study 
subject’s medical record, research chart and regulatory binder, as described. As per HICCC 
directives, no eligibility waivers will be granted by the PRMC/DSMC for HICCC Investigator 
Initiated Trials.  
 
 
 
 
 
 
 
 
 


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5. Guidelines for Affiliate Site Monitoring  
 
5.1 On-Site MCT Monitoring:  
 
1. Initial, recurrent, and close-out on-site monitoring visits will also be conducted at 
Affiliate sites, as appropriate/feasible. Other sites will have monitoring performed 
remotely (see below for further details). 
 The study Monitoring Visit Log will be completed and signed by the 
monitor and the PI/CRNP/CRN and/or CRC and will be filed in the 
regulatory binder. 
 
2. The Compliance Coordinator will communicate with the Affiliate site coordinator/Site 
 Principle Investigator to schedule the monitoring visit and arrange for access to study 
materials and documentation. 
 
3. The Compliance Coordinator will monitor IIT trials within 1 month after the first subject 
is enrolled at the Affiliate site and throughout the life of the study to ensure that the study 
is being conducted in accordance with the protocol, GCP, applicable federal and local 
regulations, and per all applicable SOPs. The Compliance Coordinator is responsible to 
notify the participating site PI and CRNP/CRN/CRC of upcoming monitor visits and 
convey what information and documentation will be required for the visit(s).  The 
Compliance Coordinator is responsible for verifying that informed consent is properly 
obtained, eligibility is met (via the central registration process), and all study procedures 
are conducted according to the study protocol. The Compliance Coordinator will also 
verify that the data reported in the CRF’s accurately reflect source documents, that all 
toxicities have been reported to date, and that all SAE’s/UPs/deviations/violations have 
been reported according to Coordinating Center, local IRB and HICCC DSMC 
requirements. The Compliance Coordinator will issue queries and ensure resolution in a 
timely and efficient manner.  The Compliance Coordinator will also monitor for 
applicable regulatory compliance and research pharmacy compliance (if applicable) and 
communicate any deficiencies as appropriate. 
 
4. An SIV (or) teleconference will be scheduled and conducted prior to study drug being 
made available (if applicable) and before any subjects are enrolled on a study at the 
Affiliate site. 
 
5.2 MCT Remote Monitoring: 
 
1. 
When necessary (due to logistical constraints), Affiliate sites will be monitored 
remotely by a designated Compliance Coordinator. Sites will be informed of this remote 
monitoring process on a site by site basis. 
 
2. 
Affiliate sites will be monitored by the Compliance Coordinator on both a regulatory 
level, as well as a clinical data/source documentation review level. 


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3. 
Redacted source documents (applicable to supporting the protocol specific CRF data 
requirements) will be sent to the designated Compliance Coordinator via fax or secure email 
for all subjects enrolled at Affiliate sites. Timelines for submission procedures will be 
defined on a case-by-case basis.   
 
4. 
The Compliance Coordinator will review all submitted redacted source documents 
against the data entered on the protocol specific CRFs. The Compliance Coordinator will 
issue queries when/if necessary. 
 
 The Affiliate site research staff will respond to queries within 30 days. If queries remain 
outstanding, the Compliance Coordinator will send a delinquent query reminder for the 
outstanding items. 
 
 The remote monitoring procedures will include review of applicable redacted source 
documentation and supporting applicable documents to determine compliance regarding: 
 
 Informed consent procedures 
 Eligibility criteria 
 Protocol specific treatment compliance 
 Protocol specific toxicity/outcome documentation/compliance 
 Protocol specific schedule of events (e.g., baseline visits, pre-treatment, on 
study, follow-up) 
 Participating site IRB documents (e.g., IRB amendment approvals, annual 
renewals, SAE/UP submissions, violation/deviation submissions, INDSR 
submissions, etc). 
 Required specimen submissions (e.g., tissue specimens, research blood 
specimens, etc.) 
 Pharmacy accountability records 
 Adherence to the CRF submission timeframes to CUMC (within the 
protocol specified timeframes) 
 
 Affiliate site remote monitoring reports will be sent to the lead PI, HICCC DSMC, and 
Affiliate sites after each remote monitoring review. Reports will include information 
regarding data submission timeliness/accuracy, protocol adherence items, query 
resolution status, regulatory status, and overall Affiliate site performance. These reports 
will be generated by the Compliance Coordinator and reviewed with the Compliance 
Core Manager prior to dissemination. 
 
 
 
 
 


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6. Dose Level Determinations: 
 
The sponsor-investigator will review enrollment for each dose level cohort during the regularly 
scheduled conference call with the affiliate sites.  
 
The dose level for newly enrolled subjects will be determined by the study statistician upon 
notification that a subject has signed informed consent to participate in the study. The assigned 
dose level for any subject to begin study treatment will be communicated to the affiliate site 
along with the determination by Central Registration that the subject is eligible for enrollment in 
the study.  
 
If a Dose Limiting Toxicity (DLT) is identified in a subject, the affiliate site must notify the 
sponsor-investigator via email at the study specific email address within 1 business day of 
identification. The lead site will communicate that a DLT has been experienced within 1 
business day.  
 
7. Confidentiality 
 
Each affiliate site will be assigned a site number. Each subject that signs consent should be 
assigned a unique code number consisting of site number followed by a number with each new 
subject being assigned the next sequential number (e.g. 04-10). All sites will be required to enter 
their data in the Velos eResearch, the Clinical Trial Management System used for all Cancer-
related clinical research at CUMC. All users must login with their own application username and 
password.  Users off campus must first access the Virtual Private Network with their assigned 
campus username and password and then use their application credentials.   
 
Subject confidentiality must be maintained according to HIPAA regulations and GCP 
recommendations.  
 
Except when required by law, study information shared with persons and organizations outside 
of Columbia University Medical Center must not identify the patient by name, social security 
number, address, telephone number, or any other direct personal identifier. 
If the results of this research project are published or presented at a scientific or medical meeting, 
the patient not be identified. Otherwise, all results will be kept confidential and will not be 
divulged (except as required by law) without permission.  
 
Data Reporting Plan 
 
Columbia University Medical Center (CUMC) is deeply committed to research integrity and 
strong credibility when it comes to the discovery of new treatment concepts, implementation of 
new clinical research techniques, and acceptance of its researcher's findings by the medical 
establishment. In accord with these ethics, CUMC encourages and supports its investigators in 
the sharing of final research data and/or details of newly developed clinical treatments. 
 
 


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CUMC's policies that pertain to patient data sharing conform to CUMC IRB rules, local and state 
laws, and HIPAA privacy regulations. The primary reason for this is to protect the privacy of 
patients who participate in clinical trials. The data can be made available for continuing review 
by federal agencies upon request and for ongoing study safety reviews by the Principal 
Investigator, Statistician, Data Safety and Monitoring Board (DSMC), and, in other instances, 
the CUMC IRB. 
 
Data collected during the course of this clinical trial will primarily be shared with other 
investigators and University staff, the IRB, FDA, and other reporting agencies, and/or transferred 
to other collaborators.  Prior to transfer, the data collected must comply with, and must be 
limited by, the CUMC's guidelines for Protecting the Rights and Privacy of Human Subjects.   
 
Data Acquisition and Submission 
 
Informed consent, including HIPPA authorization, must be obtained on all subjects prior to their 
participation. Always keep the original signed and dated consent form, with the redacted source 
documents and eligibility checklist. Velos eResearch will be used as the electronic clinical trials 
and data management system. Affiliate sites will enter data directly into Velos eResearch via 
customized case report forms for the study. The research staff will generate reports from Velos 
eResearch to ensure timely submission of data by affiliate sites. This resource allows for the 
timely analysis of particular data sets for safety analysis.