Conditions: Non-Small-Cell Lung Cancer Metastatic Non-Small Cell Carcinoma of Lung, TNM Stage 4 Nonsmall Cell Lung Cancer Non Small Cell Lung Cancer Recurrent
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 7
Healthy volunteers: no

Brief summary:
The optimal prioritization of second-line chemotherapy and immune therapy based on demographic or biomarker data is an area of ongoing investigation. The hypothesis of this study is that there may be an additive or synergistic antitumor effect of combined chemotherapy and nivolumab in the second-line treatment of NSCLC as an important concept to test in a clinical trial. Previously treated NSCLC remains a setting of unmet clinical need despite recent clinical research progress. Early progression for a subset of NSCLC patients receiving nivolumab is a specific area of clinical need.

Detailed description:
Nab-paclitaxel will be added to standard nivolumab therapy in previously treated advanced stage non-small cell lung cancer to help prevent early progression and to improve progression free survival. The primary endpoint will be to determine if the addition of nab-paclitaxel to nivolumab improves progression free survival compared to nivolumab alone. Retrospective studies will be conducted to analyze blood based immune biomarkers, and tumor biomarkers to better understand the effect that nivolumab combined with chemotherapy has on the immune system in NSCLC. Patients with advanced stage non-small cell lung cancer who have progression of cancer after receiving platinum doublet chemotherapy will be randomized to receive nivolumab with or without nab-paclitaxel. Patients on both arms will receive a maximum of one year of therapy with the option to retreat at progression.

Arms:
arm 1: Nivolumab q 14 days until disease progression/toxicity arm 2: Nivolumab every 21 days until disease progression

Nab-paclitaxel every 21 days

Interventions: intervention 1: Nivolumab intervention 2: nab-paclitaxel
Intervention descriptions: intervention 1: Arm A: Nivolumab 240 mg via intravenous infusion (IV) over 30 minutes day 1 of each 14 day cycle until disease progression or not tolerated.

Arm B: Nivolumab 360 mg via intravenous infusion (IV) over 30 minutes day 1 of every 21 day treatment cycle until progression or not tolerated. intervention 2: Patients in arm B receive nab-paclitaxel at a dose of 100 mg/m2 over intravenous infusion on Days 1 and 8 of each 21 day cycle.

Protocol document:
Prot_SAP_000.pdf: 


 
 
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PROTOCOL SIGNATURE PAGE 
 
Protocol Title:  
 
 
 
 
 
 
Protocol Number: 
 
 
 
 
 
 
 
 
 
Sponsor Name: 
Alliance Foundation Trials (AFT), LLC 
 
 
 
 
Declaration of Investigator 
 
I confirm that I have read the above-mentioned protocol and its attachments. I agree to conduct 
the described trial in compliance with all stipulations of the protocol, all applicable regulations, 
ICH Good Clinical Practice (GCP) and Declaration of Helsinki. 
 
 
 
------------------------------------------------- 
 
 
-------------------------------------- 
First Name, Last Name 
 
 
 
 
 
 
Date, Signature 
 
 
 
 
 
 
 
 
 




 
 
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I. 
Synopsis and Study Schema 
 
Study Title 
Nivolumab with or without nab-paclitaxel in previously treated, 
advanced stage, non-small cell lung cancer: a randomized phase II 
Alliance Study 
Study Number 
AFT-31 
Study Type/Phase 
Interventional Randomized Phase II 
Clinical Indication 
Previously treated advanced stage non-small cell lung cancer (NSCLC) 
ClinicalTrials.gov 
Identifier 
NCT02967133 
IND Number 
132051 
Number of Trial 
Patients 
200 
Estimated Duration 
of Trial 
48 months 
Rationale 
Patients with advanced stage non-small cell lung cancer who have 
progression of cancer after receiving platinum doublet chemotherapy 
have known benefit from nivolumab immune therapy. We hypothesize 
that the addition of nab-paclitaxel to nivolumab in this setting will 
provide additional clinical benefit compared to nivolumab alone. We 
will retrospectively study blood based immune biomarkers, and tumor 
biomarkers to better understand biomarkers associated with benefit and 
immune related side effects of the study therapy.  
Primary Objective 
The primary endpoint will be to determine if the addition of nab-
paclitaxel to nivolumab improves progression free survival compared to 
nivolumab alone.  
Secondary 
Objectives  
1) To evaluate the difference of response rates between treatment 
with nab-paclitaxel and nivolumab and treatment with 
nivolumab alone 
2) To evaluate the difference of overall survival between the two 
treatment regimens 
3) To characterize treatment related adverse events. 
4) To characterize progression-free for PDL1 positive (> 1% 
tumors positive) and PDL1 negative tumors.  
5) To study blood based immune biomarkers 
6) To study tumor based immune biomarkers 


 
 
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Translational 
Science Objectives 
 
Principal: Retrospectively analyze tumor immune biomarkers associated 
with lung cancer sensitivity and resistance to immune therapy. 
Additional:  
 
Retrospectively analyze blood immune biomarkers associated with lung 
cancer sensitivity and resistance to immune therapy.  
 
To compare clinical outcomes for PDL1 positive and PDL1 negative 
tumors.  
To compare rate of deaths in the first 3 months between the two 
treatments.  
To compare characteristics of tumors for deaths in the first 3 months 
compared to those living more than 3 months.  
 
Other Correlative 
Sciences Objectives 
N/A 
Trial Design  
Patients with previously treated advanced stage non-small cell lung 
cancer will be eligible. Patients who give written informed consent will 
be randomized to receive:  
• nivolumab every 14 days 
OR 
• nivolumab every 21 days with nab-paclitaxel on Days 1 and 8 
Patients without progression who tolerate may receive therapy for up to 
one year. If patients with disease control at the end of therapy relapse, 
they will be eligible to reinitiate therapy. Tumor assessment for 
response will be done every 6 weeks for 12 months. Both treatment 
arms will receive a maximum of 12 months of study therapy.  
Inclusion Criteria 
1. Histologically or cytologically documented non-small cell lung 
cancer 
2. Stage 4 or recurrent incurable advanced non-small cell lung 
cancer 
3. Platinum doublet chemotherapy for current diagnosis of lung 
cancer. EGFR, ALK and ROS biomarker positive tumors are 
eligible as long as the patient has received one or more courses 
of standard oral, molecular inhibitor therapy in addition to 
standard platinum doublet chemotherapy 
4. All patients must have measurable disease by CT or MRI per 
RECIST 1.1 criteria (see section 11.2.2). 
5. ECOG Performance Status: 0-1 


 
 
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6. Second malignancy: no “currently active” second malignancy 
other than non-melanoma skin cancers.  
7. Brain metastases: brain metastases must have been treated at 
least 2 weeks prior to enrollment, be asymptomatic from brain 
metastases, stable on brain imaging, and not be receiving a 
supra-physiologic dose of steroids. 
8. Non-pregnant and non-nursing. The effect of nab-paclitaxel and 
nivolumab on the fetus and infant is unknown.  
9. Age ≥ 18 years. 
10. Normal organ function 
  
See Section 3.1. 
Exclusion Criteria 
1. No prior nab-paclitaxel therapy. 
2. No prior immune therapy. 
3. No active auto-immune disease.  
 
See Section 3.2.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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II. 
Table of Contents 
Table of Contents 
1.Background Information ............................................................................................................................ 1 
1.1. 
Overview of Disease and Patient Population and Study Rationale ............................................... 1 
1.1.1 
Overview of Disease ............................................................................................................. 1 
1.1.2 
Study Rationale ..................................................................................................................... 1 
1.2. 
Study Design ................................................................................................................................. 1 
1.3. 
Study Design Rationale ................................................................................................................. 1 
1.4. 
Study Agents ................................................................................................................................. 2 
1.4.1 
Nab-Paclitaxel (Abraxane) .................................................................................................... 2 
1.4.2 
Nivolumab ............................................................................................................................. 5 
1.5. 
Risks and Benefits ......................................................................................................................... 7 
2. 
Objectives and Endpoints.................................................................................................................. 7 
2.1. 
Primary Objectives ........................................................................................................................ 7 
2.2. 
Secondary Objectives .................................................................................................................... 8 
2.3. 
Exploratory Objectives ................................................................................................................. 8 
2.4. 
Endpoints ...................................................................................................................................... 8 
2.5. 
Rationale for Endpoints ................................................................................................................ 9 
2.5.1 
Primary and Secondary Endpoints ........................................................................................ 9 
2.5.2 
Correlative Science Endpoints .............................................................................................. 9 
2.6. 
Future Biomedical Research ......................................................................................................... 9 
3. 
Patient Selection/Population ........................................................................................................... 10 
3.1. 
Inclusion Criteria ........................................................................................................................ 10 
3.2. 
Exclusion Criteria ....................................................................................................................... 11 
3.3. 
Inclusion of Women and Minorities ........................................................................................... 12 
4. 
Method of Treatment Assignment/ (Patient Numbering and Treatment Assignment) ................... 12 
4.1. 
Site Enrollment Requirements .................................................................................................... 12 
4.2. 
Patient Enrollment/Randomization Procedure ............................................................................ 12 
4.3. 
Patient Numbering ...................................................................................................................... 13 
4.4. 
Stratification Factors ................................................................................................................... 13 


 
 
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4.5. 
Treatment Assignment ................................................................................................................ 13 
4.6. 
Treatment Blinding ..................................................................................................................... 13 
5. 
Treatment Plan ................................................................................................................................ 13 
5.1. 
Treatment Regimen ..................................................................................................................... 13 
5.2. 
Pre-Treatment Criteria ................................................................................................................ 14 
5.3. 
Agent Administration .................................................................................................................. 14 
5.4. 
Order of Administration .............................................................................................................. 14 
5.5. 
Supportive Care and Concomitant Medications ......................................................................... 15 
5.6. 
AFT Policy Concerning the Use of Growth Factors ................................................................... 16 
6. 
Dose and Treatment Modifications ................................................................................................. 16 
6.1. 
Nab-Paclitaxel Dose Modifications ............................................................................................ 16 
6.1.1 
Nab-Paclitaxel Dose Levels ................................................................................................ 17 
6.1.2 
Hematologic Adverse Event ............................................................................................... 17 
6.1.3 
Nab-paclitaxel dose modifications for gastrointestinal adverse event ................................ 18 
6.1.4 
Neurotoxicity ...................................................................................................................... 18 
6.1.5 
Cardiotoxicity ..................................................................................................................... 18 
6.1.6 
Nab-paclitaxel Hypersensitivity and/or Infusion Reactions ................................................ 18 
6.2. 
Nivolumab ................................................................................................................................... 20 
6.2.1 
Nivolumab Dose Modifications .......................................................................................... 20 
6.2.2 
Dose Delay Criteria ............................................................................................................. 20 
6.2.3 
Nivolumab administration should be delayed for the following: ........................................ 20 
6.2.4 
Criteria to Resume Treatment ............................................................................................. 21 
6.2.5 
Management Algorithms ..................................................................................................... 21 
6.2.6 
Discontinuation Criteria ...................................................................................................... 22 
6.2.7 
Treatment of Nivolumab Related Infusion Reactions ......................................................... 23 
6.3. 
Dose Modifications for Obese Patients ....................................................................................... 24 
7. 
Study Assessments and Procedures ................................................................................................ 25 
7.1. 
Assessment Types ....................................................................................................................... 25 
7.1.1 
Efficacy Assessments .......................................................................................................... 25 
7.1.2 
Safety and Tolerability Assessments and Procedures ......................................................... 25 


 
 
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7.1.3 
Pharmacokinetics ................................................................................................................ 25 
7.1.4 
Biomarkers/Correlative Studies .......................................................................................... 25 
7.1.5 
Patient Reported Outcomes ................................................................................................. 26 
8. 
Study Assessment Table ................................................................................................................. 27 
9. 
Adverse Events ............................................................................................................................... 31 
9.1. 
Adverse Events - General Overview ........................................................................................... 31 
9.1.1 
Expected Toxicities ............................................................................................................. 31 
9.1.2 
Routine Adverse Event Reporting ...................................................................................... 31 
9.1.3 
Serious Adverse Event Reporting Requirements ................................................................ 32 
9.1.4 
Assessment of Causality of Adverse Events ....................................................................... 35 
9.2. 
Pregnancy Adverse Event Reporting .......................................................................................... 35 
10. 
Drug Information ........................................................................................................................ 36 
10.1. 
Nivolumab ............................................................................................................................... 36 
10.1.1 
Description of Study Agent ................................................................................................. 36 
10.1.2 
Form .................................................................................................................................... 36 
10.1.3 
Storage and Stability ........................................................................................................... 36 
10.1.4 
Availability ......................................................................................................................... 36 
10.1.5 
Administration .................................................................................................................... 36 
10.1.6 
Ordering .............................................................................................................................. 37 
10.1.7 
Accountability ..................................................................................................................... 37 
10.1.8 
Destruction and Return ....................................................................................................... 37 
10.2. 
Nab-Paclitaxel ......................................................................................................................... 37 
10.2.1 
Form .................................................................................................................................... 37 
10.2.2 
Storage and Stability ........................................................................................................... 37 
10.2.3 
Availability ......................................................................................................................... 37 
10.2.4 
Administration .................................................................................................................... 38 
10.2.5 
Ordering .............................................................................................................................. 38 
10.2.6 
Accountability ..................................................................................................................... 38 
10.2.7 
Destruction and Return ....................................................................................................... 38 
11. 
Data Collection and Management/ Data and Specimen Submission .......................................... 38 


 
 
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11.1. 
Data Collection and Submission ............................................................................................. 38 
11.2. 
Specimen Collection and Submission ..................................................................................... 38 
11.2.1 
Biospecimen Collection ...................................................................................................... 38 
11.2.2 
Biospecimen Collection Schema ........................................................................................ 39 
12. 
Correlative Studies ...................................................................................................................... 39 
12.1. 
PDL1 Expression .................................................................................................................... 39 
12.2. 
Plasma - Protein Markers Associated with Sensitivity or Resistance to Nivolumab .............. 40 
12.3. 
Plasma – Circulating, Cell-Free Tumor DNA ......................................................................... 40 
13. 
Measurement of Effect ................................................................................................................ 41 
13.1. 
Imaging Assessment Collection Plan ...................................................................................... 41 
13.2. 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria8 ................................. 41 
13.2.1 
Definitions ........................................................................................................................... 41 
13.2.2 
Disease Parameters ............................................................................................................. 41 
13.2.3 
Methods for Evaluation of Disease ..................................................................................... 42 
13.2.4 
Measurement at Follow-up Evaluation ............................................................................... 43 
13.2.5 
Response Criteria ................................................................................................................ 43 
13.2.6 
Duration of Response .......................................................................................................... 45 
13.2.7 
Overall Objective Status ..................................................................................................... 46 
13.2.8 
Symptomatic Deterioration ................................................................................................. 46 
13.2.9 
Progression-Free Survival ................................................................................................... 47 
13.2.10 
Review of Response ........................................................................................................ 47 
13.3. 
Antitumor Effect – Hematologic Tumors ............................................................................... 48 
14. 
End of Treatment ........................................................................................................................ 48 
14.1. 
Duration of Treatment ............................................................................................................. 48 
14.1.1 
CR, PR, or SD ..................................................................................................................... 48 
14.1.2 
Disease Progression ............................................................................................................ 48 
14.1.3 
Treatment Beyond Progression ........................................................................................... 48 
15. 
Statistical Considerations ............................................................................................................ 49 
15.1. 
Overview of the Study Design ................................................................................................ 49 
15.2. 
Sample Size, Accrual Time and Study Duration .................................................................... 49 


 
 
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15.3. 
Stratification Factors ............................................................................................................... 50 
15.4. 
Statement for Primary Endpoint ............................................................................................. 50 
15.5. 
Interim Analysis Design for Primary Endpoint (include DSMB reporting, if applicable) ..... 50 
15.6. 
Secondary Objectives .............................................................................................................. 51 
15.7. 
Supplementary/Secondary Analysis Plans/Statistical Analysis Plan ...................................... 52 
15.8. 
Adverse Event/Accrual Monitoring Stopping Rule ................................................................ 52 
15.9. 
Criteria for Taking a Patient Off Protocol Therapy ................................................................ 52 
15.10. 
Duration of Follow-Up............................................................................................................ 53 
15.11. 
Criteria for Taking a Patient Off Study ................................................................................... 53 
15.12. 
Extraordinary Medical Circumstances .................................................................................... 53 
15.13. 
Managing Ineligible Patients and Registered Patients Who Never Receive Protocol 
Intervention ............................................................................................................................................. 53 
15.14. 
Data and Safety Monitoring .................................................................................................... 54 
16. 
General Regulatory Considerations and Credentialing (Ethical Considerations and 
Administrative Procedures)..................................................................................................................... 54 
16.1. 
Compliance with Trial Enrollment and Results Posting Requirements .................................. 54 
16.2. 
Regulatory and Ethical Compliance ....................................................................................... 54 
16.3. 
Informed Consent .................................................................................................................... 55 
16.4. 
Responsibilities of the Investigator/IRB/IEC/REB ................................................................. 55 
16.5. 
Financial Disclosures .............................................................................................................. 56 
16.6. 
Protocol Deviations ................................................................................................................. 56 
16.7. 
Protocol Amendments ............................................................................................................. 56 
16.8. 
Retention of Records (Study Documentation, record keeping, and retention of records) ...... 56 
16.9. 
Data and Safety Monitoring Board (DSMB) .......................................................................... 56 
16.10. 
Regulatory Reporting .............................................................................................................. 57 
16.11. 
Data Confidentiality ................................................................................................................ 57 
16.12. 
Database Management and Quality Control ........................................................................... 57 
16.13. 
Site Monitoring ....................................................................................................................... 58 
16.14. 
Audits and Inspections ............................................................................................................ 58 
16.15. 
Early Discontinuation of the Study ......................................................................................... 58 
16.16. 
Publication of study protocol and results ................................................................................ 58 


 
 
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17. 
References ................................................................................................................................... 59 
18. 
Appendices .................................................................................................................................. 60 
18.1. 
Appendix I: ECOG Performance Status ................................................................................. 61 
18.2. 
Appendix II: Adverse Event Management Algorithms .......................................................... 62 
18.2.1 
Genitourinary Adverse Events ............................................................................................ 62 
18.2.2 
Renal Adverse Events ......................................................................................................... 63 
18.2.3 
Pulmonary Adverse Events ................................................................................................. 64 
18.2.4 
Hepatic Adverse Events ...................................................................................................... 65 
18.2.5 
Endocrine Adverse Events .................................................................................................. 66 
18.2.6 
Skin Adverse Events ........................................................................................................... 67 
18.2.7 
Neurological Adverse Events .............................................................................................. 68 
19. 
Approval Signatures .................................................................................................................... 69 
 


 
 
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1. Background Information 
1.1. 
Overview of Disease and Patient Population and Study Rationale 
1.1.1 Overview of Disease  
Advanced non-small cell lung cancer (NSCLC) is the most common cause of cancer related 
mortality. Treatment with chemotherapy, molecular therapy, or immunotherapy can prolong 
survival and improve quality of life. Standard first-line treatment for patients with good 
performance status and normal organ function is platinum doublet chemotherapy. On progression 
after first-line therapy, standard options would include single agent chemotherapy or a program 
death receptor 1 (PD1) masking antibody such as nivolumab.  
Nivolumab is a programmed death receptor (PD-1) masking anti-body that has shown single 
agent activity in previously treated and untreated advanced stage non-small cell lung cancer. 
Nivolumab has received FDA approval as therapy for previously treated squamous cell lung 
cancer and non-squamous cell lung cancer (1, 2).  
1.1.2 Study Rationale  
The optimal prioritization of second-line chemotherapy and immune therapy based on 
demographic or biomarker data is an area of ongoing investigation.  The hypothesis of this study 
is that there may be an additive or synergistic antitumor effect of combined chemotherapy and 
nivolumab in the second-line treatment of NSCLC as an important concept to test in a clinical 
trial. Previously treated NSCLC remains a setting of unmet clinical need despite recent clinical 
research progress. Early progression for a subset of NSCLC patients receiving nivolumab is a 
specific area of clinical need.   
1.2. 
Study Design  
We propose adding nab-paclitaxel to standard nivolumab therapy in previously treated advanced 
stage non-small cell lung cancer to help prevent early progression and to improve progression 
free survival. The primary endpoint will be to determine if the addition of nab-paclitaxel to 
nivolumab improves progression free survival compared to nivolumab alone. We will 
retrospectively study blood based immune biomarkers, and tumor biomarkers to better 
understand the effect that nivolumab combined with chemotherapy has on the immune system in 
NSCLC. Patients with advanced stage non-small cell lung cancer who have progression of 
cancer after receiving platinum doublet chemotherapy will be randomized to receive nivolumab 
with or without nab-paclitaxel. Patients on both arms will receive a maximum of one year of 
therapy with the option to retreat at progression.  
1.3. 
Study Design Rationale 
Two large randomized phase 3 trials have compared nivolumab single agent immune therapy to 
standard dose docetaxel in advanced non-small cell lung cancer after progression on platinum 
based chemotherapy. In both trials, total all grade side effects and total grade 3-5 side effects 
were less with nivolumab compared to docetaxel. In both trials, overall survival was improved in 
favor of nivolumab at clinically and statistically significant levels. Nivolumab has recently been 
established as one standard of care for previously treated NSCLC of either squamous or non-


 
 
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squamous histology. This will be one of the first trials to test whether the addition of a well-
tolerated single chemotherapy agent improves therapeutic efficacy when added to the PD1 
masking antibody nivolumab for patients with previously treated NSCLC.  
Data suggest that there may be an additive benefit of combining chemotherapy and nivolumab in 
advanced stage non-small cell lung cancer. Our hypothesis is that the addition of nab-paclitaxel 
to nivolumab for previously treated non-small cell lung cancer may be beneficial.  
The optimal duration of immune therapy is unknown for patients tolerating treatment and with 
disease control. After discussion with the Alliance and sponsor teams it was felt that one year of 
therapy with the option of retreating at progression was an appropriate duration of therapy.  
1.4. 
Study Agents 
1.4.1 Nab-Paclitaxel (Abraxane) 
1.4.1.1 Clinical Pharmacokinetics and Immunogenicity  
Nab-Paclitaxel (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.  Nab-Paclitaxel 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. 
The pharmacokinetics of total paclitaxel following 30 and 180-minute infusions of nab-paclitaxel 
at dose levels of 80 to 375 mg/m2 were determined in clinical studies. Dose levels of mg/m2 
refer to mg of paclitaxel in nab-paclitaxel.  Following intravenous administration of nab-
paclitaxel, paclitaxel plasma concentrations declined in a biphasic manner, the initial rapid 
decline representing distribution to the peripheral compartment and the slower second phase 
representing drug elimination. 
The drug exposure (AUCs) was dose proportional over 80 to 300 mg/m2 and the 
pharmacokinetics of paclitaxel for nab-paclitaxel were independent of the duration of 
intravenous administration.  The pharmacokinetic data of 260 mg/m2 nab-paclitaxel 
administered over a 30-minute infusion was compared to the pharmacokinetics of 175 mg/m2 
paclitaxel injection over a 3-hour infusion. Clearance was larger (43%) and the volume of 
distribution was higher (53%) for nab-paclitaxel than for paclitaxel injection. There were no 
differences in terminal half-lives. 
Following nab-paclitaxel administration to patients with solid tumors, paclitaxel is evenly 
distributed into blood cells and plasma and is highly bound to plasma proteins (94%). In a 
within-patient comparison study, the fraction of unbound paclitaxel in plasma was significantly 
higher with nab-paclitaxel (6.2%) than with solvent-based paclitaxel (2.3%). This contributes to 
significantly higher exposure to unbound paclitaxel with nab-paclitaxel compared with solvent-
based paclitaxel, when the total exposure is comparable. In vitro studies of binding to human 
serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 μg/mL, indicated that the 
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binding of paclitaxel. The total volume of distribution is approximately 1741 L; the large volume 
of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel. 
1.4.1.2 Preclinical Data  
In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was 
metabolized primarily to 6α-hydroxypaclitaxel by CYP2C8; and to two minor metabolites, 3’-p-
hydroxypaclitaxel and 6α, 3’-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of 
paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, 
verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and 
vincristine), but the concentrations used exceeded those found in vivo following normal 
therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific 
inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The 
pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with 
compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4. 
At the clinical dose range of Nab-Paclitaxel 80 to 300 mg/m2, the mean total clearance of 
paclitaxel ranges from 13 to 30 L/h/m2, and the mean terminal half-life ranges from 13 to 27 
hours.  After a 30-minute infusion of 260 mg/m2 doses of nab-paclitaxel, the mean values for 
cumulative urinary recovery of unchanged drug (4%) indicated extensive non-renal clearance. 
Less than 1% of the total administered dose was excreted in urine as the metabolites 6α-
hydroxypaclitaxel and 3’-p-hydroxypaclitaxel.  Fecal excretion was approximately 20% of the 
total dose administered. 
1.4.1.3 Pharmacokinetics in Hepatic Impairment 
The effect of hepatic impairment on the pharmacokinetics of paclitaxel following nab-paclitaxel 
administration was studied in patients with advanced solid tumors. The results showed that mild 
hepatic impairment (total bilirubin >1 to ≤1.5 x ULN, AST ≤10 x ULN, n=8) had no clinically 
important effect on pharmacokinetics of paclitaxel. Patients with moderate (total bilirubin >1.5 to 
≤ 3 x ULN, AST ≤10 x ULN, n=7) or severe (total bilirubin >3 to ≤5 x ULN, n=5) hepatic 
impairment had a 22% to 26% decrease in the maximum elimination rate of paclitaxel and 
approximately 20% increase in mean paclitaxel AUC compared with patients with normal 
hepatic function (total bilirubin ≤ULN, AST ≤ULN, n=130). 
Elimination of paclitaxel shows an inverse correlation with total bilirubin and a positive 
correlation with serum albumin.  Pharmacokinetic/pharmacodynamic modeling indicates that 
there is no correlation between hepatic function (as indicated by the baseline albumin or total 
bilirubin level) and neutropenia after adjusting for nab-paclitaxel exposure. Pharmacokinetic data 
are not available for patients with total bilirubin >5 x ULN or for patients with metastatic 
adenocarcinoma of the pancreas. 
1.4.1.4 Pharmacokinetics in Renal Impairment 
The effect of pre-existing mild (creatinine clearance ≥60 to <90 mL/min, n=61) or moderate 
(creatinine clearance ≥30 to <60 mL/min, n=23) renal impairment on the pharmacokinetics of 
paclitaxel following nab-paclitaxel administration was studied in patients with advanced solid 
tumors. Mild to moderate renal impairment had no clinically important effect on the maximum 
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1.4.1.5 Other Intrinsic Factors 
Population pharmacokinetic analyses for nab-paclitaxel show that body weight (40 to 143 kg), 
body surface area (1.3 to 2.4 m2), gender, race (Asian vs. White), age (24 to 85 years) and type 
of solid tumors do not have a clinically important effect on the maximum elimination rate and 
systemic exposure (AUC and Cmax) of paclitaxel. 
1.4.1.6 Nab-Paclitaxel and Carboplatin for First-Line NSCLC 
Socinski et al. conducted a Phase 3 randomized trial investigating the efficacy and safety of 
albumin-bound paclitaxel (nab-paclitaxel; Abraxane) and carboplatin compared with solvent-based 
paclitaxel and carboplatin in untreated advanced stage NSCLC patients (3). The primary endpoint 
of this trial was objective response rate with secondary endpoints of progression-free survival and 
overall survival.  Patients treated with nab-paclitaxel and carboplatin demonstrated a significantly 
improved ORR compared with patients treated with paclitaxel and carboplatin (33% vs. 25%; 
response rate ratio [RRR] 1.31; p < 0.005), with patients with squamous histology experiencing the 
greatest improvement (41% vs. 24%; RR 1.68; p < 0.001). Nab-paclitaxel and carboplatin achieved 
a similar ORR as paclitaxel and carboplatin (26% vs. 25%, respectively) in tumors with non-
squamous histology.  There was a comparable improvement in PFS (6.3 months vs. 5.8 months; 
HR 0.902, 95% CI: 0.767−1.060) and OS (12.1 months vs. 11.2 months; HR 0.922, 95% CI: 
0.797−1.066) in patients treated with nab-paclitaxel and carboplatin compared with paclitaxel and 
carboplatin. Progression free survival was similar in both arms (6.9 months [nab-paclitaxel and 
carboplatin] vs. 6.5 months [paclitaxel and carboplatin]; HR 0.933) in the non-squamous subgroup. 
Overall survival was similar in both arms (13.1 months [nab-paclitaxel and carboplatin] vs. 13.0 
months [paclitaxel and carboplatin]; HR 0.950) in the non-squamous subgroup.  A statistically non-
significant improvement in OS was seen in patients with squamous histology (10.7 months [nab-
paclitaxel and carboplatin] vs. 9.5 months [paclitaxel and carboplatin]; HR 0.890, 95% CI 
0.719−1.101). Nab-paclitaxel and carboplatin was approved for the treatment of NSCLC in the 
first-line setting in all histologies. 
1.4.1.7 Nab-Paclitaxel for Second-Line NSCLC 
A randomized phase 2 trial studied second-line therapy of nab-paclitaxel versus pemetrexed in 
NSCLC (4).  Patients with advanced stage NSCLC and progression on first-line platinum-based 
chemotherapy were eligible. One arm received pemetrexed 500 mg/m2 on day 1 of 3-week cycle. 
The second arm received nab-paclitaxel 150 mg/m2 on days 1 and 8 of 3-week cycle. The 
primary endpoint was overall survival. One hundred and eleven patients were randomly assigned 
to receive pemetrexed (n = 56) and nab-paclitaxel (n = 55). Median overall survival was similar 
between the arms, 9.4 months (95% CI 7.1-12.5 months) for pemetrexed and 9.9 months (95% 
CI 8.2-11.9 months) for nab-paclitaxel. Median progression free survival was also similar 
between the study arms, 4.6 months (95% CI 2.7-6.1 months) for pemetrexed and 5.1 months 
(95% CI 3.9-7.4 months) for nab-paclitaxel. Similar disease control rates were observed between 
both arms; PRs and SDs were seen in 32/56 (57.1%) patients in pemetrexed arm and 36/55 
(65.5%) patients in nab-paclitaxel arm. Grade 3 and grade 4 adverse events were similar between 
the two treatment arms. In this phase 2 trial, single-agent nab-paclitaxel showed similar efficacy 
and toxicity as pemetrexed in previously treated NSCLC. 


 
 
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1.4.1.8 Nab-Paclitaxel and PD1 Checkpoint Therapy 
Results from a phase 1B trial combining atezolizumab with various platinum doublet 
chemotherapy regimens were presented at the World Lung Cancer Meeting in September 
2015(5). Overall the study concluded that there were no unexpected toxicities for atezolizumab 
in combination with standard first-line chemotherapy regimens for advanced NSCLC. The 
combination of atezolizumab 15 mg/kg every 3 weeks combined with carboplatin AUC 6 every 
3 weeks and nab-paclitaxel 100 mg/m2 weekly showed no difference in serious adverse events 
compared to the other combinations, and there were no treatment related deaths for the nab-
paclitaxel arm. The nab-paclitaxel arm (n=16 evaluable) had 4 CR, 5 PR, and 4 SD for an ORR 
of 56% and disease control rate of 81%. Many of the responses were durable beyond 6 months.  
Clinical trials to study the combination of nab-paclitaxel and PD1 checkpoint masking 
antibodies are justified.   
 
A large phase 1 study studied the combination of atezolizumab and nab-paclitaxel in a cohort of 
triple negative breast cancer and the initial clinical data has been presented (6). The safety data 
from that trial showed that the combination of nab-paclitaxel with the PD1 checkpoint antibody 
was tolerable both in previously treated and untreated patients with triple negative metastatic 
breast cancer. The overall response rate was 70% with many of the responses being durable and 
ongoing. Based on the efficacy and tolerability seen in this phase 1 trial, the combination of 
atezolizumab and nab-paclitaxel is being evaluated in a Phase III study of patients with 
previously untreated metastatic triple negative breast cancer. 
1.4.2 
Nivolumab 
1.4.2.1 
General Information 
Nivolumab is a fully human, IgG4 (kappa) isotype mAb that binds PD-1 on activated immune 
cells and  disrupts inhibitory signals by masking the receptor and preventing binding of the 
ligands PD-L1 and PD-L2. Nivolumab has activity in several tumor types, including NSCLC. (1) 
In previously treated NSCLC objective response rates approached 20%, with no clear differences 
between squamous and non-squamous NSCLC (1). Many responses have been durable in 
contrast to the responses seen with cytotoxic therapy. (2) In the United States, nivolumab has 
been approved for the treatment of patients with unresectable or metastatic melanoma and 
disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF 
inhibitor. It has also been approved for use in patients with advanced (metastatic) squamous non-
small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. 
1.4.2.2 Clinical Data 
The safety profile of nivolumab monotherapy as well as combination therapy is manageable with 
no MTD reached at any dose tested up to 10 mg/kg. (1, 2) There was no pattern in the incidence, 
severity, or causality of AEs to nivolumab dose level. Most AEs were grade 1 to 2 with relatively 
few related grade 3 to 4 AEs. Most high-grade events were manageable with the use of 
corticosteroids or hormone replacement therapy (endocrinopathies) as instructed in the 
management algorithms provided in nivolumab investigator brochure.(3) In CA209003 (n=306, 
including 129 subjects with NSCLC), as of the 05-Mar-2013 data base lock, drug related AEs of 
any grade occurred in 75% of subjects. The most frequent drug-related AEs occurring in > 5% of 
subjects included fatigue (28%), rash (15%), diarrhea (13%), pruritis (11%), nausea (9%), 


 
 
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decreased appetite (9%), hemoglobin decreased (6%) and pyrexia (6%). The majority of events 
were low grade, with grade 3/4 drug-related AEs observed in 17% of patients. The most common 
Grade 3/4 drug-related AEs occurring in > 1% of subjects were fatigue (2%), pneumonitis (1%), 
diarrhea (1%), abdominal pain (1%), hypophosphatemia (1%), and lymphopenia (1%).  
1.4.2.3 Nivolumab Flat Dosing 
Nivolumab monotherapy has been extensively studied in a number of tumor types including 
NSCLC, MEL, RCC, and CRC with body weight normalized dosing (mg/kg). Nivolumab 
pharmacokinetics (PK) and exposures of subjects in these studies have been characterized by 
population pharmacokinetic (PPK) analysis of data collected these studies, together with PK data 
from several phase 1, 2, and 3 clinical studies of nivolumab monotherapy in solid tumors. 
Population PK (PPK) analyses have shown that the PK of nivolumab are linear, with dose 
proportional exposures over a dose range of 0.1 mg/kg to 10 mg/kg, and are similar across tumor 
types. Nivolumab clearance and volume of distribution were found to increase with increasing 
body weight, but the increase was less than proportional, indicating that an mg/kg dose 
represents an over-adjustment for the effect of body weight on nivolumab PK. Given the 
relationship between nivolumab PK and body weight, a flat dose is expected to lead to lower 
exposures in heavier patients, relative to the exposures in lighter patients.  
Using the PPK model, nivolumab steady-state trough, peak and time-averaged concentration 
(Cminss, Cmaxss, and Cavgss, respectively) were predicted for a flat nivolumab dose of 240 mg 
Q2W and compared to those following administration of 3 mg/kg Q2W in NSCLC subjects. A 
dose of 240 mg nivolumab is identical to a dose of 3 mg/kg for subjects weighing 80 kg, which is 
the approximate median body weight of NSCLC subjects in the 3 Phase 2 and 3 BMS clinical 
studies of nivolumab monotherapy.  The geometric mean values of Cminss, Cmaxss, and Cavgss 
with flat dosing are slightly (< 15%) higher than that produced by a 3 mg/kg dose, and the 
coefficient of variation (cv%) in these measures of exposure are only slightly (< 10%) greater 
than that of 3 mg/kg dosing.  
Across the various tumor types in the BMS clinical program, nivolumab has been shown to be 
safe and well tolerated up to a dose level of 10 mg/kg, and the relationship between nivolumab 
exposure produced by 3 mg/kg and efficacy has been found to be relatively flat. Taken together, 
the PK, safety, and efficacy data indicate that the safety and efficacy profile of 240 mg 
nivolumab will be similar to that of 3 mg/kg nivolumab. 
Thus a flat dose of 240 mg every 2 weeks is recommended for investigation in this study. 
Additional studies have indicated that the safety and efficacy of a flat dose of 360 mg every 3 
weeks will be similar to 3 mg/kg every 2 weeks, and the 360 mg flat dose every 3 weeks will 
also be used for investigation in this study.  
1.4.2.4 Nivolumab Second-Line NSCLC 
Nivolumab was compared to docetaxel as second-line therapy in advanced stage NSCLC in two 
randomized phase 3 trials, one trial for squamous histology and the other trial for non-squamous 
histology (1, 2). In the BMS017 trial for second-line squamous cell lung cancer, overall survival 
was 9.2 months with nivolumab and 6.0 months with docetaxel, HR 0.59 and p < 0.001(1). In the 
BMS057 trial for second-line non-squamous lung cancer, overall survival was 12.2 months for 
nivolumab and 9.4 months for docetaxel, HR 0.73 and p = 0.0015 (2). In both trials, total all 


 
 
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grade and total high grade toxicities were less with nivolumab compared with docetaxel. 
Nivolumab has been FDA approved for previously treated squamous and non-squamous lung 
cancer.    
 
1.4.2.5 Nivolumab plus Chemotherapy 
In study CA209012, patients with treatment naïve advanced stage NSCLC received nivolumab 
combined with platinum based chemotherapy doublets: gemcitabine, pemetrexed, or paclitaxel 
(7).  Nivolumab 10 mg/kg or 5mg/kg was given every 21 days with 4 cycles of standard dose 
chemotherapy followed by nivolumab maintenance.  In general, the 4 cycles of combined 
therapy were safe and feasible with the majority of treatment related adverse events leading to 
therapy discontinuation occurring during the nivolumab single agent maintenance phase. There 
was evidence of possible additive therapeutic benefit for the combination compared to what 
would be expected for chemotherapy or nivolumab alone with overall response rates of 40%, 
promising 1 year survival, and a number of durable responses. 
1.5. Risks and Benefits 
In this randomized phase 2 trial, the control arm will be nivolumab single agent immune therapy 
for previously treated, advanced stage non-small cell lung cancer for which it is FDA approved. .   
Immune therapy for previously treated, non-small cell lung cancer has produced durable 
responses and improved overall survival compared to standard docetaxel chemotherapy but 
disappointingly short progression free survival.  The experimental arm combines nab-paclitaxel 
to nivolumab therapy in an attempt to avoid early cancer progression on nivolumab alone, and 
enhance tumor antigen presentation to the immune system through chemotherapy induced tumor 
cell apoptosis. There is the possibility of additive typical chemotherapy toxicity and immune 
therapy toxicity with the combination of therapy. However nivolumab has been combined with 
platinum based doublets chemotherapy in untreated, advanced stage non-small cell lung cancer 
without excess toxicity. Similarly nab-paclitaxel chemotherapy combinations have been 
successfully combined with PD1 checkpoint antibody therapy, and nab-paclitaxel chemotherapy 
is the backbone of  several large randomized, phase 3 clinical trials studying PD1 checkpoint 
therapy in previously untreated, advanced stage non-small cell lung cancer.  Based on the 
empiric safety data from several clinical trials, it seems likely that the nab-paclitaxel and 
nivolumab combination will be generally safe and feasible in previously treated non-small cell 
lung cancer. This will be one of the first trials to test whether the addition of a well-tolerated 
single chemotherapy agent improves therapeutic efficacy when added to the PD1 masking 
antibody nivolumab for patients with previously treated NSCLC. 
2. Objectives and Endpoints 
2.1. Primary Objectives 
The primary objective of this study is to determine whether progression-free survival of patients 
with advanced stage non-small cell lung cancer whose cancer has progressed after standard first-
line platinum based doublet chemotherapy is improved with nivolumab plus nab-paclitaxel 
compared to nivolumab alone.  


 
 
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2.2. 
Secondary Objectives 
The secondary objectives of this study are: 
1. To evaluate the difference of response rates between two treatments. 
2. To evaluate the difference of overall survivals between two treatments. 
3. To characterize treatment related adverse events.  
4. To characterize progression-free for PDL1 positive (> 1% tumors positive) and PDL1 negative 
tumors.  
2.3. 
Exploratory Objectives 
 
1. To study immunologic biomarkers in the blood before and after nab-paclitaxel plus 
nivolumab. 
2. To study immunologic biomarkers in the tumor at baseline before nab-paclitaxel plus 
nivolumab. 
3.  To evaluate the difference of response rates in squamous cell lung cancer between the two 
treatments. 
4. To evaluate the difference in progression free survival in squamous cell lung cancer between 
the two treatments. 
5. To evaluate the difference in overall survival.  
6. To compare clinical outcomes for PDL1 positive and PDL1 negative tumors.  
7. To compare rate of deaths in the first 3 months between the two treatments.  
8. To compare characteristics of tumors for deaths in the first 3 months compared to those living 
more than 3 months.  
2.4. 
Endpoints 
 
The primary endpoint for this trial is improvement of progression free survival.  
 
Secondary endpoints are: 
1. Evaluation of response rate 
2. Overall survival 
3. Adverse events  


 
 
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2.5. Rationale for Endpoints 
2.5.1 Primary and Secondary Endpoints 
Progression of NSCLC is often accompanied by morbidity. Evaluating for an improvement in 
progression free survival is a feasible and clinically significant primary endpoint. Secondary 
endpoints of evaluation of response rate, overall survival, and adverse events are other standard 
clinical endpoints. 
2.5.2 Correlative Science Endpoints 
Program death receptor ligand 1 (PDL1) Dako IHC 28-8 assay is an FDA approved 
complementary diagnostic for nivolumab. PDL1 will be assessed retrospectively to determine 
whether PDL1 status is associated with benefit for the nivolumab and nab-paclitaxel study 
combination. Blood immune biomarkers will be evaluated in a secondary exploratory analysis. 
Archival tissue will be collected at baseline for all participants, and from patients who agree to 
an optional biopsy at progression.     
Markers of inflammation will be analyzed in the Duke Phase I Biomarker Lab, which serves as a 
core lab for these analyses for the NCI’s NCTN Alliance Trials Group. Analyses will be 
performed on pre-treatment and on-treatment plasma samples and on samples at disease 
progression as described in Section 12.   
2.6. 
Future Biomedical Research 
Tumor tissue, blood and plasma specimens will be collected at baseline as part of this study. 
Additional tissue, blood and plasma specimens will be collected during the study (See Protocol 
Section11). In addition to analysis of PDL1 expression, collected biospecimens may also be used 
to evaluate nucleic acid, proteomic, and/or metabolic biomarkers of response and outcome.  
All collected biospecimens will be stored in the Alliance Foundation Biorepository (AFB), until 
biospecimen accrual and clinical follow up is sufficiently complete to allow for the design and 
execution of specific correlative analyses.  
All collected biospecimens will be stored in the Alliance Foundation Biorepository (AFB), a 
CAP-accredited biorepository at Washington University in St. Louis, until biospecimen accrual 
and clinical follow-up is sufficiently complete to allow for the design and execution of specific 
correlative analyses using ‘state-of-the-art’ analytical platforms that will be available at that 
time.  
Such biomarker research will address emergent questions not described elsewhere in this 
protocol and will only be conducted on specimens from appropriately consented patients. The 
objective of collecting specimens for future biomedical research is to explore and identify 
biomarkers that inform the scientific understanding of disease and/or their therapeutic treatments 
in the context of this trial. Proposals for future correlative research will undergo rigorous 
scientific, programmatic, and statistical review by AFT, and biospecimens will only be released 
to those investigators who have obtained appropriate regulatory approval and demonstrate 
adequate funding to successful complete proposed research aims. AFT will ensure that all 
collected specimens are used only for approved research protocols.  


 
 
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Anonymized (de-identified) data generated from biospecimens used for future correlative 
research, including somatic and constitutional (germline) genomic data, may be shared with 
other researchers or deposited in a publicly accessible or controlled-access data repositories. 
Correlative study results and data will never be returned to individual patients.  
3. Patient Selection/Population 
3.1. 
Inclusion Criteria 
 
1. Histologically or cytologically confirmed, Stage IV non-small cell lung cancer (per 
the Union Internationale contre le Cancer/American Join Committee on Cancer 
staging system, 7th edition) or recurrent incurable non-small cell lung cancer that has 
progressed after first-line chemotherapy. 
2. Prior Therapy: Platinum doublet chemotherapy for current diagnosis of advanced 
lung cancer. Only one prior line of chemotherapy for advanced lung cancer allowed. 
Adjuvant chemotherapy, neoadjuvant chemotherapy, or chemoradiotherapy given for 
early stage lung cancer at least 6 months prior to diagnosis of recurrent/metastatic 
disease is not counted as a line of therapy for advanced lung cancer. Patients who 
received platinum doublet therapy with or without radiotherapy as part of treatment 
for early stage non-small cell lung cancer less than 6 months after developing stage 4 
or recurrent incurable disease will be considered study eligible by the criterion of 
having received one line of chemotherapy for non-small cell lung cancer.     
3. EGFR, ALK and ROS biomarker positive tumors are eligible as long as the patient 
has received at least one standard oral, molecular inhibitor therapy in addition to 
standard platinum doublet chemotherapy. More than one molecular inhibitor is 
allowed such as a first generation EGFR inhibitor followed by a next generation 
EGFR inhibitor when T790 mutation develops. Prior molecular therapy for biomarker 
positive tumors such as (but not limited to) MET, RET and BRAF allowed but not 
required.  
4. Prior chemotherapy must have been completed 21 days prior to initiation of protocol 
therapy and all toxicities must < grade 2.  
5. Patients must have < Grade 2 or pre-existing neuropathy (per CTCAE).  
6. Palliative radiation must have been completed 2 weeks prior to the initiation of study 
therapy.    
7. All patients must have measurable disease. 
Measurable disease is defined as at least one lesion that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as ≥ 20mm with 
conventional techniques or as ≥10mm with spiral CT scan.  
8. ECOG Performance Status: 0-1 
9. Second malignancy: No “currently active” second malignancy other than non-
melanoma skin cancers.  
10. Brain metastases: brain metastases must have been treated at least 2 weeks prior to 
enrollment, be asymptomatic from brain metastases, stable on brain imaging, and not 
be receiving a supra-physiologic dose of steroids (> 10 mg prednisone daily or 
equivalent).  


 
 
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11. Non-pregnant and non-nursing. The effect of nab-paclitaxel and nivolumab on the 
fetus is unknown.  
12. Women of childbearing potential (WOCBP) must be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 6 months after the last dose of study medication. Patients of 
childbearing potential are those who have not been surgically sterilized or have not 
been free of menses > 1 year.   
13. Male patients must agree to use an adequate method of contraception starting with the 
first dose of study therapy through 7 months after the last dose of study therapy.   
14. Age ≥18 years.  
15. Required Initial Laboratory Values:  
 
Leukocytes 
 
≥2000/ µl 
Hemoglobin  
 
>9.0 g/dL 
Platelets 
 
 
≥100,000/ µl 
ANC  
 
 
≥1,500/mcL 
 
Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) 
≥ 40 mL/min (if using the Cockcroft-Gault formula below): 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
                           72 x serum creatinine in mg/dL 
 
Male CrCl = (140 - age in years) x weight in kg x 1.00  
 
Total Bilirubin 
<1.5 mg/dl (except for subjects with Gilbert 
Syndrome, who can have total bilirubin < 3.0 
mg/dl) 
SGOT (AST)  
 
<2.5 x ULN  
ALP  
 
 
 
<2.5 x ULN in absence of liver metastases (<5 x 
ULN if liver metastases present 
PTT 
 
 
 
<1.5 x ULN 
 
16. An archival tumor sample from either a prior core needle biopsy or surgical specimen 
must be available to be submitted for correlative studies as an eligibility requirement 
prior to registration. The sample must be shipped within 6 weeks of enrollment. 
Participants without an available archival tumor sample are considered ineligible.  
 
3.2. 
Exclusion Criteria 
1. Prior nab-paclitaxel chemotherapy excluded.  
2. Prior immune therapy for NSCLC excluded. Patients should be excluded if they have 
had prior treatment with an anti-PD-1, anti-PD-L1, anti PD-L2, anti-CTLA-4 
antibody, or any other antibody or drug specifically targeting T-cell costimulation or 
immune checkpoint pathways.  


 
 
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3. Patients will be excluded if they have an active, known or suspected autoimmune 
disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, 
residual hypothyroidism due to autoimmune condition only requiring hormone 
replacement, psoriasis not requiring systemic treatment, or conditions not expected to 
recur in the absence of an external trigger.  
4. Patients will be excluded if they have a condition requiring systemic treatment with 
either corticosteroids (>10mg/day prednisone equivalents) or other 
immunosuppressive medications within 14 days of study drug administration. Inhaled 
or topical steroids and adrenal replacement doses >10 mg daily prednisone 
equivalents are permitted in the absence or active autoimmune disease.  
5. Patients should be excluded if they test positive for hepatitis B virus surface antigen 
(HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or 
chronic infection.  
6. Patients should be excluded if they have known history of testing positive for human 
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome 
(AIDS). 
7. Allergies and Adverse Drug Reaction: History of allergy to study drug components 
3.3. 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
4. Method of Treatment Assignment/ (Patient Numbering and Treatment Assignment) 
4.1. 
Site Enrollment Requirements 
Site must submit all required essential documents including:  
• IRB/Regulatory Approval 
• Investigator 1572 
• Institutional informed consent form  
• Essential documents must be submitted to the AFT electronic Trial Master File, accessible 
via the AFT website, https://alliancefoundationtrials.org/. 
 
4.2. 
Patient Enrollment/Randomization Procedure 
Informed consent: The patient must be aware of the neoplastic nature of his/her disease and 
willingly consent after being informed of the procedure to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Current 
human protection committee approval of this protocol and a consent form is required prior to 
patient consent and enrollment.  
Patients with impaired decision making capacity may be enrolled on this study, where 
institutional policy and IRB of record allow.  
Patient enrollment will be facilitated using the AFT web-based IRT (interactive response 
technology) system, accessible via the AFT website, https://alliancefoundationtrials.org/. 


 
 
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Patient must be enrolled prior to submission of biospecimens. After written informed consent has 
been obtained, the study site will obtain a unique patient identifier, which will stay the same 
throughout the entire study. Patients enrolled but not randomized for any reason have to be 
documented as a Screening Failure in IRT.  
Prior to accessing IRT, site staff should verify the following:  
• All eligibility criteria have been met within the protocol stated timeframes. 
• All patients have signed an appropriate consent from and HIPAA authorization form 
The AFT IRT system will provide the site with a confirmation of enrollment and treatment 
randomization information. Please retain this confirmation for your records.  
4.3. 
Patient Numbering 
After written informed consent has been obtained, the study site will obtain a unique patient 
identifier, which will stay the same throughout the entire study. 
4.4. Stratification Factors 
Patients will be stratified by: 
1) Squamous versus non-squamous histology (any histology not specified squamous only 
will be stratified as non-squamous) 
2) History of prior taxane therapy (nab-paclitaxel excluded). 
3) History of smoking versus never smoking  
4.5. Treatment Assignment 
Patients who have progression of disease after first-line platinum based doublet chemotherapy 
will be randomized to receive nivolumab alone or nivolumab plus nab-paclitaxel.  
4.6. 
Treatment Blinding 
N/A 
5. Treatment Plan 
5.1. Treatment Regimen 
 Following screening for eligibility, informed consent, and screening procedures, patients will be 
randomized to one of the following treatment arms:  
Arm A: Nivolumab 240 mg via intravenous infusion (IV) over 30 minutes day 1 of each 14 day 
cycle until disease progression or not tolerated.  
Arm B: Nivolumab 360 mg via intravenous infusion (IV) over 30  minutes day 1 of every 21 day 
treatment cycle until progression or not tolerated. Patients in this arm will also receive nab-
paclitaxel at a dose of 100 mg/m2 over intravenous infusion on Days 1 and 8 of each 21 day 
cycle.  
All therapy will be in the outpatient setting. 


 
 
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Patients on both arms will receive a maximum of 12 months of study therapy. Patients who 
tolerate therapy with tumor control at 12 months may be retreated if they experience tumor 
progression after discontinuation.  
See Section 9.1.1 for expected toxicities.  
5.2. Pre-Treatment Criteria 
• 
C1D1 results need to re-meet eligibility parameters Day 1 of each cycle to start treatment.   
• 
Day 1 labs need to be reviewed before initiating treatment. 
Laboratory values before C1D1 and each cycle day 1 of study treatment must be within 
parameters set forth in Section 3.1 (Inclusion Criteria) above. For Arm B day 8 of each cycle see 
nab-paclitaxel dose modifications Section 6.   
5.3. Agent Administration 
 
Arm A: Nivolumab will be administered as an approximate 30 minute IV infusion on Day 1 of 
every 14 day cycle at a dose of 240mg.  Participants may be dosed no less than 12 days from the 
previous dose of the drug.  
 
Arm B: Nivolumab will be administered as a 30 minute IV infusion on Day 1 of every 21 day 
cycle at a dose of 360mg. Subjects in this arm will also receive nab-paclitaxel via IV infusion on 
Days 1 and 8 of each 21 day cycle at a dose of 100 mg/m2 per institutional standards. Per 
Investigator’s Brochure, limiting the infusion to 30 minutes is recommended to minimize risk of 
infusion reactions.  
 
On the day of infusion, nivolumab is to be administered first. Infusion of nab-paclitaxel will start 
at least 30 minutes after completion of the nivolumab infusion.  
 
There are no premedications recommended for nivolumab on the first cycle.  
Nab-paclitaxel premedications are as per institutional standard.  
 
Subjects on both arms should be carefully monitored for infusion reactions during nivolumab 
administration. If an acute reaction is noted, subjections should be managed according to 
Protocol Section 6.2.7.  
 
Doses of nivolumab may be interrupted, delayed or discontinued depending on how well the 
subject tolerates the treatment. Dose reductions or escalations of nivolumab are not permitted.  
 
Dose reductions or discontinuation may be needed for nab-paclitaxel based on severe 
hematologic, neurologic, cutaneous, or gastrointestinal toxicities. Please see Section 6 for more 
information.  
5.4. Order of Administration 
On Arm B nivolumab will be administered first followed by nab-Paclitaxel (see above).  


 
 
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5.5. 
Supportive Care and Concomitant Medications 
• 
 Patients should not receive any other agent which would be considered treatment for 
the primary neoplasm or impact the primary endpoint.  
• 
As there is potential for hepatic toxicity with nivolumab, drugs with a predisposition 
to hepatoxicity should be used with caution in patients treated with nivolumab-
containing regimen.  
• 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study treatment 
administration until 30 days after the final dose will be recorded in the medical records.  
• 
Treatment with hormones or other chemotherapeutic agents may not be administered 
except for steroids given for adrenal failure; hormones administered for non-disease-
related conditions (e.g., insulin diabetes); and intermittent use of dexamethasone as an 
antiemetic in solid tumor protocols. Corticosteroids may be given for treatment of drug-
related adverse events (see section 17.4).  
• 
Antiemetics may be used at the discretion of the attending physician. 
• 
Diarrhea: Diarrhea can occur as a part of autoimmune side effect of nivolumab. For 
diarrhea diagnosed as related to nivolumab, treatment should be according to the 
nivolumab side effect management algorithms (Appendix II). 
For diarrhea not caused by nivolumab, this could be managed conservatively with 
loperamide. The recommended dose of loperamide is 4 mg at first onset, followed by 2 mg 
every 2-4 hours until diarrhea free (maximum 16mg/day).  
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreocide, and antidiarrheals.  
If diarrhea is severe (requiring intravenous rehydration) and/or associated with a fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed. Patients 
with severe diarrhea or any diarrhea associated with severe nausea or vomiting should be 
hospitalized for intravenous hydration and correction of electrolyte imbalances.  
• 
Palliative radiation therapy may be administered if repeat imaging demonstrates no new 
sites of bone metastases and the lesion being considered for palliative radiation is not a 
target lesion. (see section 13.1.2 for exception regarding pseudoprogression)   
Whole-brain irradiation given for documented CNS disease may NOT be administered. 
Hold protocol therapy during irradiation. Irradiate a symptomatic lesion, or one that may 
produce disability (e.g., unstable femur) prior to study initiation, provided other 
measurable disease is present.  


 
 
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Patients who require radiation therapy due to disease progression during protocol 
treatment will be removed from protocol therapy. Patients who require palliative radiation 
due to exacerbation of pain at a pre-existing tumor site that does not qualify as tumor 
progression may continue on protocol therapy after discussion with and approval from the 
principal investigator.  
5.6. 
AFT Policy Concerning the Use of Growth Factors 
• Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations. The use of growth factors should follow 
published guidelines of the American Society of Clinical Oncology 2006 Update of 
Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based, 
Clinical Practice guideline. J Clin Oncol 24(19): 3187-3205, 2006.  
• Epoetin (EPO): Use of epoetin in this protocol is prohibited OR permitted at discretion of 
the treating physician.  
• Filgrastim (G-CSF) and sargramostim (GM-CSF) 
1. Filgrastim (G-CSF)/pegfilgrastim and sargramostim (GM-CSF) treatment for patients 
on this study is not allowed in patients who have not had febrile neutropenia or 
another standard clinical indication for CSF support while on study therapy. 
Nivolumab with or without nab-paclitaxel would be considered low risk for severe 
neutropenia and/or febrile neutropenia.   
2. Filgrastim/pegfilgrastim and sargramostim may not be used: 
a. To avoid dose reductions, delays or to allow for dose escalations specified in 
the protocol. 
b. For the treatment of the febrile neutropenia the use of CSFs should not be 
routinely instituted as an adjunct to appropriate antibiotic therapy. However, 
the use of CSFs may be indicated in patients who have prognostic factors that 
are predictive of clinical deterioration such as pneumonia, hypotension, multi-
organ dysfunction (sepsis syndrome) or fungal infection, as per the ASCO 
guidelines. Investigators should therefore use their own discretion in using the 
CSFs in this setting. The use of CSF (filgrastim/pegfilgrastim or sagramostim) 
must be documented and reported (e.g. on CRFs per protocol requirements).  
c. If filgrastim/pegfilgrastim or sargramostim are used, they must be obtained 
from commercial sources.  
6. Dose and Treatment Modifications  
6.1. Nab-Paclitaxel Dose Modifications  
• If multiple adverse events are seen, administer dose modification based on greatest 
reduction required for any single adverse event observed. Reductions apply to treatment 
given in the preceding cycle and are based on adverse events observed since the prior dose.  
• Nab-paclitaxel will not be re-escalated once reduced. If more than 2 dose reductions for nab-
paclitaxel are required, nab-paclitaxel will be discontinued.  
Expedited reporting may be required for some adverse events (See Section 9.1.3). 
 


 
 
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6.1.1 Nab-Paclitaxel Dose Levels  
 
Table 1 
Dose 
Level 
Drug Name 
Dose 
+1 
 
No dose level +1, not applicable 
NA 
 0* 
 
Nab-paclitaxel 
100 mg/m2 IV 
-1 
 
Nab-paclitaxel 
75 mg/m2 IV 
-2 
 
Nab-paclitaxel 
50 mg/m2 IV 
 
*Dose level 0 refers to the starting dose.  
6.1.2 Hematologic Adverse Event 
6.1.2.1 Nab-paclitaxel dose guidelines for Day 1 hematologic adverse events 
For ANC < 1500 or platelets < 100,000 on Day 1, delay treatment and repeat CBC 
weekly. Resume treatment when ANC improves to ≥ 1500 platelets improve to ≥ 
100,000.  
• If treatment was delayed for 1 week, resume treatment at the previous doses of 
Nab-paclitaxel.  
• If treatment was delayed for more than one week and less than six weeks, reduce 
Nab-paclitaxel by one dose level for this and all subsequent cycles.  
For delays of 6 weeks or greater, discontinue Nab-paclitaxel for this and all subsequent 
doses.  
6.1.2.2 Nab-paclitaxel dose modifications for Day 8 hematologic adverse event 
For ANC 500-999 or platelets 50,000 – 74,999, decrease Nab-paclitaxel by one dose 
level for this and all subsequent doses.  
For ANC < 500 or platelets < 50,000, skip Nab-paclitaxel and decrease Nab-paclitaxel by 
one dose level for all subsequent doses.  


 
 
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6.1.2.3 Febrile neutropenia 
For febrile neutropenia (defined as temperature ≥ 38.5° C [101° F] sustained for more 
than one hour concomitant with ANC < 500/mm3), reduce Nab-paclitaxel by one dose 
level for this and subsequent cycles.  
6.1.3 Nab-paclitaxel dose modifications for gastrointestinal adverse event 
For grade 3 or 4 nausea or vomiting despite maximal antiemetic therapy (including 5HT-
3 antagonist, corticosterious, and aprepitant), discontinue Nab-paclitaxel.  
If the gastrointestinal adverse event is not consistent with autoimmune inflammatory 
bowel syndrome, continue nivolumab at the previous dose when symptoms resolve to ≤ 
grade 1.  
6.1.4 Neurotoxicity  
For grade 3 sensory or motor neuropathy, skip Nab-paclitaxel until the adverse event 
resolves to ≤ grade 1 and then resume therapy with one dose level reduction of Nab-
paclitaxel on Day 1 of the next scheduled cycle. If Nab-paclitaxel is skipped for two 
consecutive cycles, discontinue Nab-paclitaxel. Treatment with nivolumab may continue.  
For grade 4 sensory or motor neuropathy, skip all therapy until resolution to ≤ grade 2, 
discontinue Nab-paclitaxel; resume nivolumab at the previous dose.  
6.1.5 Cardiotoxicity 
Cardiotoxicity may include events of cardiac disorders, myocardial disorders, cardiac 
failure, angina, tachycardia, bradyarrhythmias, or ventricular arrhythmias.  
In clinical studies, the frequency of cardiotoxicity was 4% for nab-paclitaxel in 
monotherapy studies/indications; and was reported in 6% for nab-paclitaxel in 
combination with gemcitabine.  
Cardiac events are not uncommon in the indicated population, especially those who have 
previously received anthracyclines or have underlying cardiac or pulmonary disease. 
Therefore, patients receiving nab-paclitaxel should be vigilantly monitored for the 
occurrence of cardiac events.  
6.1.6 Nab-paclitaxel Hypersensitivity and/or Infusion Reactions 
Nab-paclitaxel is unlikely to be immunogenic and induce infusion or hypersensitivity 
reactions. However, if such a reaction were to occur, it might manifest with fever, chills, 
rigors, headache, rash, pruritis, arthralgias, hypo- or hypertension, bronchospasm, or 
other symptoms of allergic-like reactions.  
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. 
Infusion reactions should be graded according to NCI CTCAE Version 4.0 guidelines. 
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines as appropriate:  


 
 
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For Grade 1 symptoms: Mild reaction; infusion interruption not indicated; intervention 
not indicated. 
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 
mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 
minutes before additional nab-paclitaxel administrations.  
For Grade 2 symptoms: Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g. antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for 24 hours.  
Stop the nab-paclitaxel infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 
mg (acetaminophen); remain at bedside and monitor subject until resolution of 
symptoms. Corticosteroid or bronchodilator therapy may also e administered as 
appropriate. If the infusion is interrupted, then restart the infusion at 50% of the original 
infusion rate when symptoms resolve; if no further complications ensue after 30 minutes, 
the rate may be increased to 100% of the original infusion rate. Monitor subject closely. 
If symptoms recur then no further nab-paclitaxel will be administered at that visit. 
Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the subject 
until resolution of symptoms. The amount of study drug infused must be recorded on the 
electronic case report form (eCRF). The following prophylactic premedications are 
recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or 
paracetamol 325 to 1000 mg (acetaminophen) should be administered at least 30 minutes 
before additional nab-paclitaxel administrations. If necessary, corticosteroids 
(recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be used.  
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not 
rapidly responsive to symptomatic medication and/or brief interruption of infusion]; 
recurrence of symptoms following initial improvement; hospitalization indicated for 
other clinical sequelac [eg, renal impairment, pulmonary infiltrates]). Grade 4: (life 
threatening; pressor or ventilatory support indicated).  
Immediately discontinue infusion of nab-paclitaxel. Begin an IV infusion of normal 
saline, and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 
mg of a 1: 1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1: 
10,000 solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV 
with methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be 
monitored until the investigator is comfortable that the symptoms will not recur. Nab-
paclitaxel will be permanently discontinued. Investigators should follow their 
institutional guidelines for the treatment of anaphylaxis. Remain at bedside and monitor 
subject until recovery from symptoms.  


 
 
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In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritis within 1 week after treatment), symptomatic treatment may be given 
(eg, oral antihistamine or corticosteroids).  
6.2. 
Nivolumab 
6.2.1 Nivolumab Dose Modifications 
Dose reductions or dose escalations are not permitted for nivolumab.  
6.2.2 Dose Delay Criteria 
Because of the potential for clinically meaningful nivolumab-related AEs requiring 
early recognition and prompt intervention, management algorithms have been 
developed for suspected AEs of selected categories. See Appendix II.  
Dose delay criteria apply for all drug related adverse events (regardless of whether or not 
the event is attributed to nivolumab). All study drugs must be delayed until treatment can 
resume.  
Dose delay criteria apply for all drug-related AEs. Nivolumab must be delayed until 
treatment can resume.  
6.2.3 Nivolumab administration should be delayed for the following:  
Any Grade ≥ 2 non-skin, drug-related AE, with the following exceptions: 
1) Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment 
delay. 
2) Any Grade 2 skin, drug-related AE. 
3) Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
lymphopenia, leukopenia, AST, ALT, total bilirubin, or asymptomatic amylase or 
lipase: 
• Grade 3 lymphopenia or leukopenia does not require dose delay. 
• If a subject has a baseline AST, ALT, or total bilirubin that is within normal 
limits, delay dosing for drug-related Grade ≥ 2 toxicity. 
• If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity 
range, delay dosing for drug-related Grade ≥ 3 toxicity. 
• Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not associated 
with symptoms or clinical manifestations of pancreatitis does not require dose 
delay. The Investigator should be consulted for such Grade ≥ 3 amylase or lipase 
abnormalities. 
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication. 


 
 
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Subjects who require delay of nivolumab should be re-evaluated weekly or more 
frequently if clinically indicated and resume nivolumab dosing when re-treatment 
criteria are met. 
6.2.4 Criteria to Resume Treatment 
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to 
Grade ≤1 or baseline value, with the following exceptions: 
• Subjects may resume treatment in the presence of Grade 2 fatigue  
• Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity  
• Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose 
delays for reasons other than a 2-grade shift in AST/ALT or total bilirubin may 
resume treatment in the presence of Grade 2 AST/ALT OR total bilirubin 
• Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters should have treatment permanently discontinued 
• Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to 
baseline before treatment is resumed. Subjects with persistent Grade 1 pneumonitis 
after completion of a steroid taper over at least 1 month may be eligible for 
retreatment, if continued therapy is of likely clinical benefit and after discussion 
with and approval from the principal investigator. 
• Drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment.  
If the criteria to resume treatment are met, the subject should restart treatment at the next 
scheduled time point per protocol. However, if the treatment is delayed past the next 
scheduled time point per protocol, the next scheduled time point will be delayed until 
dosing resumes. 
If treatment is delayed or interrupted for > 6 weeks, the subject must be permanently 
discontinued from study therapy, except as specified in discontinuation section.  
6.2.5 Management Algorithms 
Guidelines for the management of immune related events can be found in the current 
Investigator Brochure AND in the approved USPI in the US. Investigators should decide 
the appropriate source of AE management for each protocol. 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and 
duration than AEs caused by other therapeutic classes. Nivolumab is considered an 
immuno-oncology agent in this protocol. Early recognition and management of AEs 
associated with immuno-oncology agents may mitigate severe toxicity. Management 
algorithms have been developed to assist investigators in assessing and managing the 
following groups of AEs: 
Gastrointestinal, Renal, Pulmonary, Hepatic, Endocrinopathies, Skin, Neurological. 


 
 
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For subjects expected to require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an AE, consider recommendations provided in the 
algorithms. These algorithms are found in the Nivolumab IB [and in Appendix] of this 
protocol. The guidance provided in these algorithms should not replace the Investigator’s 
medical judgment but should complement it. 
Management Algorithms are provided in Appendix II. 
6.2.6 Discontinuation Criteria 
Treatment should be permanently discontinued for the following: 
• 
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not 
respond to topical therapy and does not improve to Grade 1 severity within the re-
treatment period OR requires systemic treatment  
• 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the 
following exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, 
bronchospasm, hypersensitivity reactions, and infusion reactions, and endocrinopathies: 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity 
reaction, or infusion reaction of any duration requires discontinuation 
o Grade 3 drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation 
o Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except those noted below 
• Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation 
• Any drug-related liver function test (LFT) abnormality that meets the 
following criteria require discontinuation:  
• 
AST or ALT > 8 x ULN 
 
• 
Total bilirubin > 5 x ULN 
• 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
• 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 
within 1 week of onset.  
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset 
o Grade 4 lymphopenia or leucopenia 


 
 
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o Grade 4 drug-related endocrinopathy adverse events, such as adrenal 
insufficiency, ACTH deficiency, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval 
from the  principal investigator. 
o Any dosing interruption lasting > 6 weeks with the following exceptions: 
o Dosing delays or interruptions to allow for prolonged steroid tapers to manage 
drug-related adverse events are allowed. Prior to re-initiating treatment in a 
subject with a dosing interruption lasting > 6 weeks, the Investigator must be 
consulted. Tumor assessments should continue as per protocol even if dosing is 
interrupted or delayed 
o Dosing interruptions or delays lasting > 6 weeks that occur for non-drug-related 
reasons may be allowed if approved by the Investigator. Prior to re-initiating 
treatment in a subject with a dosing interruption lasting > 6 weeks, the 
Investigator must be consulted. Tumor assessments should continue as per 
protocol even if dosing is interrupted 
o Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the Investigator, presents a substantial clinical risk to the subject with 
continued nivolumab dosing 
6.2.7 Treatment of Nivolumab Related Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely 
to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, 
pruritis, arthralgias, hypo- or hypertension, bronchospasm, or other symptoms of allergic-
like reactions.  
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. 
Infusion reactions should be graded according to NCI CTCAE Version 4.0 guidelines. 
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines as appropriate: 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention 
not indicated). 
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 
mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 
minutes before additional nivolumab administrations. 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for 24 hours). 


 
 
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Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject 
with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor subject closely. If symptoms 
recur then no further nivolumab will be administered at that visit. Administer 
diphenhydramine 50 mg IV, and remain at bedside and monitor the subject until 
resolution of symptoms. The amount of study drug infused must be recorded on the 
electronic case report form (eCRF). The following prophylactic premedications are 
recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or 
paracetamol 325 to 1000 mg (acetaminophen) should be administered at least 30 minutes 
before additional nivolumab administrations. If necessary, corticosteroids (recommended 
dose: up to 25 mg of IV hydrocortisone or equivalent) may be used. 
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not 
rapidly responsive to symptomatic medication and/or brief interruption of infusion]; 
recurrence of symptoms following initial improvement; hospitalization indicated for 
other clinical sequelae [eg, renal impairment, pulmonary infiltrates]). Grade 4: (life 
threatening; pressor or ventilatory support indicated).  
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline, 
and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of 
a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 
solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored 
until the investigator is comfortable that the symptoms will not recur. Nivolumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for 
the treatment of anaphylaxis. Remain at bedside and monitor subject until recovery from 
symptoms.  
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritis within 1 week after treatment), symptomatic treatment may be given 
(eg, oral antihistamine, or corticosteroids). 
6.3. 
Dose Modifications for Obese Patients 
There is no clearly documented adverse impact of treatment of obese patients when 
dosing is performed according to actual body weight. Therefore, all dosing is to be 
determined solely by actual weight without any modification unless explicitly described 
in the protocol. This will eliminate the risk of calculation error and the possible 
introduction of variability in dose administration. Failure to use actual body weight in the 
calculation of drug dosages will be considered a major protocol deviation. Physicians 
who are uncomfortable with calculating doses based on actual body weight should 
recognize that doing otherwise would be a protocol violation. Physicians may consult the 
published guidelines of the American Society of Clinical Oncology Appropriate 


 
 
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Chemotherapy Dosing for Obese Adult Patients with Cancer: American Society of 
Clinical Oncology Clinical Practice Guideline.  J Clin Oncol 30(13): 1553-1561, 2012. 
7. Study Assessments and Procedures 
7.1. 
Assessment Types 
7.1.1 
Efficacy Assessments 
7.1.1.1 
Imaging Assessment Collection Plan 
For the purposes of this study, patients should be reevaluated with CT scan imaging to assess for 
progression of tumor every 6 weeks plus or minus 7 days for 48 weeks. Because progression free 
survival is the primary endpoint, imaging will be done every 6 week regardless of when therapy 
is given. 
After 48 weeks, imaging will be every 12 weeks and may be adjusted to conform to when the 
patient will receive therapy. 
For patients who cannot have CT scans, MRI may be substituted.       
 
7.1.2 
Safety and Tolerability Assessments and Procedures 
Medical history will be taken prior to enrollment on the study. The medical history will be 
reviewed for any changes at Day 1 of each cycle.  
Physical Examination and vital signs will be recorded prior to enrollment and at every treatment 
visit. On nivolumab single agent therapy (Arm A), physical examination and vital signs will be 
recorded every 14 days. On nivolumab plus nab-paclitaxel combination therapy (Arm B), 
physical examination and vital signs will be recorded day 1 and day 8 of each treatment cycle. 
Vitals signs may be measured per institutional standards.  
Laboratory Assessments will be done prior to each enrollment and at every treatment visit. On 
nivolumab single agent therapy (Arm A), laboratory assessments will be done every 14 days. On 
nivolumab plus nab-paclitaxel combination therapy (Arm B), laboratory assessments will be 
done day 1 and day 8 of each 1 day treatment cycle. Please see Section 8 below for a full table of 
study assessments.  
7.1.3 
Pharmacokinetics 
N/A 
7.1.4 
Biomarkers/Correlative Studies 
Nivolumab is FDA approved for non-small cell lung cancer previously treated with platinum 
based chemotherapy for both squamous and non-squamous histologies with no restriction by 
biomarker such as program death receptor ligand (PDL-1). PDL-1 tumor positivity enriches the 
chance of benefit from nivolumab therapy in non-small cell lung cancer.  
We will collect a tumor specimen at the time of enrollment in order to retrospectively assess 
whether expression of PDL-1 is associated with benefit from nab-paclitaxel in combination with 


 
 
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nivolumab. The discovery of blood immune biomarkers is of interest for immune checkpoint 
therapy, and will be investigated in an exploratory analysis.  
Blood and plasma biomarkers: Pre-treatment, post-treatment (at first restaging) and progression 
blood and plasma samples will be collected from patients in both arms for exploratory of 
analysis of various immune and inflammatory biomarkers.  Additional circulating, cell-free DNA 
(cfDNA) studies will also be conducted. See Section 12.  
Tumor biomarkers: An archival tumor sample from either a prior core needle biopsy or surgical 
specimen must be available to be submitted for correlative studies as an eligibility requirement 
prior to registration. The sample must be shipped within 6 weeks of enrollment. Based on the 
results from other multi-center studies it is estimated that 80% of specimens will be adequate to 
result PDL-1. FNAs and cytology specimens are not acceptable as the PD-L1 complementary 
diagnostic is not validated with such tumor collection methods. Biomarker testing such as tumor 
PDL-1 status will be tested retrospectively and will not be used to guide therapy. Tumor 
specimens may be archival and prior to first-line therapy. In addition, an additional tumor sample 
will be collected at progression with patient consent, when clinically feasible.  
7.1.5 
Patient Reported Outcomes 
N/A 


 
 
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8. Study Assessment Table 
Laboratory and clinical parameters during treatment are to be followed using individual institutional guidelines and the best clinical 
judgment of the responsible physician. It is expected that patients on this study will cared for by physicians experienced in the 
treatment and supportive care of patients on this trial. Laboratory assessments should be completed within 14 days of randomization. 
All other screening procedures will be done within 28 days of randomization.  
Table 2: Assessments and Procedures – Arm A – Nivolumab  
1 cycle = 14 days 
 
Frequency → 
Assessments↓ 
Screening 
Cycle 
1/Day 
 (+/- 3) 
Cycle 2+ 
/Day 
(+/- 3) 
End of Treatment/Early 
Discontinuation 
Follow Upf 
 
1 
1 
 
 
 
 
Tests and 
Observations 
History and Physical Exam 
X 
X 
X 
X 
 
X 
Vital Signs 
X 
X 
X 
 
X 
Height 
X 
 
 
 
 
Weight 
X 
X 
X 
 
X 
ECG 
X 
 
 
 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
 
X 
 
X 
X 
Laboratory 
Assessments 
Complete Blood Count, 
Differential, Platelets 
X 
X 
X 
 
X 
X 
 
X 
Serum Creatinine 
X 
X 
X 
 
X 
Albumin, Glucose 
X 
X 
X 
 
X 
AST, ALT, Alk, Phos, Bili 
X 
X 
X 
 
X 
BUN/serum urea 
X 
X 
X 
 
X 
Serum Chemistry (Ca, Mg, NA, 
K, Cl) 
X 
X 
X 
 
X 


 
 
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LDH, Amylase, Lipase  
X 
X (LDH 
only) 
X (LDH 
only) 
 
X  
TSH (Free T4 and Free T3) 
X 
Every 6 weeks  
 
 
Serum or Urine HCG 
Xa 
Every 6 weeks  
 
X 
HBV sAg and HCV Ab/ HCV 
RNAb 
X 
 
 
 
 
Pulse Oximetry 
X 
Xc 
Xc 
 
 
Staging 
Central Pathology Review for 
Eligibility 
X 
 
 
 
 
Brain Imaging (MRI or CT)d 
X 
 
 
 
 
Tumor Measurement 
Xe 
 
 
 
 
CT/MRI Chest/abdomen/pelvis 
X 
Every 6 Weeks for 48 
weeks 
Xg 
Every 12 weeks for 28 months 
from enrollment X 
Bone Scan 
 
 
 
 
 
Histologic Review 
X 
 
 
 
 
Correlative 
Assessments 
Archival Tumor Sample 
X 
 
 
 
 
Newly Obtained Biopsy 
(optional) 
 
 
 
Xi 
 
Whole Blood/Plasma Sampleh  
X 
 
 
X 
 
Study Drug 
Nivolumab 
 
X 
 
X 
 
 
 
a) 
A serum or urine pregnancy testing is required within 24 hours of study enrollment or randomization. After discontinuation from nivolumab, test should be repeated at 
approximately 30 days and approximately 70 days.  
b) 
Hepatitis B and C testing should be done within 28 days prior to first dose of nivolumab.  
c) 
Oxygen saturation by pulse oximetry at rest (also monitor amount of supplemental oxygen if applicable) should be assessed at each on-study visit prior to dosing.  
d) 
Brain scan will be performed at screening to identify patients with small asymptomatic brain lesions that should be tested prior to randomization. For patients with 
lesions at baseline, brain scans will be repeated every 12 weeks or sooner if clinically indicated. 
e) 
Baseline tumor assessments should be done within 28 days of study enrollment/randomization.  
f) 
Follow-Up visit will be 30 days from last dose of study treatment. In the long-term follow up phase, all patients are expected to be followed for progression free survival 
and overall survival every 6 months for 28 months from enrollment. 
g) 
Scan will be repeated if not performed within 6 weeks of last dose. 
h) 
Whole blood and plasma samples to study immunologic biomarkers will be collected pre-treatment, post-treatment (at first restaging), and at progression. 
i) 
Patients may consent to an optional tumor biopsy at progression.  
 
 


 
 
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Table 3: Assessments and Procedures – Arm B – Nivolumab + Nab-paclitaxel 
1 cycle = 21 days 
 
Frequency → 
Assessments↓ 
Screening 
Cycle 
1/Day 
 (+/- 3) 
Cycle 
2+ 
/Day 
(+/- 3) 
End of Treatment/Early 
Discontinuation 
Follow Upf 
1 
8 
 
1 
8 
 
 
 
Tests and 
Observations 
History and Physical Exam 
X 
X 
X 
X 
X 
 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
 
X 
ECG 
X 
 
 
 
 
 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
Assessments 
Complete Blood Count, 
Differential, Platelets 
X 
X 
X 
 
X 
X 
 
X 
Serum Creatinine 
X 
X 
 
X 
 
 
X 
Albumin, Glucose 
X 
X 
 
X 
 
 
X 
AST, ALT, Alk, Phos, Bili 
X 
X 
 
X 
 
 
X 
BUN/serum urea 
X 
X 
 
X 
 
 
X 
Serum Chemistry (Ca, Mg, NA, 
K, Cl) 
X 
X 
 
X 
 
 
X 
LDH, Amylase, Lipase  
X 
X 
 
X 
 
 
X 
TSH (Free T4 and Free T3) 
X 
Every 6 weeks  
 
 
Serum or Urine HCG 
Xa 
Every 6 weeks  
 
X 
HBV sAg and HCV Ab/ HCV 
RNAb 
X 
 
 
 
 
 
 
Pulse Oximetry 
X 
Xc 
 
Xc 
 
 
 
Staging 
Central Pathology Review for 
Eligibility 
X 
 
 
 
 
 
 


 
 
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Brain Imaging (MRI or CT)d 
X 
 
 
 
 
 
 
Tumor Measurement 
Xe 
 
 
 
 
 
 
CT/MRI Chest/abdomen/pelvis 
X 
Every 6 Weeks for 48 
weeks 
Xg 
Every 12 weeks for 28 
months from enrollment 
Bone Scan 
 
 
 
 
 
 
 
Histologic Review 
X 
 
 
 
 
 
 
Correlative 
Assessments 
Archival Tumor Sample 
X 
 
 
 
 
 
 
Newly Obtained Biopsy 
(Optional) 
 
 
 
 
 
Xi 
 
Whole Blood/Plasma Samplesh  
X 
 
 
 
 
X 
 
Study Drug 
Nivolumab 
 
X 
 
X 
 
 
 
Nab-paclitaxel 
 
X 
X 
X 
X 
 
 
a. 
A serum or urine pregnancy testing is required within 24 hours of study enrollment or randomization. After discontinuation from nivolumab, test should be repeated at 
approximately 30 days and approximately 70 days.  
b. 
Hepatitis B and C testing should be done within 28 days prior to first dose of nivolumab.  
c. 
Oxygen saturation by pulse oximetry at rest (also monitor amount of supplemental oxygen if applicable) should be assessed at each on-study visit prior to dosing.  
d. 
Brain scan will be performed at screening to identify patients with asymptomatic brain lesions that should be treated prior to randomization. For patients with lesions at 
baseline, brain scans will be repeated every 12 weeks or sooner if clinically indicated. 
e. 
Baseline tumor assessments should be done within 28 days of study enrollment/randomization.  
f. 
Follow-Up visit will be 30 days from last dose of study treatment. In the long-term follow up phase, all patients are expected to be followed for progression free survival 
and overall survival every 6 months for 28 months from enrollment. 
g. 
Scan will be repeated if not performed within 6 weeks of last dose. 
h. 
Whole blood and plasma samples to study immunologic biomarkers will be collected pre-treatment, post-treatment (at first restaging), and at progression. 
i. 
Patients may consent to an optional tumor biopsy at progression.  


 
 
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9. Adverse Events 
9.1. 
Adverse Events - General Overview 
Per the International Conference of Harmonisation (ICH) guidelines, an adverse event 
(AE) is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to 
have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product 
or protocol-specified procedure, whether or not considered related to the medicinal 
product or protocol-specified procedure.   
9.1.1 
Expected Toxicities 
Nivolumab: The most frequent drug-related AEs occurring in > 5% of subjects included 
fatigue (28%), rash (15%), diarrhea (13%), pruritis (11%), nausea (9%), decreased 
appetite (9%), hemoglobin decreased (6%) and pyrexia (6%). The majority of events 
were low grade, with grade 3/4 drug-related AEs observed in 17% of patients. The most 
common Grade 3/4 drug-related AEs occurring in > 1% of subjects were fatigue (2%), 
pneumonitis (1%), diarrhea (1%), abdominal pain (1%), hypophosphatemia (1%), and 
lymphopenia (1%). 
Nab-paclitaxel: The most clinically significant adverse reactions associated with the use 
of nab-paclitaxel across all studied indications are related to the blood and lymphatic 
system (neutropenia), the nervous system (peripheral neuropathy), the musculoskeletal 
system (arthralgia/myalgia), and the gastrointestinal system (nausea, vomiting, and 
constipation). Other adverse events include myelosuppression, cranial nerve palsies, 
pneumonitis, sepsis, cardiotoxicity, cystoid macular edema, acute renal failure and 
hemolytic-uremic syndrome. For a full list of expected toxicities, refer to the 
Investigator’s Brochure.  
9.1.2 
Routine Adverse Event Reporting 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Baseline conditions will be recorded as 
part of medical history during Screening.   Any new AEs or increase of a documented 
baseline condition after screening/history will be recorded from the time of signing 
informed consent through 100 days following cessation of treatment. All adverse events 
are entered into the eCRF in the Rave® Electronic Data Capture (Rave EDC) system. 
SAEs will be collected for 100 days after the last treatment.  Treatment-related adverse 
events should be followed to resolution or stabilization (≤Grade 2). Adverse events 
should be followed for resolution or stabilization, or reported as SAEs if they become 
serious. Follow-up is also required for adverse events that cause interruption or 


 
 
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discontinuation of study drug and for those present at the end of study treatment as 
appropriate.  
Laboratory Test Abnormalities: 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. Test results that constitute SAEs should be documented and 
reported as such. 
The following laboratory abnormalities should be documented and reported 
appropriately: 
o any laboratory test result that is clinically significant or meets the 
definition of an SAE 
o any laboratory abnormality that required the subject to have study drug 
discontinued or interrupted 
o any laboratory abnormality that required the subject to receive specific 
corrective therapy.  
9.1.3 
Serious Adverse Event Reporting Requirements 
Investigators are required by Federal Regulations to report serious adverse events as 
defined in the table below. Investigators are required to notify AFT and their Institutional 
Review Board if a patient has a reportable serious adverse event. The descriptions and 
grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4 will be utilized for AE reporting.  The CTCAE is identified and 
located on the CTEP website at: 
ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All appropriate 
treatment areas should have access to a copy of the CTCAE.   
 
All SAEs must be collected that occur from the time of first protocol-specific study 
intervention up to within 100 days of last dose. Treatment-related adverse events should 
be followed to resolution or stabilization (≤Grade 2). SAEs must be entered into the 
eCRF via Rave Electronic Data Capture System (Rave EDC) as applicable within 24 
hours of learning of the event.  
Note:  All deaths on study require reporting via Rave EDC, regardless of causality.  
Attribution to treatment or other cause should be provided. 
 
 
REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS  
NOTE:  Investigators MUST report to the sponsor (AFT) ANY Serious Adverse Events, whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 
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 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  
7) Or is a new cancer (that is not a condition of the study). 
8) Or is associated with an overdose. Overdose is defined as dosing only. On a per dose 
basis, an overdose is defined as the following amount over the protocol specified dose 
of nivolumab/nab-paclitaxel assigned to a given patient, regardless of any associated 
adverse events or sequelae:  
PO: Any amount over the protocol-specified dose 
IV: 10% over the protocol-specified dose 
SC: 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 of 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.  
9) Potential Drug Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event.  All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs Potential drug induced liver injury is 
defined as: 
• ALT or AST elevation > 3 times upper limit of normal (ULN)  
AND 
• Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase) 
AND 
• No other immediately apparent possible causes of AST/ALT elevation and 




 
 
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9.1.4 
Assessment of Causality of Adverse Events 
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The casual relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and the AE. 
Not related: There is not a reasonable causal relationship between study drug administration and 
the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.  
9.2. 
Pregnancy Adverse Event Reporting 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half lives after the product administration, the investigational product 
will be permanently discontinued in an appropriate manner (eg, dose tapering, if necessary for 
subject safety).   
Because the study drug(s) may have an effect on sperm, pregnancies in partners of male subjects 
exposed to a study investigational drug will be reported by sites within 24 hours of their 
knowledge of the event using the pregnancy case report form within Rave EDC. AFT will report 
to Celgene/BMS within 24 hours of the receipt of the event.  
Pregnancies that occur from the time of treatment allocation/randomization through 100 days 
following cessation of the investigational product must be reported by the investigator.  
 
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify AFT immediately about the outcome of the pregnancy (either normal or abnormal 
outcome) using the approved form. 
 
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 by sites within 24 hours of their knowledge of the 
event using the Pregnancy case report form within Rave EDC. AFT will report to Celgene/BMS 
within 24 hours of the receipt of the event. 
 
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 investigational product should also be reported by sites 
within 24 hours of their knowledge of the event using the Adverse Event form within Rave EDC. 
AFT will report to Celgene/BMS within 24 hours of the receipt of the event.  


 
 
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10. Drug Information 
10.1. Nivolumab 
10.1.1 Description of Study Agent 
Nivolumab is manufactured by Bristol Myers-Squibb and is also known as BMS-936558-011. 
Other names for this agent are MDX1106, ONO-4538, and anti-PD-1. It has a molecular weight 
of 146,221 Daltons (143,619.17, protein portion).  
10.1.2 Form  
Nivolumab Injection, 100 mg/10 mL (10mg/mL).  
10.1.3 Storage and Stability 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL)  
 
Vials of nivolumab injection must be stored at 2°to 8°C (36°to 46°F) and protected from light 
and freezing as labeled.  
 
Please refer to the most recent Investigator’s Brochure for detailed instructions.  
10.1.4 Availability 
Bristol Myers-Squibb is the manufacturer of nivolumab and will be supplying it for this study 
free of charge.  
10.1.5 Administration 
• Nivolumab will be given every two weeks at a dose of 240mg to be administered 
as a 30 minute IV infusion. 
• Subjects may be dosed no less than 12 days from the previous dose of drug. There 
are no premedications recommended for nivolumab on the first cycle. 
• Subjects should be carefully monitored for infusion reactions during nivolumab 
administration. If an acute infusion reaction is noted, subjects should be managed 
according to Protocol Section 6.2.7. 
• Doses of nivolumab may be interrupted, delayed, or discontinued depending on 
how well the subject tolerates the treatment. 
Nivolumab Injection, 100 mg (10 mg/mL): Nivolumab injection is to be administered as an IV 
infusion through a 0.2-micron to 1.2-micron pore size, low-protein binding polyethersulfone 
membrane in-line filter at the protocol-specified doses. It is not to be administered as an IV push 
or bolus injection. Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 
0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to protein concentrations 
as low as .35 mg/mL. Care must be taken to assure sterility of the prepared solution as the 
product does not contain any antimicrobial preservative or bacteriostatic agent.  
Refer to the Investigator’s Brochure/Pharmacy Manual for detailed administration instructions 
for nivolumab.  


 
 
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10.1.6 Ordering 
A procedure to determine initial and re-supply of nivolumab will be finalized and provided to 
sites as an appendix or addendum to this protocol.  
Pharmacy supplies not provided by BMS:  Empty IV bags/containers, approved diluents, in-line 
filters and infusion tubing. 
10.1.7  Accountability 
Site investigators or designated responsible parties must maintain a record of the inventory of 
distribution of the study drug using the appropriate documentation method. This procedure will 
be finalized and provided to sites as an appendix or addendum to this protocol.  
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Bristol Myers-Squibb or designee, the amount dispensed to patients and the amount remaining at 
the conclusion of the trial. 
10.1.8  Destruction and Return 
Sites may destroy unused study drug according to their institutional policies. If any study drug is 
lost or damaged, its disposition should be documented in the source documents. Patients will be 
instructed to return empty vials or unused vials to the clinic site.  
10.2. Nab-Paclitaxel 
The information provided below is per the most current Investigator’s brochure (IB). Please refer 
to the IB,  local prescribing information (package insert), pharmacy manual, or  institutional 
standards for detailed information  regarding the storage/stability, compatibility, handling, 
preparation and administration of study agents used in this trial.  
10.2.1 Form 
Nab-Paclitaxel 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 120 nanometers. Paclitaxel exists in the particles in a non-
crystalline, amorphous state. Nab-paclitaxel 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.  
10.2.2 Storage and Stability 
Please see local prescribing information (package insert) for detailed instructions on the 
reconstitution, storage conditions and IV administration of nab-paclitaxel.  
10.2.3 Availability 
Celgene Corporation is the manufacturer of nab-paclitaxel and will be providing it for use in this 
research study.  Labels will bear Celgene’s name and address, the protocol number, product 
name, dosage form and strength, medication identification/kit number, 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 nab-
paclitaxel upon identification and screening of a potential trial subject.   


 
 
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Each single-use vial contains 100 mg of paclitaxel and approximately 900 mg of human albumin. 
Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel.  
10.2.4 Administration 
Nab-paclitaxel is injected into a vein (intravenous IV) 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 9mg/dl (0.9%) solution for injection to ensure complete 
administration of the complete dose, according to local practice.  
10.2.5 Ordering 
A procedure to determine initial and re-supply of nab-paclitaxel will be finalized and provided to 
sites as an appendix or addendum to this protocol.  
10.2.6 Accountability 
Site investigators or designated responsible parties must maintain a record of the inventory of 
distribution of the study drug using appropriate documentation for accountability purposes. This 
procedure will be finalized and provided to sites as an appendix or addendum to this protocol.  
The investigator or his/her designee is responsible for keeping accurate records of the clinical 
supplies received from Celgene, the amount dispensed to patients and the amount remaining at 
the conclusion of the trial. 
10.2.7  Destruction and Return 
Sites may destroy unused study drug according to their institutional policies. If any study drug is 
lost or damaged, its disposition should be documented in the source documents. Patients will be 
instructed to return empty vials or unused vials to the clinic site.  
11. Data Collection and Management/ Data and Specimen Submission 
11.1. 
Data Collection and Submission 
Data collection for this study will be done through the Medidata Rave clinical data management 
system. Access to the trial in Rave is granted through the iMedidata application to all persons 
with the appropriate roles assigned in AFT CTMS System.  See Data Entry Guidelines for 
additional instructions. 
11.2. 
Specimen Collection and Submission 
11.2.1 Biospecimen Collection  
Screening/Registration 
The following biospecimens will be collected: 
 
A. An archival tumor specimen from a prior core needle biopsy or surgical specimen 
will be collected and submitted within 6 weeks of enrollment. Availability of this 
tissue is required for eligibility.  
B. Whole blood and plasma samples will be collected for biomarker analysis.  
 


 
 
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On Study: 
 
A. Whole blood and plasma samples will be collected from all patients at the following 
time points: 
a. First restaging  
b. Progression 
 
Please see the biospecimen collection schema below. Detailed information regarding the 
collection, processing and shipping of samples collected for screening are included in the 
correlative sciences manual.  
11.2.2 Biospecimen Collection Schema 
 
 
*At screening, patients must be determined to have tissue available to be sent within 6 weeks of 
enrollment.  
12. Correlative Studies 
12.1. PDL1 Expression  
Nivolumab is FDA approved for non-small cell lung cancer previously treated with platinum based 
chemotherapy for both squamous and non-squamous histologies with no restriction by biomarker such 
as program death receptor ligand (PDL-1). PDL-1 tumor positivity enriches the chance of benefit from 


 
 
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nivolumab therapy in non-small cell lung cancer. However even tumors that are completely PDL-1 
negative can have durable responses to nivolumab therapy.  We will collect a tumor specimen at the 
time of enrollment in order to retrospectively assess whether expression of PDL-1 is associated with 
benefit from nab-paclitaxel in combination with nivolumab. A tumor specimen will also be obtained 
from patients who consent to an additional biopsy at progression. Program death receptor ligand 1 
(PDL1) Dako IHC 28-8 assay is an FDA approved complementary diagnostic for nivolumab. PDL1 will 
be assessed retrospectively to determine whether PDL1 status is associated with benefit for the 
nivolumab and nab-paclitaxel study combination.  
12.2. Plasma - Protein Markers Associated with Sensitivity or Resistance to Nivolumab  
Multiplex ELISA assays have been developed to analyze over 25 inflammatory and immune-related 
markers in less than 0.5 ml of plasma.  Coefficients of variation for most analytes are <10%.  This 
platform has been successfully applied to several in-house phase I and II studies, as well as several 
phase III, Alliance-conducted studies at Duke University. Markers of inflammation will be analyzed in 
the Duke Phase I Biomarker Lab, which serves as a core lab for these analyses for the NCI’s NCTN 
Alliance Trials Group. 
Analyses will be performed on pre-treatment and on-treatment plasma samples and on samples at 
disease progression. Analyte levels, and changes in analyte levels, will be correlated with clinical 
outcome (ORR, PFS, and OS).  These may include CRP and other markers of inflammation, including 
but not limited to IFNγ, IL1β, IL6, sILR6R, sGP130, IL4, IL7, IL10, IL12, IL17A, IL17E, and IL23. 
Additional markers of proteins regulated by the PD-1/PD-L1 interaction and the IL6/JAK-STAT axis 
may also be assessed, including but not limited to VEGF, HER and TGFβ family members. 
12.3. Plasma – Circulating, Cell-Free Tumor DNA 
Apoptotic and necrotic cells release DNA fragments into the circulation creating a pool of circulating 
cell-free DNA (cfDNA). Tumor-derived cfDNA (ctDNA) has become the focus of intensive 
investigation in the search for genomic biomarkers that can be used to monitor the presence or absence 
of disease, disease progression, or the development of resistance mechanisms during the course of 
treatment. Isolation of ctDNA from patient plasma samples will be done in the laboratory of Dr. Andrew 
Nixon at Duke University Medical Center.  The Maxwell® RSC (Promega) instrument will be used for 
the automated extraction of high-quality ctDNA.  All cfDNA will be quantified using a fluorescent dye 
method. Additional quantification methods such as real-time PCR may be used if they are deemed 
necessary for downstream applications.  
 
A targeted NGS panel will be constructed to measure multiple target genes in parallel. The NGS panel 
will include genes commonly associated with lung cancer, as well as genes associated with immune 
function and checkpoint inhibition. NGS libraries will be generated using standardized protocols. All 
procedures have been optimized for use with plasma samples similar to those collected during this study. 
If NGS assays lack the sensitivity to detect rare mutations in cfDNA, or if the cfDNA isolated from a 
sample is insufficient for NGS, then Taqman assays will be used as secondary analyses. Taqman assays 
are ideal for identifying the presence of specific, known genomic alterations.  
  
Associations between fluorescent quantification of total cfDNA and markers of clinical benefit (DFS 
and OS) will be modeled using Cox proportional hazards models. Associations between a potentially 
predictive SNP or genomic alteration and markers of clinical benefit (DFS and OS) will be modeled 


 
 
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using Cox proportional hazards models. 
13. Measurement of Effect 
13.1. 
Imaging Assessment Collection Plan 
For purposes of this study, patients should be reevaluated with imaging to assess for progression of 
tumor every 6 weeks for 48 weeks and thereafter every 12 weeks for 28 months from enrollment until 
disease progression, initiation of an alternate treatment, or withdrawal from study protocol.  
Testing, including imaging performed as routine clinical management, are acceptable for use in 
screening as long as they are in compliance with time parameters in Section 7.  
13.2. 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria8  
13.2.1 Definitions  
Evaluable for Target Disease Response.  Only those participants 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 target disease response.  These participants will have their response classified 
according to the definitions stated below.  (Note:  Participants who exhibit objective disease progression 
prior to the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response.  Participants 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.  
13.2.2 Disease Parameters 
Measurable Disease  
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in at least 
one dimension (longest diameter to be recorded) as ≥ 20 mm by chest x-ray or ≥10 mm with CT scan, 
MRI, or 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.  
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, abdominal masses (not followed by CT or 
MRI), and cystic lesions are all considered non-measurable. 


 
 
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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 participant, 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.  
13.2.3 Methods for Evaluation of Disease  
All measurements should be taken and recorded in metric notation using a ruler, calipers, or a digital 
measurement tool.  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.  
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT thickness is 5mm or less. If CT scans have slice thickness greater than 5 mm, the 
minimum size of 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 


 
 
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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. 
13.2.4 Measurement at Follow-up Evaluation  
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. 
13.2.5 Response Criteria 
All target lesions and target lymph nodes followed by CT/MRI/PET-CT/Chest X-ray/physical 
examination must be measured on re-evaluation at evaluation times specified in Section 11.1.  
Specifically, a change in objective status to either a PR or CR cannot be done without re-measuring 
target lesions and target lymph nodes.  
 
Note: Non-target lesions and non-target lymph nodes should be evaluated at each assessment, especially 
in the case of first response or confirmation of response.  In selected circumstances, certain non-target 
organs may be evaluated less frequently.  For example, bone scans may need to be repeated only when 
complete response is identified in target disease or when progression in bone is suspected. 
13.2.5.1 
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, 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. 
13.2.5.2 
Evaluation of Non-Target Lesions 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a patient to 
be considered in complete clinical response. 


 
 
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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). 
13.2.5.3 
Evaluation of New Lesions 
The finding of a new lesion should be unequivocal (i.e. not due to difference in scanning technique, 
imaging modality, or findings thought to represent something other than tumor (for example, some 
‘new’ bone lesions may be simply healing or flare of pre-existing lesions). However, a lesion identified 
on a follow-up scan in an anatomical location that was not scanned at baseline is considered new and 
will indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up evaluation will 
clarify if it truly represents new disease and if PD is confirmed, progression should be declared using the 
date of the initial scan on which the lesion was discovered (see Section 14.1.2 regarding 
pseudoprogression). 
13.2.5.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded 
since the treatment started).  The patient's best response assignment will depend on the achievement of 
both measurement and confirmation criteria. 
For Participants with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks from baseline** 


 
 
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PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
13.2.6 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time measurement 
criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started, or death due to any cause. Participants without 
events reported are censored at the last disease evaluation). 




 
 
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13.2.9 Progression-Free Survival 
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or registration) to 
death due to any cause, or censored at date last known alive. 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from randomization 
(or registration) to the earlier of progression or death due to any cause. Participants alive without disease 
progression are censored at date of last disease evaluation. PFS will be censored for radiotherapy or 
tumor-directed surgery.  
Time to Progression: Time to Progression (TTP) is defined as the time from randomization (or 
registration) to progression, or censored at date of last disease evaluation for those without progression 
reported. 
13.2.10 Review of Response 
13.2.10.1 
Target Lesions & Target Lymph Nodes 
• 
Measurable lesions (as defined in Section 13.2.2) up to a maximum of 5 lesions, representative 
of all involved organs, should be identified as “Target Lesions” and recorded and measured at baseline.  
These lesions can be non-nodal or nodal (as defined in Section 13.2), where no more than 2 lesions are 
from the same organ and no more than 2 malignant nodal lesions are selected.  
Note: If fewer than 5 target lesions and target lymph nodes are identified (as there often will be), there is 
no reason to perform additional studies beyond those specified in the protocol to discover new lesions.   
• 
Target lesions and target lymph nodes should be selected on the basis of their size, be 
representative of all involved sites of disease, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion (or 
malignant lymph node) does not lend itself to reproducible measurements in which circumstance the 
next largest lesion (or malignant lymph node) which can be measured reproducibly should be selected.   
• 
Baseline Sum of Dimensions (BSD):  A sum of the longest diameter for all target lesions plus 
the sum of the short axis of all the target lymph nodes will be calculated and reported as the baseline 
sum of dimensions (BSD).  The BSD will be used as reference to further characterize any objective 
tumor response in the measurable dimension of the disease.   
• 
Post-Baseline Sum of the Dimensions (PBSD):  A sum of the longest diameter for all target 
lesions plus the sum of the short axis of all the target lymph nodes will be calculated and reported as the 
post baseline sum of dimensions (PBSD). If the radiologist is able to provide an actual measure for the 
target lesion (or target lymph node), that should be recorded, even if it is below 0.5 cm. If the target 
lesion (or target lymph node) is believed to be present and is faintly seen but too small to measure, a 
default value of 0.5 cm should be assigned. If it is the opinion of the radiologist that the target lesion or 
target lymph node has likely disappeared, the measurement should be recorded as 0 cm.  
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and the PBSD.  
13.2.10.2 
Non-Target Lesions and Non-Target Lymph Nodes 
Non measurable sites of disease (Section 13.2.2) are classified as non-target lesions or non-target lymph 
nodes and should also be recorded at baseline. These lesions and lymph nodes should be followed in 
accordance with Section 12.2.2. 


 
 
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13.2.10.3 
New Lesions 
New lesions are considered measureable at the time of initial progression if the longest diameter is at 
least 10 mm (except for pathological lymph nodes which must have a short axis of at least15 mm). Any 
new lesion considered non-measureable at the time of initial progression may become measureable and 
therefore included in the tumor burden if the longest diameter increases to at least 10 mm (except for 
pathological lymph nodes which must have a short axis of at least 15 mm). In situations where the 
relative increase in total tumor burden by 10% is solely due to inclusion of new lesions which become 
measurable, these new lesions must demonstrate an absolute increase of at least 5 mm. 
 
13.3. Antitumor Effect – Hematologic Tumors 
14. End of Treatment  
14.1. Duration of Treatment 
14.1.1 CR, PR, or SD 
Patients who are in CR, PR or SD (as defined in Section 14) will continue on therapy for a total of 12 
months. Patients with CR, PR, or SD at 12 months, and then have progression are potentially eligible for 
retreatment. After treatment is discontinued, patients will be followed per the study calendar in Section 
8.0. 
14.1.2 Disease Progression 
Remove from protocol therapy any patient with disease progression on study therapy. Details of 
progression, including tumor measurements, should be documented on the appropriate form.  
 
After disease progression, patients should be followed for survival per the study calendar (Section 8.0). 
Patients receiving immune therapy sometimes have symptomatic and/or radiographic progression as 
enlarged pre-existing lesions or new lesions that constitute “pseudoprogression” from an inflammatory 
anti-tumor effect. Patients who are felt to be clinically benefiting from study therapy may be allowed to 
continue on study therapy, if the patient is not having clinical deterioration consistent with true cancer 
progression. Treating “beyond progression” must be discussed and approved by the principal 
investigator or their designee (See Section 14.1.3). 
14.1.3 Treatment Beyond Progression  
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive clinical 
benefit despite initial evidence of PD.   
Subjects will be permitted to continue treatment beyond initial RECIST 1.1 defined PD as long as they 
meet the following criteria determined by the investigator: 
• Investigator-assessed clinical benefit and subject is tolerating study drug. 
• Tolerance of study drug 
• Stable performance status 


 
 
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The assessment of clinical benefit should take into account whether the subject is clinically deteriorating 
and unlikely to receive further benefit from continued treatment.  
Treatment beyond progression will not delay an imminent intervention to prevent serious complications 
of disease progression (eg, CNS metastases) A radiographic assessment/ scan should be performed 
within 6 weeks of initial investigator-assessed progression to determine whether there has been a 
decrease in the tumor size or continued PD. The assessment of clinical benefit should be balanced by 
clinical judgment as to whether the subject is clinically deteriorating and unlikely to receive any benefit 
from continued treatment with nivolumab. 
15. Statistical Considerations  
15.1. 
Overview of the Study Design  
Eligible patients will be randomized with equal allocation to nivolumab alone (arm A) and nivolumab 
plus nab-paclitaxel (arm B). Randomization will be done through stratified permuted block design 
algorithm with stratification on (a) Histology (Squamous vs. non-squamous); (b) History of prior taxane 
therapy (Yes vs. No); and (c) smoking history.  
Assuming 5% rate of cancellation prior to treatment and ineligibility, a total of 200 patients will be 
randomized. All patients will be evaluated for response rate and adverse events during protocol 
treatments. All patients will be assessed for progression-free survival by repeated CT scans every 6 
weeks for 48 weeks and then every 12 weeks until 28 months from enrollment, until lost to follow-up, 
withdrawal, progression or death. All patients are expected to be followed for progression free survival 
and overall survival for 28 months after enrollment. 
It is now recognized that a subset of patients < 5% with non-small cell lung cancer will have 
pseudoprogression when treated with nivolumab. In this context pseudoprogression means that when the 
immune system attacks tumors, the radiographic images show tumor enlargement or new lesions prior to 
the tumors shrinking. Therefore it has become common practice in immune therapy trials to allow 
“treatment beyond progression” when the patient seems to be having clinical benefit despite evidence of 
disease progression by radiograph images.    
For the subjects who continue nivolumab study therapy beyond progression, further progression is 
defined as an additional 10% increase in tumor burden from time of initial PD. This includes an increase 
in the sum of diameters of all target lesions and/ or the diameters of new measurable lesions compared to 
the time of initial PD. Nivolumab treatment should be discontinued permanently upon documentation of 
further progression. 
15.2. 
Sample Size, Accrual Time and Study Duration 
The sample size of this randomized phase II trial is justified by having adequate statistical power to test 
an improvement of  progression-free survival in a second line setting for advanced NSCLC patients 
receiving nivolumab plus nab-paclitaxel (arm B) as compared to those receiving nivolumab alone (arm 
A). 
  
Nivolumab was compared to docetaxel as second-line therapy in advanced stage NSCLC in two 
randomized phase 3 trials. In the BMS017 trial for second-line squamous cell lung cancer, overall 
survival was 9.2 months with nivolumab and 6.0 months with docetaxel, HR 0.59 and p < 0.001. In the 


 
 
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BMS057 trial for second-line non-squamous lung cancer, overall survival was 12.2 months for 
nivolumab and 9.4 months for docetaxel, HR 0.73 and p = 0.0015. For the BMS057 non-squamous trial, 
the median PFS was 2.3 months and for BMS017 squamous trial, the median PFS was 3.5 months. We 
would expect 2/3 of patients to be non-squamous for this concept. Based on these findings, we design 
the trial to test an expected median PFS improvement of 1.5 months (approximately 50% increase) from 
3 months to 4.5 months.  
 
 The following assumptions are made while determining the statistical power:  
(i) 
the median PFS is 3 months for patients on nivolumab alone (arm A) and 4.5 months 
for nivolumab plus nab-paclitaxel (arm B), a 50% increase in median PFS and a 
corresponding hazard ratio λB/λA = 0.67 under constant hazards;  
(ii) 
190 eligible patients (95 per arm) will be randomized with 1:1 allocation;  
(iii) 
an accrual period of 20 months (approximately 10 patients per month) ; and  
(iv) 
an additional follow-up of 8 months for PFS after the enrollment of the last patient. 
Using a stratified log rank test at a two-sided significance level of 0.10, the study has 
approximately 85.5% power to reject the null hypothesis λB/λA = 1 and accept the 
alternative hypothesis λB/λA < 1 when the true λB/λA = 0.67. At the time of analysis, or 
approximately 28 months after the first enrollment, a total of 178 events (92 on arm A 
and 86 on arm B) are anticipated under the alternative hypothesis. After adjusting for 
the small loss of power due to interim analysis (see next section for details), the actual 
power will be approximately 84.5%. 
 
After the initiation of protocol treatment, all registered patients will be followed for 28 months from 
enrollment to observe progression-free survival and overall survival.  
15.3. 
Stratification Factors 
Patients will be stratified by: 
1) Squamous versus non-squamous histology (any histology not specified squamous only will be 
stratified as non-squamous) 
2) History of prior taxane therapy (nab-paclitaxel excluded). 
3) Smoking history 
15.4. 
Statement for Primary Endpoint 
The primary objective is to determine whether the progression free survival of patients with advanced 
stage non-small cell lung cancer whose cancer has progressed after first-line chemotherapy is improved 
with nivolumab plus nab-paclitaxel compared to nivolumab alone.  
15.5. Interim Analysis Design for Primary Endpoint (include DSMB reporting, if 
applicable) 
AFT DSMB will review the study data at each of its semiannual meetings after first enrollment. This 
will include toxicity, progression free survival and overall survival information. In determining whether 
the trial should be continued, the DSMB will use its discretion in weighing the combined impact of 
treatment-related toxicity, disease recurrence and overall survival. The first formal interim analysis for 
efficacy will occur once 104 events (58% information) have been observed with two treatment arms 
combined or approximately 16 months after first enrollment. After that, 2nd formal interim analyses will 


 
 
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be conducted at 156 events (approximatively at months 22) and the final analysis at 178 events (months 
28). Early stopping at any of these times could occur for superiority (arm B is superior to arm A) and for 
futility (arm B is equivalent or inferior to arm A) on progression-free survival. The log rank test will be 
used to generate the one-sided p-values for both tests. Using RCTdesign (9), we will construct two-sided 
boundaries in the spirit of O’Brien and Fleming (10). We will truncate alpha level at 0.001 for the 
futility boundary to echo the spirit of the paper by Freidlin and Korn (11). The final analysis at 28 
months after study activation will conclude a superiority of arm B to arm A if the p-value of a two-sided 
log rank test for superiority is less than 0.10 as the alpha spent under such early stopping boundaries is 
minimal. The following table displays operating characteristics, including actual power, average study 
size, stopping probabilities under true hazard ratios of 0.6, 0.667, 0.7, 0.8, 0.9, 1.0.  
Table 4 
Hazard Ratio 
(λB/λA) 
Expected 
Number of 
Events 
Prob. to 
Reject H0: 
λB/λA =1 
(Power) 
Prob. of early 
stop prior to 
final analysis 
for superiority 
Prob. of early 
stop prior to 
final analysis 
for futility 
0.6 
125 
0.9568 
0.9091 
0.0002 
0.67 
140 
0.8457 
0.7522 
0.0017 
0.7 
147 
0.7567 
0.6476 
0.0041 
0.8 
163 
0.4269 
0.3271 
0.0322 
0.9 
168 
0.1692 
0.1201 
0.1274 
1 
162 
0.0500 
0.0343 
0.3099 
1.2 
138 
0.0024 
0.0017 
0.7337 
 
15.6. 
Secondary Objectives 
The secondary objectives for this study are as follows: 
1) To evaluate the difference of response rates between two treatments; 
2) To evaluate the difference of overall survivals between two treatments; 
3) To characterize the treatment related adverse events 
4) 
To characterize progression free survival for PDL1 positive (>1% tumors positive) and 
PDL1 negative tumors 
5) 
To study immunologic biomarkers in the blood before and after nab-paclitaxel plus 
nivolumab. 
6) 
To study immunologic biomarkers in the tumor at baseline before nab-paclitaxel plus 
nivolumab. 
7) 
To evaluate the difference of response rates in squamous cell lung cancer between the 
two treatments.  
8) 
To evaluate the difference in progression free survival in squamous cell lung cancer 
between the two treatments.  
9) 
To evaluate the difference in overall survival. 
10) To compare clinical outcomes for PDL1 positive and PDL1 negative tumors. 
11) To compare rate of deaths in the first 3 months between the two treatments. 


 
 
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12) To compare characteristics of tumors for deaths in the first 3 months compared to those 
living more than 3 months.  
15.7. 
Supplementary/Secondary Analysis Plans/Statistical Analysis Plan  
A modified ITT approach will be used for the statistical analyses. In other words, ineligible patients, 
who have received at least one cycle of protocol treatment will be included in the analysis of adverse 
events. The statistical analysis cohort for treatment efficacy will include all randomized patients but 
exclude in eligible patients or patients who cancel this study before receiving any protocol treatment. 
The primary efficacy endpoint is progression-free survival (PFS), which is the time from the date of 
randomization to the date of the earliest radiographic disease progression or death, the data will be 
censored at the date of the last disease assessment.  
PFS will be analyzed by Kaplan Meier methodology and compared between arm A and arm B, using a 
log-rank test stratified by histology, history of prior taxane therapy and smoking history (12). A two-
sided p value will be provided. Median PFS will be estimated and its 95% confidence interval for 
median PFS will be presented for each arm. Overall survival (OS), which is the time from randomization 
to deaths of all causes, will be analyzed in a similar manner as PFS.  
All subjects who receive at least one dose of the study drug will be included in safety analysis. 
Treatment-related toxicity will be summarized by grade, type and system organ class. Comparisons of 
the percentages of subjects experiencing an adverse event between arm A and arm B will be performed 
using Fisher’s exact test (13).  
The objective of the correlative sciences study is to study immunologic biomarkers in the blood before 
and after nab-paclitaxel plus nivolumab and to study immunologic biomarkers in the tumor at baseline 
before nab-paclitaxel plus nivolumab. The association of baseline value and the changes of these 
biomarkers with clinical outcomes will be evaluated. The association of these biomarker measures with 
response will be evaluated with Wilcoxon rank sum test and multivariable logistic regression with 
adjustment for other risk factors. The association between these biomarker measures and survival 
endpoints, including PFS and OS, will be using single-predictor and multivariable Cox models (14). The 
biomarkers measured in tumor samples at baseline will be evaluated in similar approaches. The PDL 
status determined by biomarker analysis will be used to test the interaction between PDL status and 
treatments and the treatment effect on PDL positive will also be estimated (15).  
15.8. 
Adverse Event/Accrual Monitoring Stopping Rule 
Overall, if 5 or more of the first 20 patients in the nivolumab plus nab-paclitaxel arm (arm B) experience 
grade 4/5 non hematologic adverse events (excluding diarrhea and rash) that are probably, possibly, or 
definitely related to study treatment, OR if the rate of treatment-related deaths within the first 60 days of 
the first dose of the protocol treatment exceeds 4 or more in either arm among the first 20 patients at any 
time, accrual to the study will be suspended to allow for one investigation. After consideration by the 
study team and the primary IRB, a decision will be made as to whether accrual can be resumed 
potentially with modifications to entry criteria and/or study conduct.  
15.9. 
Criteria for Taking a Patient Off Protocol Therapy  
Patients in Arm A and Arm B will receive study therapy until progression or not tolerated. Patients having 
durable disease control after 12 months will stop study therapy. If the cancer then progresses during the 28 


 
 
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months of planned follow-up after enrollment, the patient may receive an additional 12 months of therapy,  
if the patient otherwise meets all criteria to receive study therapy. Dose reductions established during the 
first 12 months of therapy will continue in the potential second 12 months of therapy.   
Patients will be removed from study for one of the following: 
• Unacceptable toxicity 
• Progression of disease 
• Patient/physician withdrawal  
The reason for treatment discontinuation must be entered into the eCRF. Patients who discontinue 
treatment will remain on study in Follow-Up Phase.  
15.10. 
Duration of Follow-Up 
Patients will be followed for 28 months after enrollment. After the end of treatment visit, the patient 
should be followed by institutional standard. Follow-up data may be acquired by phone for patients who 
are no longer returning to the treating institution for follow-up.  
15.11. 
Criteria for Taking a Patient Off Study 
Patients will continue study therapy until one of the following, whichever occurs first: 
• Lost to follow up 
• Withdrawal of consent for data submission 
• Death 
 
The date of death or last known alive should be entered into the eCRF when a patient is removed from 
study.  
15.12. 
Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the patient no 
longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In this event: 
• 
Document the reason(s) for discontinuation of therapy on data forms. 
• 
Follow the patient for protocol endpoints as required by the Study Calendar. 
15.13. 
 Managing Ineligible Patients and Registered Patients Who Never Receive Protocol 
Intervention 
Definition of ineligible patients: A study participant who is registered to the trial but does not meet all 
of the eligibility criteria is deemed to be ineligible. Patients who are deemed ineligible may continue 
protocol treatment, provided the treating physician, study chair, and executive officer agree there are no 
safety concerns if the patient continues protocol treatment. All scans, tests, and data submission are to 
continue as if the patient were eligible. Notification of the local IRB may be necessary per local IRB 
policies. 
Study participants who are registered to the trial but never receive study intervention (for a reason other 
than because they were deemed ineligible) must still complete follow-up requirements as specified 
below: 


 
 
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Baseline, on-study, endpoint (e.g. relapse or progression), off treatment, and survival data submission 
required.  
 
15.14. 
Data and Safety Monitoring  
Interim Reports from the statistical team will be generated for the Data and Safety Monitoring Board 
(DSMB), as per the safety monitoring plan.  
16. 
General Regulatory Considerations and Credentialing (Ethical Considerations and 
Administrative Procedures) 
16.1. 
Compliance with Trial Enrollment and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food and 
Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely responsible for 
determining whether the trial and its results are subject to the requirements for submission to the Clinical 
Trials Data Bank, http://www.clinicaltrials.gov.  Information posted will allow patients to identify 
potentially appropriate trials for their disease conditions and pursue participation by calling a central 
contact number for further information on appropriate trial locations and trial site contact information. 
16.2. 
Regulatory and Ethical Compliance 
By signing the Protocol the investigator agrees to treat all of the information that is provided with the 
strictest confidentiality and to require the same of his personnel as well as the IRB. Study documents 
(protocols, investigator`s brochures, eCRFs, etc.) provided by the AFT will be stored in an appropriate 
manner in order to ensure confidentiality. The information provided to the investigator by AFT must not 
be made available to other parties without a direct written authorization by the aforesaid parties, with the 
exception of the extent to which disclosure is necessary in order to obtain informed consent from the 
patients who wish to participate in the study. 
 
This study will be conducted in compliance with the study protocol, subsequent amendment(s) and with 
the study-specific manuals/guidelines, if applicable. These documents ensure that the ICH E6 guideline 
for Good Clinical Practice is maintained as well as compliance with the principles of the Declaration of 
Helsinki (World Medical Association), or the laws and regulations of the country in which the research 
is conducted, whichever afford the greater protection to the individual. The study will comply with the 
requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting). 
 
Studies conducted in the United States or under a U.S. Investigational New Drug (IND) application will 
comply with U.S. FDA regulation and applicable local, state and federal laws. 
 
By signing the study protocol the investigator agrees to comply with the instructions and procedures 
described therein and thus to adhere to the principles of good clinical practice, which these instructions 
and procedures reflect. 


 
 
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16.3. 
Informed Consent 
It is the responsibility of the Investigator, or a person designated by the Investigator (if acceptable by 
local regulations), to obtain written Informed Consent from each patient participating in this study, after 
adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study. This 
information must be provided to the patient prior to undertaking any trial-related procedure which is not 
part of the routine clinical management of the patient (i.e. would not be indicated outside the study).  
 
For patients not qualified or incapable of giving legal consent, written consent must be obtained from 
the legally acceptable representative. In the case where both the patients and his/her legally acceptable 
representative are unable to read, an impartial witness should be present during the entire informed 
consent discussion. After the patient and representative have orally consented to participation in the trial, 
the witness’ signature on the form will attest that the information in the consent form was accurately 
explained and understood. The Investigator or designee must also explain that the patients are 
completely free to refuse to enter the study or to withdraw from it at any time, for any reason.  
 
Furthermore, it is the investigator’s responsibility to obtain the signed Informed Consent Form, and a 
signature from the person conducting the informed consent discussion, prior to undertaking any trial-
related procedure. The proposed Informed Consent Form must comply with the ICH GCP guideline and 
regulatory requirements.  
16.4. 
Responsibilities of the Investigator/IRB/IEC/REB 
The regulatory requirements for the Investigator can be found in Subpart D of 21CFR312 (21CFR 
312.60: General Responsibilities of Investigators) and in ICH E6 Section 4.  
 
Additional requirements are also outlined in the Statement of Investigator Responsibilities (Form FDA 
1572) and the Site Services Agreement.  Alliance Foundation Trials, LLC (AFT) will supply the 
protocol and subsequent amendments.  
 
The Investigator is responsible for ensuring all patients and/or parents or legal guardian of each patient, 
if applicable, are informed about the study and that written consent is obtained prior to the conduct of 
any study related procedures.  
 
In addition, the Investigator is responsible for reviewing all health related information collected for each 
study patient in order to identify any safety related issues/adverse events (AE) or Infusion Associated 
Reactions (IAR).  All Serious Adverse Events (SAEs) and IARs are to be reported within 24 hours to 
AFT via the Rave Electronic Data Capture system of becoming aware of the event.  If this is not 
reported within 24 hours, a Protocol Deviation will be documented.    
 
As specified in 21CFR 312.62 (Investigator Record Keeping and Record Retention) and ICH E6 
Sections 4.9 and 8, the Investigator is responsible for ensuring that their study staff maintains and retains 
all study related documentation, including but not limited to: signed Informed Consent forms, medical 
records that are applicable for this study and source documents, the AFT-31 protocol, Institutional 
Review Board (IRB) approvals, relevant IRB and Sponsor correspondence, and assorted regulatory 
documents.  The Investigator is responsible for retaining and keeping safe all patient related 


 
 
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documentation.  In order to do this, the site staff will complete electronic case report forms (eCRFs) in a 
timely manner.  
16.5. 
Financial Disclosures 
Investigators will provide AFT with adequate and accurate financial information in accordance with 
local regulations and laws in order to allow AFT to submit complete and accurate financial certification 
or disclosure statements to the appropriate health authorities. Investigators are responsible for providing 
updated information on financial interests during the course of the study as well as for 1 year after 
completion of the study. 
 
16.6. 
Protocol Deviations 
The investigator is responsible to document and explain any deviations from the approved protocol. The 
investigator should promptly report any deviations that might impact patient safety and data integrity to 
AFT and if locally applicable, to the respective IRB in accordance with local IRB policies and 
procedures.  
A deviation is a departure from the protocol.   If deviations are discovered by the monitor or data 
manager, other member of study staff or otherwise, they will be discussed with the Investigator and 
study staff. AFT does not provide waivers for protocol deviations.    
16.7. 
Protocol Amendments 
Any modifications to the protocol or the Informed Consent Form which may impact on the conduct of 
the study, potential benefit of the study, or may affect patient safety, including changes of study 
objectives, study design, patient population, sample sizes, study procedures, or significant administrative 
aspects will require a formal amendment to the protocol. Such amendment will be released by AFT, 
agreed by the investigator(s) and approved by relevant IRBs prior to implementation. A signed and 
dated statement that the protocol, any subsequent relevant amended documents and the Informed 
Consent Form have been approved by relevant IRBs must be provided to AFT before the study is 
initiated.  
 
Administrative changes of the protocol are minor corrections and/or clarifications that have no effect on 
the way the study is to be conducted. These administrative changes will be released by the AFT, agreed 
by the investigator(s) and notified to the IRB.  
16.8. Retention of Records (Study Documentation, record keeping, and retention of 
records) 
Any records and documents relating to the conduct of this study and the distribution of investigational 
drug, including ICFs, eCRFs, PRO data, laboratory test results, and medication inventory records, must 
be retained by the study chair until notification by AFT, or for the length of time required by relevant 
national or local health authorities, whichever is longer. After that period of time, the documents may be 
destroyed, subject to local regulations. No records may be disposed of without the written approval of 
AFT. Written notification should be provided to AFT prior to transferring any records to another party 
or moving them to another location. 
16.9. Data and Safety Monitoring Board (DSMB) 
The Alliance Foundation Trials Data Safety Monitoring Board will be monitoring this study.  


 
 
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16.10. Regulatory Reporting 
Serious adverse events will be forwarded to FDA by the IND Sponsor according to 21 CFR 312.32.  
It is the responsibility of the investigator and the research team to ensure that serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices (GCP), the protocol 
guidelines, AFT’s guidelines, and Institutional Review Board (IRB) policy.  
16.11. Data Confidentiality  
Patient medical information both, associated with biologic specimens or not, is confidential and may 
only be disclosed to third parties as permitted by the ICF (or separate authorization for use and 
disclosure of personal health information) which has been signed by the patient, unless permitted or 
required by law. Data derived from biologic specimen analysis on individual patients will in generally 
not be provided to study investigators unless a request for research use is granted. The overall results of 
any research conducted using biologic specimens will be available in accordance with the effective AFT 
policy on study data publication. 
16.12. Database Management and Quality Control  
The Site Principal Investigator and/or his/her designee will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study. 
Rave EDC will be used for this study. The study data will be transcribed by study-site personnel from 
the source documents onto an eCRF, and transmitted in a secure manner to AFT within the timeframe 
agreed upon between the sponsor and the study site. The electronic file will be considered to be the 
eCRF. 
The Clinical Research Coordinator (CRC) or designated study site personnel will complete the eCRFs in 
a timely manner after the information is collected, preferably within 3-5 business days after the study 
procedure has been performed. The Investigator will review and approve the completed eCRFs.   
Subjects will not be identified by name in the study database or on any study documents to be collected 
by the AFT (or designee), but will be identified by a site number, subject number. 
In accordance with federal regulations, the Investigator is responsible for the accuracy and authenticity 
of all clinical and laboratory data entered onto eCRFs.  
At study completion, when the database has been declared to be complete and accurate, the database will 
be locked.  
After data have been entered into the study database, a system of computerized data validation checks 
will be implemented and applied to the database on a regular basis.  
AFT will review eCRFs for accuracy and completeness during on-site monitoring visits and after 
transmission to the AFT; any discrepancies will be resolved with the investigator or designee, as 
appropriate. After upload of the data into the clinical study database they will be verified for accuracy 
and consistency with the data sources. Queries are entered, tracked, and resolved through the EDC 
system directly. The study database will be updated in accordance with resolved queries. All changes to 
the study database will be documented. 
At critical junctures of the protocol (e.g., production of interim and final reports), data for analysis is 
locked and cleaned per established procedures.  


 
 
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If the Investigator becomes unable for any reason to continue to retain study records for the required 
period (e.g. retirement, relocation), AFT should be prospectively notified. The study records must be 
transferred to a designee acceptable to AFT, such as another investigator, another institution, or to AFT 
itself. The Investigator must obtain AFT’s written permission before disposing of any records, even if 
retention requirements have been met.  
16.13. Site Monitoring 
Monitoring visits will be conducted by representatives of the Alliance Foundation according to the US 
CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6). By signing this protocol, the 
Investigator grants permission to AFT (or designee), and appropriate regulatory authorities to conduct 
on-site monitoring and/or auditing of all appropriate study documentation. 
16.14. Audits and Inspections 
To enable evaluations and/or audits from regulatory authorities or AFT, the Investigator agrees to keep 
records, including the identity of all participating subjects (sufficient information to link records, e.g., 
eCRFs and hospital records), all original signed informed consent forms, copies of all eCRFs, safety 
reporting forms, source documents, and detailed records of treatment disposition, and adequate 
documentation of relevant correspondence (e.g., letters, meeting minutes, telephone calls reports).   
The records should be retained by the Investigator according to ICH, local regulations, or as specified in 
the Clinical Trial Agreement, whichever is longer, but at a minimum, all study documentation must be 
retained for 2 years after the last marketing application approval in an ICH region or after at least 2 
years have elapsed since formal discontinuation of clinical development of AFT-31. 
16.15. Early Discontinuation of the Study 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
16.16. Publication of study protocol and results 
AFT prioritizes the timely presentation and publication of study results. Publications and any kind of 
presentations of any results from the study shall be in accordance with accepted scientific practice, 
academic standards and customs and must be approved in writing by AFT as the sponsor of this trial. No 
investigator may present or publish any portion of this trial without written approval by AFT.  
 
 
 


 
 
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17. References 
 
1. Brahmer J, et al. N Engl J. Med. 2015 Jul 9; 373(2): 123-35. 
2. Borghai H, et al. N Engl J Med. 2015 Sept. E Pub 
3. Socinski MA, et al. J Clin Oncol 2012; 30:2055-62. 
4. Liu Z, et al. Med Oncol. 2015 Aug; 32(8):216. 
5. Camidge R. et al. World Lung Cancer Meeting, Denver, CO September 2015. 
6. Adams S, et al. San Antonio Breast Cancer Meeting, San Antonio, TX December 2015. 
7. Antonia SJ, et al. ASCO Annual Meeting, Chicago, IL 2014 
8. E.A. Eisenhauer, P. Therasse, J. Bogoaerts, L.K. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. 
Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (Version 1.1). Eur J Cancer. 2009 Jan; 45(2): 228-47. 
9. Emerson, S., S+SEQTRIAL: technical overview, in Data Analysis Products Division, 
MathSoft, Inc. 2000. 
10. O’Brien, P.C. and T.R. Fleming, A multiple testing procedure for clinical trials. Biometrics, 
1979. 35(3):p. 549-56. 
11. Freidlin, B., E.L. Korn, and S.L. George, Data monitoring and committees and interim 
monitoring guidelines. Control Clin Trials, 1999. 20(5): p. 395-407. 
12. Kaplan, E.L., Meier, P., Nonparametric estimation from incomplete observations. J Am Stat 
Assoc, 1958. 53(282): p. 457-481.  
13. Mantel, N., Evaluation of survival and data and two new rank order statistics arising in its 
consideration. Cancer Chemotherapy Rep. 1966. 50(3): p. 163-70. 
14. Cox, D.R. Regression models and life-tables. J R Stat Soc 1972 34: p.187-220.  
15. Fine, J., Gray R., A proportional hazards model for the sub distribution of a competing risk. J 
Am Stat Assoc, 1999. 94: p. 496-509.  
 
 
 
 
 


 
 
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18. Appendices 
Appendix I: ECOG Performance Status 
Appendix II: Adverse Event Management Algorithms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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18.1.  Appendix I: ECOG Performance Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.  Oaken, M.M., Creech, R.H., Toomey, D.C., 
Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Is J Clin Oncol 5:649-655, 
1982? The Eastern Cooperative Oncology Group, Robert Comes M.D., Group Chair. 


 
 
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18.2. Appendix II: Adverse Event Management Algorithms 
18.2.1 Genitourinary Adverse Events 
 
 
 
 
 


 
 
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18.2.2 Renal Adverse Events 
 
 
 
 
 


 
 
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18.2.3 Pulmonary Adverse Events 
 
 
 
 


 
 
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18.2.4  Hepatic Adverse Events 
 
 
 


 
 
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18.2.5  Endocrine Adverse Events 
 
 
 


 
 
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18.2.6  Skin Adverse Events 
 
 
 


 
 
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18.2.7  Neurological Adverse Events 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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19. Approval Signatures 
 
Printed 
Signature 
Title 
Date 
Suzanne George, 
M.D. 
 
 
 
Xiaofei 
Wang, 
Ph.D. 
 
 
 
Neal Ready, MD 
PhD