Conditions: Lung Cancer
Keywords: Lung Cancer
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 9
Healthy volunteers: no

Brief summary:
This research study is studying a drug intervention as a possible treatment for lung cancer.

The drugs involved in this study are:

* Nivolumab
* Carboplatin
* Pemetrexed
* Ipilimumab

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease.

The FDA (the U.S. Food and Drug Administration) has approved Nivolumab as a treatment for other types of cancers including lung cancer. However, the combination of Nivolumab with other drugs (such as those being tested in this study) has not been approved by the FDA as a treatment for this type of lung cancer.

The purpose of this study is to test the effectiveness (how well the drug works), safety, and tolerability of the drug Nivolumab in combination with standard of care chemotherapies, or in combination with Ipilimumab. Nivolumab and Ipilimumab are antibodies (a type of human protein) that are being tested to see if they will allow the body's immune system to work against tumor cells. This study is being done to see if Nivolumab and Ipilimumab, or Nivolumab and chemotherapy drugs (Carboplatin and Pemetrexed), are more effective against cancer when administered together.

These drugs are given as infusions. They are designed to "boost" the immune system's ability to suppress or kill cancer cells that are foreign to the human body.

Arms:
arm 1: Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks arm 2: Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks arm 3: Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks arm 4: Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks

Interventions: intervention 1: Carboplatin intervention 2: Nivolumab intervention 3: pemetrexed intervention 4: Ipilimumab
Intervention descriptions: intervention 1: Chemotherapy intervention 2: will allow the body's immune system to work against tumor cells intervention 3: Chemo therapy intervention 4: will allow the body's immune system to work against tumor cells

Protocol document:
Prot_SAP_000.pdf: 




  
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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................2 
1. OBJECTIVES ...........................................................................................................................5 
1.1 Study Design ...............................................................................................................6 
1.2 Primary Objectives......................................................................................................7 
1.3 Secondary Objectives..................................................................................................7 
1.4 Exploratory Objectives ...............................................................................................8 
2. BACKGROUND ......................................................................................................................8 
2.1 Advanced NSCLC ......................................................................................................8 
2.2 Overview of Nivolumab ...........................................................................................10 
2.3 Overview of Carboplatin and Pemetrexed Combination ..........................................13 
2.4 Overview of Bevacizumab and Combination with Chemotherapy ..........................16 
2.5 Study Rationale .........................................................................................................16 
2.6 Correlative Studies Background ...............................................................................22 
3. PARTICIPANT SELECTION ................................................................................................23 
3.1 Eligibility Criteria .....................................................................................................23 
3.2 Exclusion Criteria .....................................................................................................25 
3.3 Inclusion of Women and Minorities .........................................................................27 
4. REGISTRATION PROCEDURES ........................................................................................27 
4.1 General Guidelines for DF/HCC Institutions ...........................................................27 
4.2 Registration Process for DF/HCC Institutions ..........................................................28 
5. TREATMENT PLAN .............................................................................................................28 
5.1 Treatment Regimen ...................................................................................................28 
5.2 Agent Administration................................................................................................31 
5.3 General Concomitant Medication and Supportive Care Guidelines .........................33 
5.4 Criteria for Taking a Participant Off Protocol Therapy ............................................35 
5.5 Duration of Follow Up ..............................................................................................36 
5.6 Criteria for Taking a Participant Off Study ..............................................................36 
6. DOSING DELAYS/DOSE MODIFICATIONS ....................................................................37 
6.1 Dose Delay Criteria...................................................................................................37 
6.2 Dose Reduction Criteria ............................................................................................39 
6.3 Criteria to Resume Dosing ........................................................................................41 
6.4 Criteria to Discontinue Treatment ............................................................................42 
6.5 Management Algorithms for Immuno-Oncology Agents .........................................44 
6.6 Treatment of Nivolumab Infusion Reactions ............................................................44 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .................................46 
7.1 Adverse Events .........................................................................................................46 
7.2 Adverse Event Characteristics ..................................................................................57 


  
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7.3 Expedited Adverse Event Reporting .........................................................................58 
7.4 Pregnancy ..................................................................................................................59 
7.5 Expedited Reporting to the Food and Drug Administration (FDA) .........................59 
7.6 Expedited Reporting to Hospital Risk Management ................................................59 
7.7 Routine Adverse Event Reporting ............................................................................60 
8. PHARMACEUTICAL INFORMATION ...............................................................................60 
8.1 Nivolumab.................................................................................................................60 
8.2 Bevacizumab .............................................................................................................62 
8.3 Pemetrexed ................................................................................................................64 
8.4 Carboplatin ................................................................................................................66 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES .............................................67 
9.1 Tumor Tissue Collection...........................................................................................67 
9.2 Blood for Germline DNA Collection ........................................................................68 
9.3 Handling and Shipping of Specimens .......................................................................68 
10. STUDY CALENDAR ..........................................................................................................68 
10.1 Study Assessments ..................................................................................................72 
11. MEASUREMENT OF EFFECT...........................................................................................74 
11.1 Antitumor Effect – Solid Tumors ...........................................................................74 
12. DATA REPORTING / REGULATORY REQUIREMENTS ..............................................79 
12.1 Data Reporting ........................................................................................................79 
12.2 Data Safety Monitoring...........................................................................................79 
13. STATISTICAL CONSIDERATIONS..................................................................................80 
13.1 Study Design/Endpoints..........................................................................................80 
13.2 Sample Size, Accrual Rate and Study Duration .....................................................80 
13.3 Interim Monitoring Plan .........................................................................................81 
13.4 Analysis of Primary Endpoints ...............................................................................81 
13.5 Analysis of Secondary Endpoints ...........................................................................81 
14. PUBLICATION PLAN ........................................................................................................83 
REFERENCES ..............................................................................................................................84 
APPENDIX A PERFORMANCE STATUS CRITERIA ...........................................................90 
 
APPENDIX B    MANAGEMENT ALGORITHMS……………………………………………89 
 
 


  
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1. OBJECTIVES 
 
Genotype-directed therapy is currently the standard of care for patients with advanced non-small-
cell lung cancer (NSCLC) harboring targetable driver gene mutations. Epidermal growth factor 
receptor (EGFR) activating mutations and anaplastic lymphoma kinase (ALK) rearrangements 
define the two best characterized molecular subsets of NSCLC, with remarkable sensitivity to 
tyrosine kinase inhibitors (TKIs) targeting EGFR and ALK, respectively (1-14). However, most 
patients relapse on TKI therapy within 1-2 years due to acquired resistance. The underlying 
mechanism of resistance at the time of progression can guide the choice of next-line therapy. For 
example, 50-60% of EGFR-mutant NSCLC patients who relapse on a first- or second-generation 
EGFR inhibitor (i.e., erlotinib, gefitinib, or afatinib) carry the EGFR T790M gatekeeper 
mutation, and these patients can be effectively treated with a third-generation T790M-selective 
EGFR TKI such as osimertinib (8). Similarly, ALK-positive NSCLC patients who relapse on the 
first-generation ALK TKI crizotinib may then be treated with one of several next-generation 
ALK TKIs (e.g., ceritinib, alectinib, with others in development including brigatinib and 
lorlatinib) (12-14).  
 
Once the available TKI options are exhausted, however, chemotherapy becomes the standard of 
care. In randomized trials assessing the efficacy of first-line platinum-based chemotherapy as the 
control arm in EGFR- or ALK-positive NSCLC (i.e., LUX-Lung 3 or PROFILE 1014), responses 
were seen in ~45% of patients with median progression-free survival (PFS) limited to ~7 months 
(6, 11). These trials, however, were performed in treatment-naïve patients. The efficacy of 
cytotoxic chemotherapy in patients previously treated with multiple TKIs may be significantly 
lower, closer to 20-30% (2, 15, 16). Patients with EGFR- or ALK-positive NSCLC who exhaust 
TKIs and also progress on platinum-based chemotherapy have even more limited therapeutic 
options. In a preliminary report of a phase III study in patients with ALK-rearranged NSCLC 
who failed crizotinib and prior chemotherapy, docetaxel or pemetrexed led to responses in less 
than 7% of patients (17), and median PFS was only 1.6 months. Therefore, there is an urgent 
unmet need for better therapeutic strategies in TKI-resistant patients. 
 
Nivolumab is a monoclonal antibody directed against programmed death receptor 1 (PD-1), 
approved in the U.S. to treat advanced NSCLC after progression on platinum-based 
chemotherapy. This approval was based on randomized studies demonstrating improved overall 
survival in patients treated with second-line nivolumab compared to chemotherapy, and a 
favorable safety profile (18, 19). Combining nivolumab with chemotherapy, or other 
immunotherapeutic agents with a different mechanism of action, may enable a synergistic 
response. In an early-phase study of first-line nivolumab plus platinum-based chemotherapy in 
advanced NSCLC, there were no dose-limiting toxicities, and responses were seen in 33-47% of 
patients (20). The majority of patients in these studies had EGFR- and ALK-wild-type tumors. 
Thus, the effectiveness of nivolumab combination regimens in EGFR-mutant and ALK-
rearranged patients remains unknown. In the IMpower150 study, the combination of 
pembrolizumab (another PD-1 inhibitor) with chemotherapy and bevacizumab demonstrated 
clinical benefit compared to chemotherapy and bevacizumab in patients with advanced NSCLC 
including those with EGFR-mutant and ALK-rearranged NSCLC (21). It is plausible that the 
addition of bevacizumab, an anti-angiogenesis agent, may enhance the anti-tumor activity of the 
combination of immunotherapy and chemotherapy.  


  
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We hypothesize that the combination of nivolumab and platinum-doublet chemotherapy may 
improve tumor responses in patients with TKI-pre-treated, chemotherapy-naïve EGFR- or ALK-
positive NSCLC. For patients who are eligibile for treatment with bevacizumab, the combination 
of nivolumab and platinum-double chemotherapy plus bevacizumab may further improve tumor 
responses.   
 
1.1 
Study Design 
 
This is a phase II, multi-cohort trial evaluating the efficacy and safety of nivolumab administered 
in combination with platinum-doublet, with or without bevacizumab, in TKI-pre-treated patients 
who are chemotherapy-naïve. Patients with advanced EGFR-mutant or ALK-rearranged NSCLC 
will be eligible. The patients must have advanced EGFR-mutant NSCLC that progressed on a 
third-generation EGFR TKI, or advanced ALK-rearranged NSCLC which progressed on at least 
one next-generation ALK TKI. Patients must be chemotherapy-naïve.  
 
• Eligible patients who are bevacizumab-eligible will receive nivolumab plus carboplatin 
and pemetrexed plus bevacizumab for 4 cycles, followed by nivolumab, pemetrexed and 
bevacizumab maintenance therapy at the pre-specified doses.  
 
• Eligible patients who are bevacizumab-ineligible will receive nivolumab plus carboplatin 
and pemetrexed for 4 cycles, followed by nivolumab and pemetrexed maintenance 
therapy at the pre-specified doses.  
 
Therefore, in total, this study will consist of 4 cohorts: 
 
Nivolumab Plus Carboplatin and Pemetrexed Plus Bevacizumab (Cohorts E and F): 
 
• Cohort E: EGFR-mutant advanced NSCLC, previously treated with at least one third-
generation EGFR TKI and are chemotherapy-naïve and bevacizumab-eligible. 
 
• Cohort F: ALK-rearranged advanced NSCLC, previously treated with at least one next-
generation ALK TKI and are chemotherapy-naïve and bevacizumab-eligible. 
 
Nivolumab Plus Carboplatin and Pemetrexed (Cohorts G and H): 
 
• Cohort G: EGFR-mutant advanced NSCLC, previously treated with at least one third-
generation EGFR TKI and are chemotherapy-naïve and bevacizumab-ineligible. 
 
• Cohort H : ALK-rearranged advanced NSCLC, previously treated with at least one next-
generation ALK TKI and are chemotherapy-naïve and bevacizumab-ineligible. 
 
Our primary objective will be to evaluate the efficacy of these combinations using objective 
response rate (ORR) in the treated subjects. Secondary endpoints will include the disease control 
rate (DCR), duration of response (DOR), duration on treatment, progression-free survival (PFS) 


  
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(including PFS rates at 6 months and at 12 months), and overall survival (OS) (including OS 
rates at 1 year and at 2 years). Safety and tolerability of the combination regimen will be 
assessed. As an exploratory analysis, efficacy endpoints will be calculated in subjects with PD-
L1-expressing tumors (defined as PD-L1 expression in ≥1% of tumor cells) versus subjects with 
PD-L1-non-expressing tumors. Exploratory endpoints will also include molecular profiling of 
baseline tumor biopsy tissues to evaluate for biomarkers of response or resistance to the 
combination therapy (e.g., expression of immunoregulatory molecules such as PD-L1, PD-L2 
cytokines, T-cell subsets).   
 
Efficacy assessments (CT chest/abdomen) will be performed every 6 weeks for the first 6 
months, after which assessments will be performed every 12 weeks. Treatment will continue 
until disease progression, unacceptable toxicity, patient withdrawal, death or discontinuation 
from the study for any other reason. Subjects may be allowed to continue study therapy after 
investigator-assessed progression defined by Response Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST 1.1), if, in the opinion of the treating investigator, they are deriving clinical 
benefit and tolerating the study drugs. 
 
1.2 
Primary Objectives 
 
• To evaluate the objective response rate (ORR) of nivolumab administered in combination 
with carboplatin and pemetrexed, with or without bevacizumab, to patients with 
advanced EGFR-mutant NSCLC, who have been previously treated with a third-
generation EGFR-TKI but are chemotherapy-naive. 
 
• To evaluate ORR of nivolumab administered in combination with carboplatin and 
pemetrexed, with or without bevacizumab, to patients with advanced ALK-positive 
NSCLC, who have been previously treated with one or more next-generation ALK-TKIs 
but are chemotherapy-naive. 
 
1.3 
Secondary Objectives 
 
• Disease control rate (DCR), based on RECIST 1.1 
 
• Duration of response (DOR), based on RECIST 1.1 
 
• Duration on therapy  
 
• Progression-free survival (PFS), including PFS rate at 6 months, and at 12 months, based 
on RECIST 1.1 
 
• Overall survival (OS), including OS rate at 1 year, and at 2 years 
 
• Safety profile and tolerability of the combination regimen, based on reporting of adverse 
events and laboratory abnormalities 
 


  
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1.4 
Exploratory Objectives 
 
• To assess the ORR, DCR, DOR, duration on therapy, PFS (including PFS rates at 6 
months and 12 months), and OS (including OS rates at 1 year and 2 years) in PD-L1(+) 
and in PD-L1(-) treated subjects. PD-L1(+) will be defined as subjects with tumors that 
express PD-L1 in ≥1% of tumor cells. 
 
• To assess the abundance of immunoregulatory proteins (e.g., PD-L1) in tumor tissue 
samples prior to treatment. 
 
• To investigate the presence of immune cytokines and/or genetic mutations in baseline 
tumor tissue or peripheral blood samples as biomarkers of response to nivolumab 
combination regimens (optional). 
 
 
2. BACKGROUND 
 
2.1 
Advanced NSCLC 
 
Lung cancer has been one of the most common cancers in the United States and in the world for 
decades. It is the leading cause of cancer-related deaths, accounting for over 25% of cases in the 
United States (22). NSCLC comprises approximately 85% of all lung cancers. The majority of 
NSCLC patients present with advanced or metastatic disease at the time of diagnosis. For these 
patients, five-year survival rate remains less than 5% (22). The current standard of care first-line 
therapy for advanced NSCLC without a molecular driver consists of platinum-based combination 
chemotherapy. First-line platinum doublet chemotherapy regimens generate an ORR of 
approximately 20-35% in advanced NSCLC, with median PFS ranging 4-6 months and overall 
survival (OS) ranging 8-11 months (23-25). The discovery of subsets of NSCLC harboring 
targetable driver oncogene mutations, such as EGFR mutations or ALK rearrangements, has led 
to a paradigm shift in the diagnostic and therapeutic approach to NSCLC. The presence of these 
molecular driver alterations in NSCLC guides patient treatment, and molecular testing of 
NSCLC at the time of diagnosis is thus recommended. 
 
2.1.1 EGFR-Mutant NSCLC 
 
Activating somatic mutations in EGFR were first reported in NSCLC in 2004, and are identified 
in 10-20% of NSCLC patients in the West and 30-40% in Asia (27). Clinically, oncogenic EGFR 
mutations are associated with adenocarcinoma histology, never or light smoking history, and 
female gender. The most common activating EGFR mutations—exon 19 deletions and the 
L858R point mutation in exon 21—account for approximately 90% of EGFR-mutant NSCLC 
cases. In vitro, these mutations lead to constitutively active EGFR and activation of multiple 
downstream signaling pathways that promote survival, proliferation, and angiogenesis (27, 28).  
 
Numerous randomized trials have demonstrated the superior efficacy of EGFR TKI(s) over 
chemotherapy in patients with advanced EGFR-mutant NSCLC. Selective inhibition of EGFR in 
this patient population using a first-generation EGFR TKI (i.e., erlotinib and gefitinib) leads to 


  
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responses in 60-80% of patients (versus 20-30% in the chemotherapy control arms), with median 
PFS of 8-14 months (versus 4-6 months in the chemotherapy control arms) (1-8). The median OS 
of patients with advanced EGFR-mutant NSCLC treated with EGFR-directed therapy now 
exceeds 2 years (29, 30).  
 
Despite the remarkable initial efficacy, the duration of response to EGFR TKIs is invariably 
limited because the tumor cells acquire resistance. While numerous resistance mechanisms have 
been described, the predominant mechanism is acquisition of the gatekeeper mutation in EGFR, 
T790M. This mutation is identified in 50-60% of patients after relapse on a first- or second-
generation EGFR TKI, and leads to increased ATP-binding affinity of the EGFR kinase (26). 
Third-generation, irreversible EGFR TKIs such as osimertinib, rociletinib, and EGF816 spare the 
wild-type EGFR, but inhibit the sensitizing EGFR mutants L858R and exon 19 deletion and the 
resistant EGFR mutant T790M with similar potencies. In EGFR T790M-positive patients who 
have progressed after prior EGFR TKIs, osimertinib is associated with an ORR of 61% (8). 
Osimertinib has been approved in the U.S. for use in this patient population. Furthermore, based 
on the phase III FLAURA trial which compared osimertinib to a first-generation EGFR TKI in 
untreated EGFR-mutant advanced NSCLC, osimertinib is now considered the standard first-line 
therapy in these patients (31).   
 
However, acquired resistance to third-generation EGFR TKIs also emerges, limiting the duration 
of clinical benefit (8). Studies investigating resistance mechanisms to osimertinib and/or 
rociletinib have identified a novel EGFR C797S mutation in 20-30% of resistant cases, and copy 
number gains in MET, ERBB2, and EGFR (32, 33).  Once patients progress on a third-generation 
EGFR TKI, the standard treatment becomes platinum-based combination chemotherapy (or 
clinical trials of targeted therapies, if an actionable resistance mechanism is discovered in an 
individual patient). Platinum-doublet chemotherapy following progression on a prior EGFR TKI 
generally leads to responses in 20-30% with a PFS of 3-6 months (2, 15, 16). If patients 
subsequently progress on the platinum-based chemotherapy or cannot tolerate this regimen, then 
the options become further narrowed to single-agent chemotherapy, clinical trials, or 
immunotherapy. Studies evaluating single-agent second-line chemotherapy in unselected 
advanced NSCLC have generally demonstrated low response rates (<10%) with short median 
PFS (<3 months) (34, 35). Therefore, a significant unmet need exists for more effective and 
tolerable treatment options for patients with EGFR-mutant NSCLC after they exhaust EGFR 
TKIs. 
 
2.1.2 ALK-Rearranged NSCLC 
 
Chromosomal rearrangements involving the ALK gene were first identified in a small cohort of 
Japanese NSCLC patients in 2007 (36). Since then, ALK gene fusions have been found in 3-7% 
of NSCLCs, associated with never or light smoking history, younger age, and adenocarcinoma 
histology (37). The most common fusion partner for ALK in NSCLC is the echinoderm 
microtubule associated protein-like 4 (EML4) gene. More than 10 variants of EML4-ALK have 
been reported, all of which arise from an intrachromosomal inversion event in the short arm of 
chromosome 2 and preserve the ALK kinase domain (exons 20-29) (38). ALK rearrangements 
result in ligand-independent oligomerization and constitutive activation of ALK, promoting 
downstream survival and proliferation. Preclinical studies have demonstrated the potent 


  
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transforming capacity of ALK fusions like EML4-ALK (36, 39). Furthermore, ALK-rearranged 
NSCLC cells are dependent on continued ALK signaling for survival and growth (39). 
 
The remarkable sensitivity of ALK-rearranged NSCLCs to ALK inhibition first became clinically 
evident with crizotinib. Crizotinib was originally synthesized as a potent MET inhibitor, but 
biochemical kinase assays revealed its additional activity against ALK and ROS1. In the phase I 
study of 82 patients with ALK-rearranged NSCLC, most of whom had received prior treatment, 
the ORR was 57% with a disease control rate (DCR) of 90% (9). Crizotinib was granted 
accelerated approval by the U.S. Food and Drug Administration (FDA) in 2011 based on the 
remarkable anti-tumor efficacy demonstrated in phase I/II studies. Subsequently, two 
randomized phase III studies demonstrated the superior efficacy of crizotinib over chemotherapy 
in both the second-line (ORR 65%, median PFS 7.7 months) and first-line setting (ORR 74%, 
median PFS 10.9 months) (10, 11).  
 
Most patients ultimately relapse on crizotinib due to acquired resistance. Resistance can arise due 
to a broad array of mechanisms, including secondary ALK mutations (including the most 
common L1196M and G1269A resistance mutations), ALK amplification, and bypass signaling 
track activation (e.g., EGFR, c-KIT activation, MEK activation) (40-42). Once ALK-rearranged 
NSCLC patients progress on (or are intolerant of) crizotinib, they may be treated with next-
generation ALK inhibitors such as ceritinib, alectinib, and brigatinib, which are FDA-approved. 
Responses to ceritinib and alectinib are seen in ~50% of crizotinib-pre-treated ALK-rearranged 
NSCLC patients (12-14). Multiple additional next-generation ALK inhibitors including lorlatinib 
are in clinical development. Again, acquired resistance to these TKIs due to various mechanisms 
limits the duration of responses (43).  
 
Following progression on a second-generation ALK TKI (e.g., ceritinib, alectinib, brigatinib) 
and/or third-generation ALK TKI (e.g., lorlatinib), the resistance mechanism(s) operant in an 
individual patient’s tumor may guide the choice of next-line therapy (43). For example, 
identification of an ALK resistance mutation (e.g., ALK G1202R) after failure on ceritinib, 
alectinib or brigatinib, may suggest lorlatinib as the next therapy, as lorlatinib has been shown to 
overcome all known resistance mutations. However, patients still relapse on lorlatinib and 
typically become refractory to all ALK TKIs.  In this setting, options may include combination 
regimens in clinical trials or standard cytotoxic chemotherapy (i.e., platinum-based 
combination). Once these patients also progress on the platinum-containing chemotherapy, 
treatment using single-agent chemotherapy is generally ineffective (ORR <10%) (17). Better 
treatment options are thus needed for ALK-rearranged NSCLC patients after they have 
progressed on the available ALK TKIs.  
 
 
2.2 
Overview of Nivolumab 
 
2.2.1 Nivolumab Pharmacology and Nonclinical Data 
 
Nivolumab (also referred to as BMS-936558 or MDX-1106) is a fully human, immunoglobulin 
G4 (IgG4) isotype monoclonal antibody directed against the immune checkpoint cell surface 
receptor, programmed death-1 (PD-1) (44). PD-1 is predominantly expressed on activated T and 
B lymphocytes and memory T cells. It binds to two known ligands, programmed death-ligand 1 


  
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(PD-L1, also called B7-H1) and programmed death-ligand 2 (PD-L2, also called B7-DC), 
expressed on antigen-presenting cells (APCs) and dendritic cells (DCs). This interaction leads to 
the inhibition of CD28-mediated IL-2/IL-10/IL-13 and interferon-γ (IFN-γ) upregulation, and 
inhibition of T cell activation and proliferation, effectively modulating the physiologic peripheral 
T cell response and mediating tolerance to self-antigens (45).   
 
While PD-1 belongs to the CD28 family of receptors including CD28, CD28 inducible co-
stimulator (ICOS), cytotoxic T-lymphocyte antigen 4 (CTLA-4), and B and T lymphocyte 
attenuator (BTLA), nivolumab has been shown to bind specifically to PD-1 and not to the related 
CD28 family members. In vitro studies have demonstrated that nivolumab binds PD-1 with high 
affinity (EC50 0.39-2.6 nM) and disrupts its interaction with PD-L1 and PD-L2 with an IC50 of ~1 
nM (44). This results in abrogation of the inhibitory signals, enhanced T-cell proliferation and 
IFN-γ release in vitro (46-48). In mouse tumor models, expression of PD-L1 promotes immune 
resistance and tumor growth, and PD-1/PD-L1 blockade using monoclonal antibodies leads to 
anti-tumor immune responses (48-50). Repeat-dose toxicology studies of nivolumab in 
cynomolgus monkeys suggested that the drug was well tolerated at tested doses, with no clinical 
effects on body weight, food consumption, or vital sign parameters (44). 
 
2.2.2 Nivolumab Clinical Data 
 
The dose escalation study of nivolumab provided preliminary evidence for its clinical anti-tumor 
efficacy. In a phase I study of nivolumab in refractory solid tumors (including metastatic 
melanoma (n = 104), NSCLC (n = 122), castration-resistant prostate cancer (n = 17), renal cell 
carcinoma (n = 34), and colorectal cancer (n = 19)), a total of 296 patients were treated with 
nivolumab at doses of 0.1-10 mg/kg every 2 weeks (51). Nivolumab was generally well 
tolerated, and a maximal tolerated dose (MTD) was not defined. Most frequent adverse events 
(AEs) were fatigue, decreased appetite, diarrhea, nausea, cough, dyspnea, constipation, and 
nausea. Common treatment-related AEs included fatigue, rash, diarrhea, pruritus, decreased 
appetite, and nausea. Treatment-related AEs of special interest, including pneumonitis, colitis, 
hepatitis, hypophysitis, vitiligo, uveitis, and thyroiditis, occurred in 44% of patients. Grade ≥3 
AEs were noted in a total of 14% of patients, and drug-related serious AEs occurred in 11% of 
patients. The spectrum, frequency, and severity of AEs did not differ across doses (51). In this 
study, anti-tumor activity of nivolumab was observed at all doses in NSCLC, melanoma, and 
renal cell carcinoma. In 76 patients with lung cancer, ORRs of 6%, 32%, and 18% were observed 
at doses of 1.0, 3.0, or 10.0 mg/kg, respectively. Responses were seen in 6 of 18 patients (33%) 
with squamous NSCLC, and 7 of 56 patients (12%) with non-squamous NSCLC (51).  
 
In the phase I dose escalation cohort expansion trial, 129 patients with pretreated advanced 
NSCLC (at least one line of platinum- or taxane-based regimen) were treated with nivolumab at 
doses of 1, 3, or 10 mg/kg every 2 weeks (52). The ORR was 17% across all doses, 24% at the 3 
mg/kg and 20% at the 10 mg/kg dose levels. The median duration of response was 17 months, 
and median PFS among the responders was 20.6 months. Median OS for all patients was 9.9 
months, but in the patients receiving nivolumab 3 mg/kg (n = 37), median OS was 14.9 months. 
The most common treatment-related AEs were fatigue (24%), decreased appetite (12%), and 
diarrhea (10%). Among the 14% of patients who experienced graded ≥3 treatment-related AEs, 
the most common was fatigue, which occurred in 3%. In 41% of 129 patients, treatment-related 


  
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select AEs of any grade were noted, including most commonly, skin (16%), GI (12%), and 
pulmonary events. Four patients (3%) experienced treatment-related grade ≥3 pneumonitis, and 
three treatment-related deaths occurred, associated with pneumonitis (52).  
 
Subsequently, two randomized phase III trials demonstrated the superior activity of nivolumab 
versus docetaxel in advanced non-squamous (CheckMate 057) and squamous (CheckMate 017) 
NSCLC (18, 19). In CheckMate 057, 582 patients with advanced non-squamous NSCLC who 
progressed on or after one prior chemotherapy regimen (platinum-based doublet) were 
randomized to nivolumab (3 mg/kg every 2 weeks) versus docetaxel. ORR was significant higher 
for nivolumab compared to docetaxel (19% versus 12%), and median duration of response was 
17.2 months versus 5.6 months, respectively (19). OS was also improved with nivolumab 
(median, 12.2 months versus 9.4 months; hazard ratio (HR), 0.73). Notably, the benefit from 
nivolumab correlated with PD-L1 expression in the tumor. In 53% of patients with PD-L1-
expressing tumor (at the cut-off of PD-L1 ≥1%), ORR to nivolumab was 31%, and in 41% of 
patients with PD-L1 ≥5%, ORR was 36%. There was similarly a significant correlation between 
OS and PD-L1 expression (19). Because the study met its primary endpoint of superior OS, it 
was stopped at a pre-planned interim analysis by the Independent Data Monitoring Committee.  
 
In the CheckMate 017 study, 272 patients with advanced squamous NSCLC who progressed on 
first-line platinum-based chemotherapy were randomized to nivolumab versus docetaxel (18). 
Again, nivolumab demonstrated a superior clinical efficacy with ORR of 20% (versus 9% for 
docetaxel). Median OS was 9.2 months with nivolumab compared to 6.0 months with docetaxel 
(HR for risk of death, 0.59). Although the PD-L1 expression did not significantly correlate with 
clinical benefit, there was a trend for longer survival in the PD-L1-expressing subgroups (18). 
Based on the data from these two phase III trials, nivolumab was granted approval by the U.S. 
FDA for use in both squamous and non-squamous metastatic NSCLC after progression on or 
after platinum-based chemotherapy.  
 
Most recently, activity of nivolumab monotherapy as first-line therapy for advanced NSCLC was 
investigated. In the phase I CheckMate 012 study, 52 treatment-naïve patients received 
nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity (53). The primary 
endpoint was safety. The most common treatment-related AEs of any grade included fatigue 
(29%), rash (19%), nausea (14%), diarrhea and pruritus (12% each), and arthralgia (10%). Grade 
≥3 treatment-related AEs occurred in 19% of patients, including rash (4%), increased amylase 
and lipase, increased liver enzymes, hyperglycemia, cardiac failure, dehydration and diarrhea, 
hyponatremia, lung infection, and pneumonitis (1 patient each). Six patients (12%) discontinued 
treatment due to drug-related toxicity. The confirmed ORR was 23% with 4 ongoing responses. 
ORR was 28% in patients with PD-L1 expressing tumors (versus 14% in PD-L1 non-expressors). 
Responses were durable (median DOR, not reached, range 4.2-25.8+ months). The median OS 
was 19.4 months, with 1-year OS rate of 73% and 18-month OS rate of 57% (53). Based on these 
findings, nivolumab monotherapy as first-line therapy is being evaluated in phase III trials 
(CheckMate 227, NCT02477826; CheckMate 026, NCT02041533).  
 
2.2.3 Nivolumab Pharmacokinetics (PK) 
 
The single-dose PK of nivolumab was investigated in 39 patients with cancer, and found to be 


  
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linear and dose-proportional at doses ranging 0.3 mg/kg to 10 mg/kg (44, 54). The median Tmax 
ranged from 1.6 to 3 hours. Across the tested doses, the geometric mean total clearance ranged 
from 0.13 mL/h/kg to 0.19 mL/h/kg, and the mean volume of distribution during the terminal 
phase (Vz) varied from 83 mL/kg to 113 mL/kg, demonstrating approximate dose 
proportionality. The mean terminal elimination half-life (t1/2) was 17 to 25 days, consistent with 
the half-life of IgG4. 
 
Single- and multiple-dose PK of nivolumab was studied in patients with various tumor types 
including melanoma and NSCLC, at doses ranging 0.1 to 10 mg/kg (single dose, or multiple 
doses given every 2 or 3 weeks) (44). After the first dose, geometric mean of Cmax ranged 1.9 to 
191.2 µg/mL, and AUC ranged 279 to 31095 µg.h/mL. At the steady-state PK on cycle 3 day 1, 
geometric mean of Cmax ranged 3.7 to 475 µg/mL, and AUC ranged 1104 to 99621 µg.h/mL. The 
exposure to nivolumab increased in a dose-proportional manner over the dose levels of 0.1 to 10 
mg/kg administered every 2 weeks. The geometric mean AUC was 2.9 to 3.3 µg.h/mL. The 
geometric mean clearance (CL) was 9.5 mL/h. Geometric mean volume of distribution at steady 
state (Vss) was 8.0L, and the geometric mean t1/2 was 26.7 days.  
 
Based on the population PK analysis, the clearance of nivolumab increased with increasing body 
weight. It was not dependent on age, gender, race, PD-L1 expression, tumor type, or baseline 
tumor size. It also did not appear to be affected by renal impairment (as measured using baseline 
glomerular filtration rate (GFR)) or mild hepatic impairment (total bilirubin 1.0 to 1.5 times the 
upper limit of normal (ULN) or AST > ULN as defined using the National Cancer Institute 
criteria of hepatic dysfunction) (44).  
 
Please refer to the Nivolumab Investigator’s Brochure for detailed information regarding the 
pharmacology, toxicology, drug metabolism, and adverse event profile of nivolumab.  
 
2.3 
Overview of Carboplatin and Pemetrexed Combination 
 
2.3.1 Carboplatin 
 
Carboplatin is a platinum coordination compound (chemical name: platinum, diammine[1,1-
cyclobutane-dicarboxylato(2-)-0,0’]-,(SP-4-2)). Like cisplatin, carboplatin predominantly 
introduces inter-strand DNA cross-links to interfere with DNA repair. Carboplatin is used for the 
treatment of several cancers including ovarian, endometrial, lung, head and neck, esophageal, 
bladder, breast, and cervical cancers; it is currently approved by the U.S. FDA for use in ovarian 
and lung cancers. The most commonly observed side effects include anemia, leukopenia, 
neutropenia, thrombocytopenia, nausea and vomiting, hypomagnesemia, hyponatremia, 
hypocalcemia, hypokalemia, and liver enzyme abnormalities. Peripheral neuropathies and 
nephrotoxicity are significantly less frequent and less severe than with cisplatin (55). 
 
PK studies have revealed that carboplatin plasma levels decline in a biphasic manner after a 30-
minute intravenous infusion of 300 to 500 mg/m2 doses (55). The initial plasma half-life (alpha) 
was 1.1-2 hours, and the post-distribution plasma half-life (beta) was 2.6-5.9 hours. The total 
body clearance of carboplatin was 4.4 L/hour, and apparent volume of distribution was 16 L. PK 
of carboplatin was linear over the tested dose ranges of 300 to 500 mg/m2. While carboplatin is 


  
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not bound to plasma proteins, platinum from carboplatin is irreversibly bound to plasma proteins 
and eliminated with a minimum half-life of 5 days. The major route of elimination is renal 
excretion. Therefore, carboplatin doses should be reduced in patients with renal impairment 
(creatinine clearance <60 mL/min). In patients with normal renal function (creatinine clearance 
of ≥60 mL/min), 65% of the dose is excreted in the urine within 12 hours, and 71% within 24 
hours. Only 3-5% of the administered platinum is excreted in the urine between 24-96 hours.  
 
2.3.2 Pemetrexed 
 
Pemetrexed is an anti-folate antineoplastic agent. It disrupts several folate-requiring enzymes 
essential for cell replication, including thymidylate synthase (TS), dihydrofolate reductase 
(DHFR), and glycinamide ribonucleotide formyltransferase (GARFT) (56). Pemetrexed has been 
investigated in a number of tumor types. The most common AEs include fatigue, nausea, and 
anorexia. When used in combination with cisplatin, additional common AEs include vomiting, 
neutropenia, leukopenia, anemia, oral mucositis, thrombocytopenia, and constipation. 
Supplementation with folate and vitamin B12 reduces the frequency and severity of drug-related 
toxicities.  
 
The PK of pemetrexed has been evaluated in 426 cancer patients with solid tumors, at doses 
ranging from 0.2 to 838 mg/m2 infused over 10 minutes (56). The total systemic exposure (AUC) 
and Cmax were found to increase in a dose-proportional manner. PK parameters did not change 
over multiple treatment cycles. The Vss of pemetrexed is 16.1 L, and approximately 81% of 
pemetrexed is bound to plasma proteins. Pemetrexed is primarily excreted in the urine 
unchanged, with 70% to 90% of the dose excreted within the first 24 hours. The clearance 
decreases with decreasing renal function, with resultant increase in systemic exposure. The total 
systemic clearance of pemetrexed is 91.8 mL/min, and t1/2 is 3.5 hours in patients with normal 
renal function (56). 
 
2.3.3 Carboplatin Plus Pemetrexed Chemotherapy 
 
Platinum-based combination chemotherapy is the standard first-line treatment for patients with 
advanced NSCLC without targetable driver mutations. In the phase III study by the Eastern 
Cooperative Oncology Group (ECOG), E1594, four platinum-based doublet regimens were 
compared in 1,207 patients with treatment-naïve advanced NSCLC (23). No significant clinical 
advantage was identified for one specific regimen among cisplatin plus gemcitabine, cisplatin 
plus docetaxel, carboplatin plus paclitaxel, or cisplatin plus paclitaxel. The ORR was 19% for all 
patients, with a median OS of 7.9 months.  
 
Subsequently in a multi-centered randomized phase III study, cisplatin (75 mg/m2) plus 
pemetrexed (500 mg/m2) given on day 1 of a 21-day cycle was demonstrated to be non-inferior 
to cisplatin (75 mg/m2 on day 1) plus gemcitabine (1250 mg/m2 on days 1 and 8) of a 21-day 
cycle, in chemotherapy-naïve patients with advanced NSCLC (25). Notably, in patients with 
non-squamous histology, cisplatin plus pemetrexed produced statistically superior median OS 
(11.8 months, versus 10.4 months for cisplatin plus gemcitabine in adenocarcinoma histology; 
adjusted HR, 0.81). In the squamous patient population, median OS was 9.4 months and 10.8 
months for the cisplatin/pemetrexed and cisplatin/gemcitabine arms, respectively (adjusted HR, 


  
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1.23). The incidence of grade 3 or 4 hematologic drug-related AEs was significantly lower for 
cisplatin/pemetrexed compared to cisplatin/gemcitabine. With cisplatin/pemetrexed, neutropenia 
occurred in 15.1%, anemia in 5.6%, thrombocytopenia in 4.1%, and leukopenia in 4.8%. Drug-
related grade ≥3 febrile neutropenia occurred in 1.3%, alopecia of all grades in 11.9%, grade ≥3 
nausea in 7.2%, grade ≥3 vomiting in 6.1%, grade ≥3 fatigue in 6.7% (25).  
 
The combination of carboplatin and pemetrexed was found to confer efficacy comparable to 
cisplatin and pemetrexed in phase II studies (57, 58). In one phase II study, 50 patients with 
chemotherapy-naïve, advanced NSCLC were treated with carboplatin (AUC = 6) and 
pemetrexed (500 mg/m2) given every 3 weeks for 6 cycles (57). Partial responses were seen in 
24% of patients, with median OS of 13.5 months and 1-year OS rate of 56%. Grade 3/4 
neutropenia occurred in 26%, and grade 3/4 thrombocytopenia occurred in 2% of patients. Three 
patients (6%) experienced grade 3 non-hematologic AEs including diarrhea, neutropenia 
pneumonia, and fatigue. In another phase II study, 83 chemotherapy-naïve patients with 
advanced NSCLC were randomized to receive pemetrexed (500 mg/m2) plus either oxaliplatin 
(120 mg/m2) or carboplatin (AUC = 6) given every 3 weeks for up to 6 cycles (58). In the 39 
patients receiving pemetrexed and carboplatin, the ORR was 31.6%, and median OS was 10.5 
months with a 1-year OS rate of 43.9%. Common grade ≥3 AEs included neutropenia (25.6%), 
thrombocytopenia (17.9%), anemia (7.7%), fatigue (7.7%), stomatitis (2.6%), and febrile 
neutropenia (2.6%). Based on these studies demonstrating its efficacy and tolerability, the 
carboplatin/pemetrexed doublet has become a commonly used regimen in clinical practice.  
  
2.3.4 Pemetrexed Maintenance Therapy 
 
The survival benefit of maintenance therapy using single-agent pemetrexed has been 
demonstrated in two large trials. In one phase III study, 663 patients with advanced NSCLC who 
had not progressed on 4 cycles of platinum-based chemotherapy were randomized to receive 
pemetrexed (500 mg/m2) or placebo in 21-day cycles (59). Maintenance pemetrexed led to 
increased median PFS (4.3 months versus 2.6 months; HR, 0.50) and median OS (13.4 months 
versus 10.6 months; HR, 0.79) compared to placebo. Treatment-related grade ≥3 AEs occurred 
in 16% of patients treated with pemetrexed, the most common of which included fatigue (24%), 
anorexia (19%), nausea (19%), anemia (15%), ALT elevation (10%), vomiting (9%), sensory 
neuropathy (9%), and AST elevation (8%). Treatment discontinuation due to drug-related 
toxicities was noted in 5% of patients.  
 
In the PARAMOUNT trial, 539 patients with advanced NSCLC who achieved disease control 
after 4 cycles of cisplatin/pemetrexed were randomized to maintenance pemetrexed (500 mg/m2 
every 21 days) versus placebo (60). The mean number of pemetrexed cycles was 7.9 (range, 1 to 
44). Median PFS was significantly increased with pemetrexed compared to placebo (4.1 versus 
2.8 months; HR, 0.62). OS was also significantly increased (13.9 versus 11.0 months; 1-year OS 
rate, 58 versus 45%; HR, 0.78). The most common drug-related grade ≥3 AEs included anemia 
(6.4%), neutropenia (5.8%), fatigue (4.7%), leukopenia (2.2%), thrombocytopenia (1.9%), and 
febrile neutropenia (1.9%). Based on these studies, patients who achieve an objective response or 
stable disease with 4-6 cycles of platinum/pemetrexed typically continue on maintenance 
pemetrexed, until they develop disease progression or inability to tolerate chemotherapy. 


  
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2.4 
Overview of Bevacizumab and Combination with Chemotherapy 
 
2.4.1 Bevacizumab 
 
Bevacizumab is a recombinant humanized monoclonal antibody targeting vascular endothelial 
growth factor (VEGF), an important pro-angiogenic factor (61). EGF has been implicated in 
angiogenesis associated with tumor growth, and increased levels of VEGF have been detected in 
multiple tumor types including lung cancer. Bevacizumab may exert a direct anti-angiogenic 
effect by binding to and clearing VEGF from the tumor environment, and additionally impact 
tumor vasculature and blood vessel permeability to enhance chemotherapy delivery to tumor 
cells (62).  
 
Bevacizumab-associated safety signals identified in the initial phase I/II trials include 
hypertension, proteinuria, thromboembolic events, and hemorrhage. Additional safety signals 
include congestive heart failure, gastrointestinal perforations, wound healing complications, and 
arterial thromboembolic events. Reversible posterior leukoencephalopathy syndrome and fistula 
have also been reported infrequently. Further details on the safety profile of bevacizumab are 
available in the bevacizumab investigator’s brochure. 
 
2.4.2 Bevacizumab in Combination with Chemotherapy 
 
Bevacizumab has been evaluated in phase II and III studies in various types of solid tumors. Two 
phase III trials have demonstrated the benefit of bevacizumab administered in combination with 
platinum-based chemotherapy as first-line therapy in advanced non-squamous NSCLC. In the 
Eastern Cooperative Oncology Group phase III study (E4599), bevacizumab combined with 
first-line carboplatin/paclitaxel in patients with non-squamous advanced NSCLC demonstrated 
an improvement in OS and PFS compared to chemotherapy alone (OS 12.3 months versus 10.3 
months, respectively, HR 0.79, p = 0.003) (63). In the AVAIL study (BO17704), two doses of 
bevacizumab (7.5 mg/kg and 15 mg/kg every 3 weeks) in combination with cisplatin and 
gemcitabine were evaluated in comparison to chemotherapy alone, and again demonstrated a 
PFS benefit (64).   
 
2.5 
Study Rationale 
 
2.5.1 Rationale for Doses and Schedules of Nivolumab in Combination with 
Carboplatin/Pemetrexed 
 
Cancer immunity is regulated by complex interactions between the tumor and its 
microenvironment. Soluble and membrane-bound molecules on tumors and the tumor 
microenvironment (such as PD-1/PD-L1, transforming growth factor-ß (TGF-ß), and tumor 
necrosis factor (TNF)) can induce tumor tolerance, limit tumor antigen presentation, inhibit the 
cytolytic activity of effector T cells, and increase the immunosuppressive CD4+CD25+FOXP3+ 
regulatory T cells (Tregs) (65). Together, these mechanisms lead to the evasion of immune-
mediated tumor killing. Modulation of these interactions may help shift the equilibrium towards 


  
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immune activation rather than suppression, and boost anti-tumor immunity. 
 
Cytotoxic chemotherapy can facilitate an anti-tumor immune response through multiple 
immunomodulatory effects (65). It has been shown that certain chemotherapy drugs—including 
platinum compounds—can induce immunogenic cell death, mediated by the toll-like receptor-4 
(TLR-4) or purinergic receptor P2RX7 (66-68). This process triggers the release of chemotactic 
signals that recruit dendritic cells (DCs) and macrophages to the tumor site, enhanced expression 
of co-stimulatory molecules, and increased secretion of pro-inflammatory cytokines. 
Furthermore, chemotherapy agents can enhance the intrinsic tumor cell immunogenicity (e.g., 
increase the expression of MHC class I and antigen-processing machinery components, regulate 
PD-L1 expression), decrease Treg number or function, increase peripheral myeloid-derived 
suppressor cells, and impact DC phenotype and function (67) Platinum compounds, in particular, 
have been found to strongly enhance T cell activation by DCs in vitro, through the loss of 
STAT6 phosphorylation and downregulation of PD-L2 (66, 69). STAT3 expression and 
phosphorylation may also be modulated by platinum compounds (66, 70, 71). 
 
Based on the immunogenic properties of standard chemotherapies and their limited duration of 
benefit when used alone, various regimens combining platinum-based doublet chemotherapy 
(PT-DC) with immune checkpoint inhibitors are now being tested. In the CheckMate 012 phase I 
study, 56 treatment-naïve advanced NSCLC patients received one of 4 regimens: nivolumab 10 
mg/kg plus cisplatin/gemcitabine (squamous; n = 12) or cisplatin/pemetrexed (nonsquamous; n = 
15), or nivolumab 5 mg/kg or 10 mg/kg plus carboplatin/paclitaxel (all histologies; n = 15 and n 
= 14, respectively). Nivolumab and PT-DC were given intravenously on day 1 of each 21-day 
cycle (and also on day 8 for the cisplatin/gemcitabine cohort) for 4 cycles, followed by 
nivolumab monotherapy every 3 weeks at the same dose (20). 
 
No DLTs were reported during the first 6 weeks of treatment. The overall safety profile reflected 
the additive side effects of the PT-DC and nivolumab (20). Forty-five percent (45%) of the 
overall population experienced grade ≥3 treatment-related AEs, the most common of which were 
pneumonitis, fatigue, and acute renal failure (Table 2.5.1-1).  
 
Table 2.5.1-1: 
Treatment-Related AEs Reported in ≥10% of All Patients with Advanced 
NSCLC Treated with Nivolumab Plus PT-DC, and of Patients Treated 
with Nivolumab Plus Cisplatin/Pemetrexed 
 
Treatment-related AE 
No. of Patients (%) 
Nivolumab + Cis/Pem (n = 15) 
All Patients (n = 56) 
Any Grade 
Grade 3 or 4 
Any Grade 
Grade 3 or 4 
Any event 
14 (93) 
7 (47) 
53 (95) 
25 (45) 
Fatigue 
12 (80) 
1 (7) 
40 (71) 
3 (5) 
Nausea 
10 (67) 
1 (7) 
26 (46) 
1 (2) 
Decreased appetite 
7 (47) 
0 
20 (36) 
1 (2) 
Alopecia 
1 (7) 
0 
17 (30) 
0 
Anemia 
2 (13) 
0 
15 (27) 
2 (4) 
Rash 
5 (33) 
0 
15 (27) 
1 (2) 
Diarrhea 
2 (13) 
0 
12 (21) 
1 (2) 


  
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Arthralgia 
3 (20) 
0 
12 (21) 
0 
Constipation 
4 (27) 
0 
11 (20) 
0 
Peripheral neuropathy 
2 (13) 
0 
11 (20) 
0 
Dysgeusia 
2 (13) 
0 
8 (14) 
0 
Hypersensitivity 
3 (20) 
1 (7) 
8 (14) 
1 (2) 
Vomiting 
4 (27) 
0 
8 (14) 
0 
Mucosal inflammation 
1 (7) 
0 
7 (13) 
0 
Myalgia 
0 
0 
7 (13) 
0 
Pneumonitis 
3 (20) 
2 (13) 
7 (13) 
4 (7) 
Infusion-related reaction 
4 (27) 
0 
6 (11) 
0 
Leukopenia 
2 (13) 
0 
6 (11) 
0 
Lymphopenia 
1 (7) 
0 
6 (11) 
0 
Peripheral sensory neuropathy 
1 (7) 
0 
6 (11) 
0 
Pruritus 
2 (13) 
0 
6 (11) 
0 
Tinnitus 
4 (27) 
0 
5 (9) 
0 
Cough 
2 (13) 
0 
3 (5) 
0 
Dry skin 
2 (13) 
0 
2 (4) 
0 
 
The immune-related AEs affecting the skin, GI, renal, and pulmonary occurred in 36%, 23%, 
14%, and 7% of patients, respectively (Table 2.5.1-2). Among the patients receiving nivolumab 
with cisplatin/pemetrexed, the immune-related AEs affecting the skin, GI, renal, and pulmonary 
occurred in 40%, 20%, 20%, and 20% of the patients. Treatment-related AEs led to drug 
discontinuation in 21% of the patients, including 33% of patients (5 of 15 patients) in the 
nivolumab plus cisplatin/pemetrexed arm. Most discontinuations were observed during the 
nivolumab maintenance therapy. The treatment-related AEs including pneumonitis were 
effectively managed with steroids or infliximab. No treatment-related deaths were reported (20). 
 
Table 2.5.1-2: 
Treatment-Related Immune AEs Reported in ≥10% of All Patients with 
Advanced NSCLC Treated with Nivolumab Plus PT-DC, and of Patients 
Treated with Nivolumab Plus Cisplatin/Pemetrexed 
 
Immune AE 
No. of Patients (%) 
Nivolumab + Cis/Pem (n = 15) 
All Patients (n = 56) 
Any Grade 
Grade 3 or 4 
Any Grade 
Grade 3 or 4 
Skin 
6 (40) 
0 
20 (36) 
3 (5) 
   Rash 
5 (33) 
0 
15 (27) 
1 (2) 
   Pruritus 
2 (13) 
0 
6 (11) 
0 
   Rash maculopapular 
0 
0 
3 (5) 
2 (4) 
   Erythema 
1 (7) 
0 
1 (2) 
0 
   Rash pruritic 
0 
0 
1 (2) 
0 
GI 
3 (20) 
1 (7) 
13 (23) 
2 (4) 
   Diarrhea 
2 (13) 
0 
12 (21) 
1 (2) 
   Colitis 
1 (7) 
1 (7) 
2 (4) 
1 (2) 
Hypersensitivity/infusion 
reaction 
6 (40) 
1 (7) 
13 (23) 
1 (2) 
   Hypersensitivity 
3 (20) 
1 (7) 
8 (14) 
1 (2) 


  
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   Infusion-related reaction 
4 (27) 
0 
6 (11) 
0 
Renal 
3 (20) 
1 (7) 
8 (14) 
3 (5) 
   Blood creatinine increased 
1 (7) 
0 
4 (7) 
0 
   Acute renal failure 
1 (7) 
1 (7) 
3 (5) 
3 (5) 
   Allergic nephritis 
1 (7) 
1 (7) 
2 (4) 
2 (4) 
   Blood urea increased 
0 
0 
1 (2) 
0 
   Creatinine renal clearance 
decreased 
1 (7) 
0 
1 (2) 
0 
   Renal failure 
0 
0 
1 (2) 
0 
   Tubulointerstitial nephritis 
1 (7) 
0 
1 (2) 
0 
Pulmonary 
3 (20) 
2 (13) 
7 (13) 
4 (7) 
   Pneumonitis 
3 (20) 
2 (13) 
7 (13) 
4 (7) 
 
The ORRs for all nivolumab and chemotherapy arms ranged 33% to 47%, with DCRs ranging 
73% to 93% (20). In the nivolumab plus cisplatin/pemetrexed arm, ORR was 47% (7 of 15 
patients), and DCR was 93% (14 of 15 patients). The 24-week PFS rate for all arms ranged 38% 
to 71% (in the nivolumab plus cisplatin/pemetrexed cohort, 71%). The median OS for patients 
that received nivolumab plus cisplatin/pemetrexed was 19.2 months, with 1-year OS rate of 87% 
and 2-year OS rate of 33%.  
 
These data suggest that the regimen combining nivolumab with platinum plus pemetrexed is 
overall tolerable, and effective in patients with advanced NSCLC. Moreover, they provide the 
rationale for investigating the efficacy of nivolumab plus PT-DC in TKI-pre-treated but 
chemotherapy-naïve patients with advanced EGFR-mutant or ALK-rearranged NSCLCs. The 
majority of patients in the CheckMate 012 study (89%) did not have EGFR mutations in the 
tumor, and were not evaluated for the presence of ALK rearrangements (20). The efficacy of 
combining nivolumab and PT-DC in TKI-pre-treated patient populations is also unknown. 
 
The present study will evaluate the PT-DC regimen of carboplatin (AUC = 5) and pemetrexed 
(500 mg/m2) in combination with nivolumab. Carboplatin plus pemetrexed is a standard of care 
chemotherapeutic regimen for treatment-naïve patients with advanced non-squamous NSCLC 
without molecular alterations, and also for patients with EGFR-mutant or ALK-rearranged 
NSCLC after progression on available TKIs.  
 
Patients will receive 4 cycles of carboplatin and pemetrexed plus nivolumab on an every 3-week 
cycle, followed by maintenance of pemetrexed plus nivolumab every 3 weeks until disease 
progression, inability to tolerate, study termination, or death, whichever occurs first. The 
duration of the initial platinum-based induction is based on multiple trials and a meta-analysis of 
5 trials that compared 6 cycles versus 3-4 cycles (72). There was no statistically significant 
improvement in OS with 6 cycles versus 3-4 cycles (9.5 versus 8.7 months), although there was a 
modest improvement in the PFS (6.09 versus 5.33 months). Notably, severe anemia occurred 
more frequently with 6 cycles compared to 3-4 cycles (7.8% versus 2.9%) (72). 
 
Flat dosing of nivolumab will be used at 360 mg every 3 weeks. Based on the nivolumab PK 
analysis, the simulated steady state concentration at trough (Cminss), peak (Cmaxss), and average 
(Cavgss) with 360 mg are less than those of 10 mg/kg given every 2 weeks. Prior PK data and AE 


  
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profiles from multiple trials have demonstrated nivolumab to be safe and well tolerated at doses 
up to 10 mg/kg every 2 weeks (18-20, 44, 51-53). Therefore, the 360 mg dosing on an every 3-
week schedule is expected to be safe and tolerable. 
 
2.5.2 Rationale for the Dosing of Bevacizumab in Combination with Nivolumab 
and Carboplatin/Pemetrexed 
 
Emerging evidence suggests that VEGF may play a role in cancer immune evasion through 
several mechanisms. For example, VEGF may reduce lymphocyte adhesion to vessel walls and 
contribute to decreased immune cell recruitment (73). In a mouse melanoma model, VEGF 
blockade was shown to synergize with adoptive immunotherapy, resulting in improved anti-
tumor activity, prolonged survival, and increased T cell trafficking into tumors (74). Synergistic 
effects have also been observed in patients with melanoma treated with ipilimumab and 
bevacizumab (75).  
 
In NSCLC, bevacizumab has been tested in combination with atezolizumab (a PD-L1 antibody) 
and carboplatin/paclitaxel in metastatic non-squamous NSCLC (IMpower150) (76). In this phase 
III study, patients were randomized to receive atezolizumab plus chemotherapy, bevacizumab 
plus chemotherapy, or atezolizumab plus chemotherapy plus bevacizumab. PFS and OS were 
longer in the atezolizumab plus chemotherapy plus bevacizumab group versus the bevacizumab 
plus chemotherapy group. Notably, this study allowed patients with EGFR and ALK alterations 
who had failed prior TKI therapy. Clinical benefit of the combination of atezolizumab plus 
bevacizumab plus chemotherapy was observed in this subgroup (76). 
 
The dosing of bevacizumab used in the IMpower150 study was 15 mg/kg every 3 weeks, the 
standard dosing schedule used in metastatic NSCLC (76). With this dosing of bevacizumab, the 
combination with atezolizumab and chemotherapy was generally well-tolerated. This dosing of 
bevacizumab (15 mg/kg every 3 weeks) was also tested in combination with nivolumab in 
previously treated metastatic NSCLC (77). No treatment-related grade 4 AEs were reported; 
grade 3 AEs included pneumonitis (n = 2) and cough and Tubulointerstitial nephritis (n = 1 
each). This study will evaluate the safety and efficacy of bevacizumab 15 mg/kg every 3 weeks 
combined with nivolumab 360 mg every 3 weeks plus carboplatin/pemetrexed.  
 
2.5.3 Rationale for Assessing PD-L1 Expression in Baseline Tumor Tissue 
 
Numerous studies have suggested a correlation between the level of PD-L1 expression in tumor 
and clinical benefit from nivolumab (and other PD-1/PD-L1 inhibitors) (18-21, 51-53). As an 
example, in the CheckMate 057 phase III study of nivolumab in patients with advanced NSCLC 
progressing on platinum-based chemotherapy, ORR to nivolumab was 9% in patients with PD-
L1 non-expressing tumors (47% of the study cohort), 31% in those with PD-L1 ≥1% (53% of the 
study cohort), and 36% in those with PD-L1 ≥5% (41% of the study cohort) (19). Median OS 
was 10.5 months in PD-L1 non-expressors, 17.7 months in patients with PD-L1 ≥1%, and 19.4 
months in patients with PD-L1 ≥5% (19).  
 
Similarly, in the CheckMate 012 study, efficacy of nivolumab plus ipilimumab was enhanced 
with increasing PD-L1 expression (78). The ORR of the N3 Q2W + I1 Q6W regimen was 0% 


  
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21 
(0/7) in PD-L1 non-expressing tumors, 57% (13/23) in tumors with ≥1% PD-L1, and 86% (6/7) 
with ≥50% PD-L1. Efficacy of first-line nivolumab plus ipilimumab in advanced NSCLC by 
tumor PD-L1 expression is shown in Table 2.5.3-1.  
 
Table 2.5.3-1: 
Efficacy of First-Line Nivolumab Plus Ipilimumab in NSCLC by Tumor 
PD-L1 Expression 
 
 
N3 Q2W + I1 Q12W 
(n = 38) 
N3 Q2W + I1 Q6W 
(n = 39) 
N3 Q2W  
(n = 52) 
ORR, % (n/N) 
 
 
 
   <1% PD-L1 
30 (3/10) 
0 (0/7) 
14 (2/14) 
   ≥1% PD-L1 
57 (12/21) 
57 (13/23) 
28 (9/32) 
   ≥50% PD-L1 
100 (6/6) 
86 (6/7) 
50 (6/12) 
Median PFS, mo 
 
 
 
   <1% PD-L1 
4.7 
2.4 
6.6 
   ≥1% PD-L1 
8.1 
10.6 
3.5 
   ≥50% PD-L1 
13.6 
NR 
8.4 
1-year OS rate, % 
 
 
 
   <1% PD-L1 
NC 
NC 
79 
   ≥1% PD-L1 
90 
83 
69 
   ≥50% PD-L1 
NC 
100 
83 
NR, not reached; NC, not calculated 
 
However, not all studies have shown a correlation between PD-L1 expression and nivolumab 
activity. In the CheckMate 012 trial evaluating first-line nivolumab plus PT-DC chemotherapy, 
for example, a clear association between PD-L1 and ORR, PFS, and OS endpoints could not be 
detected (20). 
 
Therefore, the current study will require a baseline tumor tissue for examination of the PD-L1 
expression status. Exploratory analysis will be performed to look for any association between 
clinical benefit from the nivolumab combination regimens and tumor PD-L1 positivity (defined 
as PD-L1 ≥1%). 
 
2.5.4 Rationale for Allowing Continued Treatment in Select Cases of 
Progressive Disease 
 
Studies have shown that up to ~10% of patients treated with immunotherapeutic agents may 
manifest an atypical, immune-related pattern of response, whereby there is initial increase in 
tumor burden (progressive disease based on the conventional RECIST criteria) before disease 
control is achieved (79-81). This phenomenon has been termed tumor pseudoprogression. Tumor 
lesions may initially increase in size—or new lesions may appear—because of inflammatory cell 
infiltrates or necrosis within the tumor. Furthermore, in some cases, patients may have subtle 
radiographic progression of disease but continue to benefit clinically.  
 
Therefore, patients in this study will be allowed to continue study therapy after a RECIST v1.1-
defined progression if they are tolerating the study drug(s) and are deemed to be deriving clinical 


  
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benefit based on the investigator assessment.  
 
2.6 
Correlative Studies Background 
 
Although immunotherapies using anti-PD-1/PD-L1 antibodies are demonstrating efficacy across 
a spectrum of malignancies, the response rates have been variable. Therefore, intensive efforts 
are underway to identify blood- and tumor-based biomarkers that may predict response to these 
agents.  
 
One of the first potential tumor-based biomarkers explored was PD-L1 status in the tumor cells. 
A number of clinical studies have suggested a correlation between the level of PD-L1 expression 
in tumors and responses to nivolumab (18-20, 51-53, 78), as detailed in Section 2.5.3. However, 
this correlation is imperfect. Patients who have PD-L1 non-expressing tumors may still respond 
to anti-PD-1/PD-L1 therapies such as nivolumab; conversely, patients with tumors expressing a 
high level of PD-L1 may fail to respond. At least partially, this discrepancy may be due to the 
dynamic nature of PD-L1 expression, influenced by concurrent and/or prior treatments and 
timing of the biopsy (82-85). There is also spatial heterogeneity in the expression of PD-L1. 
Therefore, alternative biomarker approaches are being investigated.  
 
Other potential biomarkers aside from PD-L1 have been proposed, derived from tumor cells or 
immune cells in the tumor microenvironment. These biomarkers, detectable by IHC, include 
immunoregulatory molecules PD-L2, FOXP3, PD-1, CTLA-4, LAG-3, co-stimulatory molecules 
and tumor-associated antigens (85, 86). Furthermore, several studies have found that the 
mutational load and/or the number of predicted neoantigens are relevant in predicting response to 
checkpoint inhibition. The total burden of nonsynonymous mutations as determined by whole 
genome or exome sequencing of tumor DNA has been shown to correlate with clinical benefit of 
anti-PD-1 therapy in various cancers including NSCLC. Similarly, the number of candidate 
tumor neoantigens, predicted using in silico algorithms that account for MHC binding, is 
associated with response to anti-PD-1/PD-L1 and anti-CTLA-4 therapies (87-89). Other tumor-
associated biomarkers that have been proposed include tumor-based multigene signatures and the 
presence of tumor-infiltrating lymphocytes (TILs) measured using multiplex IHC or 
immunofluorescence (IF) for molecules such as CD3, CD4, CD8, FOXP3, PD-L1 (86, 90).  
 
Biomarkers derived from the blood are also being explored, given the relative ease of collection 
and potential for serial monitoring. Soluble mediator detection methods such as enzyme-linked 
immunoabsorbent assay (ELISA) and enzyme-linked immunospot (ELISPOT) can be used to 
detect the relative abundance of cytokines and chemokines (e.g., IFN-ϒ, IL-2, IL-5, IL-10, IL-17, 
granzyme B, TNF, GM-CSF) and tumor antigen-specific antibodies in the peripheral blood (86).  
 
As part of this study, we will collect pre-treatment archival (within 6 months of starting the 
study) or fresh FFPE tumor biopsy specimens. These biopsies will be evaluated for potential 
biomarkers of response to the study drugs in the study population. Specifically, the level of PD-
L1 expression in the tumor cells will be determined using IHC. Additional IHC on FFPE tissue 
may be performed to detect the expression of immunoregulatory proteins such as, but not limited 
to, PD-L2, PD-1, and other markers associated with tumor-infiltrating lymphocytes (TILs) (e.g., 
CD4, CD8, FOXP3). FFPE tissue and/or peripheral blood sample may be further evaluated by 


  
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molecular techniques including but not limited to: IF, QPCR, and/or genetic sequencing. 
Because of the evolving nature of the field, not all of the potential biomarkers of interest can be 
pre-specified in this document.  
 
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
Participants must meet the following eligibility criteria for study entry: 
 
• Histologically or cytologically confirmed advanced (stage IIIB or IV) non-small-cell lung 
cancer (NSCLC). 
 
o ALK-rearranged NSCLC: ALK rearrangement as assessed by ALK FISH, IHC, or next-
generation sequencing (NGS). For ALK FISH, rearrangements must be detected in >15% 
of tumor cells.  
 
o EGFR-mutant NSCLC: EGFR activating gene mutation (e.g., L858R, exon 19 deletion) 
per local testing. 
 
• Patients receiving bevacizumab (Cohorts E and F) must have non-squamous histology 
NSCLC. 
 
• Presence of at least one measurable lesion as defined by RECIST v1.1. A previously 
irradiated site lesion may only be counted as a target lesion if there is clear sign of 
progression since the completion of irradiation. 
 
• Prior treatment with appropriate tyrosine kinase inhibitors (TKIs) as follows: 
 
o ALK-positive NSCLC (Cohorts F and H): Participants must have progressed on or after 1 
or more next-generation ALK-TKI(s).  
 
o EGFR-mutant NSCLC (Cohorts E and G): Participants must have progressed on or after 
1 or more third-generation EGFR-TKI(s). 
 
• No prior systemic chemotherapy is allowed.  
NOTE: Prior adjuvant or neoadjuvant chemotherapy is allowed if received more than 12 
months prior to the study. In addition, one prior cycle (dose) of chemotherapy is allowed 
if there was no evidence of disease progression following the dose. 
 
• Tumor tissue sample is required within 6 months prior to study enrollment. Tissue sample 
may be fresh (core needle, excisional, or incisional biopsy), or archival if obtained within 6 
months prior to enrollment. If a tissue sample is available but it has been > 6 months, the 


  
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Principal Investigator may approve the sample after discussion. PD-L1 IHC testing will be 
performed on the tumor tissue, but positivity on the PD-L1 IHC testing is not required to 
enroll in the study. 
 
• Clinically asymptomatic and stable central nervous system (CNS) metastases are allowed 
(including untreated CNS metastases) if they have not required increasing doses of steroids 
or stable doses equivalent to prednisone > 10 mg daily within 2 weeks prior to study entry for 
CNS symptoms.  
 
• Prior palliative radiotherapy must have been completed at least 2 weeks prior to study entry.  
 
• Subjects must have been off any prior TKIs for at least 5 half-lives of that drug. 
 
• Age ≥ 18 years old. 
 
• ECOG performance status of 0 or 1. 
 
• Life expectancy ≥ 12 weeks. 
 
• Screening laboratory values must meet the following criteria: 
 
o WBC ≥ 2.0 x 109/L 
o Neutrophils ≥ 1.5 x 109/L 
o Platelet ≥ 100 x 109/L 
o Hemoglobin ≥ 9/dL 
o Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance using Cockcroft-Gault 
formula ≥ 50 mL/min 
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 
                              72 x serum creatinine in mg/dL 
o Total bilirubin ≤ 1.5 x ULN (except in patients with Gilbert’s syndrome who may have 
total bilirubin < 3.0 mg/dL) 
o AST and ALT ≤ 3.0 x ULN (or ≤ 5.0 x ULN if liver metastases are present) 
 
• Females of child-bearing potential (defined as a sexually mature woman who has not 
undergone a hysterectomy or bilateral oophorectomy or has not been naturally post-
menopausal for at least 24 consecutive months) must: 
o Have a negative serum or urine pregnancy test obtained within 24 hours prior to starting 
the investigational drug. 
o Not be breastfeeding. 
o Agree to use, and be able to comply with, highly effective contraception (failure rate less 
than 1% per year) without interruption while on study treatment plus 5 half-lives of 


  
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nivolumab (half-life up to 25 days) plus 30 days (duration of ovulatory cycle) for a total 
of 23 weeks post treatment completion. Complete abstinence is acceptable if it is in line 
with the preferred and usual lifestyle of the patient. Period abstinence (e.g., calendar, 
ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable 
methods of contraception. Examples of non-hormonal contraceptive methods with a 
failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal 
implants, established and proper use of combined oral or injected hormonal 
contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two 
barrier methods from the options of diaphragm, cervical cap, vaginal sponge, and 
condom, or progesterone-only oral hormonal contraception where inhibition of ovulation 
is not the primary mode of action) may be combined to achieve a failure rate of < 1% per 
year. Barrier methods must always be supplemented with the use of a spermicide.  
 
• Male subjects agree to remain abstinent or use a condom plus an additional contraceptive 
method that result in a failure rate of <1% per year during sexual contact with a female of 
childbearing potential while participating in the study, during dose interruptions, and for 31 
weeks following the last dose of the study treatment, even if he has undergone a successful 
vasectomy. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle 
of the patient. Periodic abstinence and withdrawal are not acceptable.  
 
• Subject has the ability to understand and provide signed informed consent. 
 
• Subject has the willingness and ability to comply with scheduled visits, treatment plans, 
laboratory tests, and other study procedures. 
 
3.2 
Exclusion Criteria 
 
Participants who meet any of the following criteria will be excluded from the study entry: 
 
• Subjects previously treated with T cell immune-modulating antibodies, including anti-CTLA-
4, anti-PD-1 and/or anti-PD-L1 agents. 
 
• Subjects with symptomatic brain metastases, carcinomatous meningitis, spinal cord 
compression, or intractable back pain due to compression of destructive mass.  
 
• Subjects with active, known, or suspected autoimmune disease. Subjects with type I diabetes 
mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as 
vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to 
recur in the absence of an external trigger are permitted to enroll.  
 
• Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization (unless used to treat investigational drug-related adverse events). Inhaled or 
topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, 
are permitted in the absence of active autoimmune disease.  


  
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26 
 
• Subjects with interstitial lung disease or interstitial pneumonitis that is symptomatic or may 
interfere with the detection or management of suspected drug-related pulmonary toxicity. 
 
• For Cohorts E and F (bevacizumab cohorts) only (not applicable to cohorts G and H):  
 
o Previous history of hemoptysis (expectoration of more than 2.5 mL of blood) 
within 3 months prior to enrollment.  
o History of hemorrhagic CNS metastases or intracranial hemorrhage.   
o History of or genetic predisposition to a bleeding diathesis or coagulopathy.   
o Therapeutic anticoagulation, including but not limited to: low-molecular weight 
heparin, heparin, or warfarin. Anticoagulants must be discontinued 10 days prior 
to the first administration of bevacizumab. Prophylactic use of anticoagulants is 
allowed. 
o Current or recent (within 10 days of first dose of bevacizumab) use of aspirin (> 
325 mg/day) or other non-steroidal anti-inflammatories known to inhibit platelet 
function.  
o Clinically significant heart disease (i.e., active), stroke or myocardial infarction 
within 6 months prior to enrollment, unstable angina pectoris, congestive heart 
failure of grade > II according to the New York Heart Association (NYHA), or 
cardiac arrhythmia requiring specific treatment during the study and that may 
interfere with the follow-up of the study treatment or poorly controlled by 
treatment. 
o Arterial or venous thromboembolic events within 6 months of study enrollment. 
o Poorly controlled arterial hypertension (systolic > 150 mm Hg and/or diastolic > 
100 mm Hg), with or without antihypertensive medication. Patients presenting 
with high blood pressure are eligible if the dose or adjustment of anti-
hypertensives lowers blood pressure to meet the inclusion criteria of the study.  
o Minor surgical intervention, including placement of a permanent catheter, within 
24 hours prior to the first infusion of bevacizumab. 
o Non-healing wound, active peptic ulcer, or untreated bone fracture. 
o Previous history of abdominal fistula, tracheoesophageal fistula or other fistula 
with grade 4 severity, gastrointestinal perforation or intra-abdominal abscess 
within 6 months prior to enrollment.  
o Proteinuria at baseline. Subjects unexpectedly found to have 2+ or greater 
proteinuria on a urine dipstick at baseline should undergo a 24-hour urine which 
must be an adequate collection and must demonstrate <2 g of protein/24 hr to 
allow participation in the study.  
o Patients who have received previous anti-angiogenic treatment (experimental or 
marketed: bevacizumab, thalidomide, CP-547632, sunitinib, sorafenib, or others).  
 
• Subjects must have recovered from the effects of major surgery or significant traumatic 
injury at least 14 days prior to screening. No major surgery, other than diagnostic surgery, is 
allowed within 4 weeks prior to treatment in the study. 
 


  
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• Co-administration of anti-cancer therapies other than those administered in the study.  
 
• Subjects with other active malignancy requiring concurrent intervention.  
 
• Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). HIV-positive participants are ineligible 
because these participants are at increased risk of lethal infections when treated with marrow-
suppressive therapy, and because there is the potential for pharmacokinetic interactions with 
combination antiretroviral therapy and study drugs.  
 
• Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic 
infection. 
 
• Subjects with ≥ grade 2 peripheral neuropathy at enrollment per the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE). 
 
• Pregnant or lactating women. Pregnant women are excluded from this study because the 
study drugs (i.e., nivolumab, carboplatin, pemetrexed, and/or bevacizumab) have the 
potential for teratogenic or abortifacient effects. Because there is an unknown but potential 
risk for adverse events in nursing infants secondary to treatment of the mother with these 
agents, breastfeeding should be discontinued.   
 
• Subjects currently enrolled in any other clinical protocol or investigational trial that involves 
administration of experimental therapy and/or therapeutic devices, or investigational drug. 
 
• History of allergy or hypersensitivity to any study drugs or their excipients. 
 
• Any known clinically significant concomitant medical condition, laboratory abnormality, or 
psychiatric illness that, in the investigator’s opinion, would prevent the subject from 
participating in the study, pose an unacceptable risk to the patient in this study, or interfere 
with the interpretation of safety results. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 


  
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28 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible.  
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
 
5. TREATMENT PLAN 
 
In this phase II trial, subjects with TKI-pre-treated, advanced EGFR-mutant or ALK-rearranged 
NSCLC will be enrolled. Subjects must be chemotherapy-naïve, and have EGFR-mutant NSCLC 
which progressed on a third-generation EGFR TKI, or ALK-rearranged NSCLC which 
progressed on at least one next-generation ALK TKI. We will evaluate the efficacy of nivolumab 
plus carboplatin and pemetrexed plus bevacizumab in patients who are bevacizumab-eligible, 
and the efficacy of nivolumab plus carboplatin and pemetrexed in patients who are bevacizumab-
ineligible. Cohorts of the study are as specified below: 
 
Nivolumab Plus Carboplatin and Pemetrexed Plus Bevacizumab: 
• Cohort E: EGFR-mutant advanced NSCLC, previously treated with at least one third-
generation EGFR TKI and chemotherapy-naïve, who are bevacizumab-eligible. 
• Cohort F: ALK-rearranged advanced NSCLC, previously treated with at least one next-
generation ALK TKI and chemotherapy-naïve, who are bevacizumab-eligible. 
 
Nivolumab Plus Carboplatin and Pemetrexed: 
• Cohort G: EGFR-mutant advanced NSCLC, previously treated with at least one third-
generation EGFR TKI and chemotherapy-naïve, who are bevacizumab-ineligible. 
• Cohort H: ALK-rearranged advanced NSCLC, previously treated with at least one next-
generation ALK TKI and chemotherapy-naïve, who are bevacizumab-ineligible. 
 
 
5.1 
Treatment Regimen 
 
Nivolumab, carboplatin and pemetrexed, with or without bevacizumab will be administered 
every 3 weeks, with 21 consecutive days defined as a treatment cycle, until disease progression, 
unacceptable toxicity, or completion of 4 cycles, whichever comes first. A ±3-day window 
period will be authorized throughout the study period. Treatment will be administered as 
intravenous (IV) infusion. On Day 1 of each cycle, all eligible patients will receive the drug 


  
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29 
infusions in the following order: 
 
Cohorts E and F: Nivolumab 360 mg will be administered IV over approximately 30 minutes 
(with a window of ±5 minutes), followed at least 30 minutes later by bevacizumab (15 mg/kg) 
IV over 90 minutes (with a window of ±15 minutes) for the first infusion shortening to 60 (±10) 
minutes then 30 (±10) minutes for subsequent infusions if tolerated, followed by pemetrexed 
(500 mg/m2) IV over approximately 10 minutes and carboplatin (AUC 5) IV over approximately 
60 minutes.  
 
Cohorts G and H: Nivolumab 360 mg will be administered IV over approximately 30 minutes 
(with a window of ±5 minutes), followed at least 30 minutes later by pemetrexed (500 mg/m2) 
IV over approximately 10 minutes and carboplatin (AUC 5) IV over approximately 60 minutes. 
 
Subjects who have stable disease or response after 4 cycles will continue nivolumab and 
pemetrexed with bevacizumab (Cohorts E and F) or without bevacizumab (Cohorts G and H) at 
the same doses as maintenance therapy on Day 1 every 3 weeks, until disease progression, 
unacceptable toxicity, or withdrawal of consent, whichever occurs first.  
 
Pemetrexed and carboplatin and bevacizumab may be prepared and administered according to 
institutional standards. 
 
Reported adverse events and potential risks are described in Section 7. Appropriate dose 
modifications are described in Section 6. No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the participant's 
malignancy. 
 
Please see Table 5.1.1 and Table 5.1.2 for the Regimen Description.  
 
Table 5.1.1: 
Regimen of Nivolumab Plus Bevacizumab Plus Carboplatin and 
Pemetrexed 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Nivolumab 
N/A 
 
360 mg 
 
 
IV over 
approximately 
30 minutes 
before 
bevacizumab 
 
Day 1, 
week 1 
21 days  
(3 weeks) 
 
 
 
Bevacizumab  
N/A 
15 mg/kg 
IV over 
approximately 
90 minutes 
before 
carboplatin and 
Day 
1,week 1 


  
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30 
pemetrexed for 
the first infusion 
– if tolerated, 
can shorten to 
IV over 
approximately 
60 minutes and 
then over 
approximately 
30 minutes for 
the subsequent 
infusions 
Carboplatin 
Anti-emetics per local 
standards, including 
dexamethasone and 5-HT3 
receptor antagonist. 
AUC 5 
 
 
IV over 
approximately 
60 minutes, to 
start at least 30 
minutes after 
the completion 
of nivolumab 
 
Day 1, 
week 1, for 
4 cycles 
Pemetrexed 
Premedicate with 
dexamethasone on the day 
before, day of, and day 
after pemetrexed. Oral 
folic acid (continued daily) 
and IM vitamin B12 (every 
3 cycles) should be 
initiated 1 week prior to 
pemetrexed treatment. 
500 mg/m2 
IV over 
approximately 
10 minutes, to 
start at least 30 
minutes after 
the completion 
of nivolumab 
Day 1, 
week 1 
 
Table 5.1.2: 
Regimen of Nivolumab Plus Carboplatin and Pemetrexed 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Nivolumab 
N/A 
 
360 mg 
 
 
IV over 
approximately 
30 minutes 
before 
carboplatin and 
pemetrexed 
 
Day 1, 
week 1 
21 days  
(3 weeks) 
 
 
 
Carboplatin 
Anti-emetics per local 
standards, including 
AUC 5 
 
IV over 
approximately 
Day 1, 
week 1, for 


  
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dexamethasone and 5-HT3 
receptor antagonist. 
 
60 minutes, to 
start at least 30 
minutes after 
the completion 
of nivolumab 
 
4 cycles 
Pemetrexed 
Premedicate with 
dexamethasone on the day 
before, day of, and day 
after pemetrexed. Oral 
folic acid (continued daily) 
and IM vitamin B12 (every 
3 cycles) should be 
initiated 1 week prior to 
pemetrexed treatment. 
500 mg/m2 
IV over 
approximately 
10 minutes, to 
start at least 30 
minutes after 
the completion 
of nivolumab 
Day 1, 
week 1 
 
5.2 
Agent Administration 
 
For subjects enrolled in Cohorts E and F, nivolumab 360 mg will be administered IV over 30 
minutes (with a window of ±5 minutes), followed by bevacizumab (15 mg/kg) IV (over the time 
period as specified above), followed by pemetrexed (500 mg/m2) IV over 10 minutes and 
carboplatin (AUC 5) IV over 30 minutes, on Day 1 of each 21-day cycle. For subjects enrolled in 
Cohorts G and H, nivolumab 360 mg will be administered IV over 30 minutes (with a window of 
±5 minutes), followed by pemetrexed (500 mg/m2) IV over 10 minutes and carboplatin (AUC 5) 
IV over 30 minutes, on Day 1 of each 21-day cycle. A ±3-day window period will be authorized 
throughout the study period.  
 
This combination will continue until disease progression, unacceptable toxicity, or completion of 
4 cycles, whichever comes first. Subjects who have stable disease or response after 4 cycles will 
discontinue carboplatin, and continue nivolumab 360 mg and pemetrexed 500 mg/m2 with 
(Cohorts E and F) or without (Cohorts G and H) bevacizumab as maintenance therapy on Day 1 
every 3 weeks. Again, a ±3-day window period will be authorized throughout the study period. 
Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of 
consent, whichever occurs first.  
 
In subjects who require pemetrexed dose reduction, the dose of pemetrexed may be escalated to 
500 mg/m2 after the discontinuation of carboplatin at the investigator’s discretion, if the prior 
toxicity was felt to be related mainly to carboplatin.  
 
If a subject receiving nivolumab and pemetrexed (with or without bevacizumab) maintenance 
experiences an adverse event, and the investigator can attribute it to either nivolumab or 
pemetrexed or bevacizumab, then that agent can be discontinued and the remaining agent(s) can 
be continued until disease progression or unacceptable toxicity.  
 
On the day of the infusion, nivolumab is to be administered first. Infusion of the bevacizumab 
and/or platinum-doublet chemotherapy will start at least 30 minutes after the completion of 


  
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32 
nivolumab infusion. Pemetrexed and carboplatin and bevacizumab may be prepared and 
administered according to institutional standard.  
 
Pemetrexed dosing calculations are based on the body weight. If the subject’s weight on the day 
of the dosing differs by >10% from the weight used to calculate the prior dose, the pemetrexed 
dose must be re-calculated. All doses should be rounded to the nearest milligram or per 
institutional standard for bevacizumab, carboplatin and pemetrexed. It is permissible to re-
calculate the doses more frequently for weight changes greater than 5%.  
 
The carboplatin dose is calculated using the Calvert formula as follows: 
• Carboplatin dose (mg) = Target AUC x [(CrCl (mL/min) + 25] 
• Creatinine clearance (CrCl) calculation is based on the Cockroft-Gault formula (see 
Inclusion Criteria in Section 3.1) and should include the most recent serum creatinine and 
most recent weight. If calculation of the CrCl by the Cockroft-Gault formula yields a 
result of > 125 mL/min, then a CrCl should be calculated by an alternative formula per 
institutional standards or capped at 125 mL/min.  
• The dose of carboplatin may be capped per local standards. 
 
Pre-medication for use with pemetrexed: Oral corticosteroid should be given according to local 
standards at a dose equivalent to dexamethasone 4 mg BID on the day prior to, day of, and day 
after the administration of pemetrexed during the carboplatin, pemetrexed, and nivolumab 
induction cycles. Once participants are receiving maintenance therapy of pemetrexed plus 
nivolumab, steroid dose ≤ dexamethasone 4 mg BID on the day prior to, day of, and day after the 
administration of pemetrexed will be allowed.  
 
Oral folic acid 350 to 1000 mcg daily should be given starting 1 week prior to the first dose of 
pemetrexed, with at least 5 doses of folic acid administered in the 7 days prior to the first dose. 
Folic acid should be continued daily for the duration of pemetrexed treatment, and for 21 days 
after the last dose of pemetrexed. Intramuscular (IM) injection of vitamin B12 1000 mcg should 
be administered approximately 1 week prior to the first dose of pemetrexed, and repeated every 3 
cycles (every 9 weeks) thereafter during pemetrexed treatment. Subsequent injections of vitamin 
B12 may be given on the same day as pemetrexed. 
 
Pre-medications are allowed to be administered during the wait time after the nivolumab 
infusion.  
 
Pre-medications for use with carboplatin/pemetrexed: Anti-emetic premedication(s) will be 
administered according to local standards. Recommended anti-emetic treatments are 
dexamethasone (dosing according to local standards, and an equivalent dose of another 
corticosteroid may be substituted) and a 5-HT3 receptor antagonist (type per investigator 
discretion and local standards of care). Additional use of anti-emetic medications is allowed at 
the investigator’s discretion.  
 
Pre-medications are allowed to be administered during the wait time after the nivolumab 
infusion.  
 


  
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Guidelines for appropriate dose modifications and treatment interruptions or discontinuation due 
to specific adverse events are provided in Section 6.. 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
5.3.1 Permitted Therapy 
 
Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (< 3 weeks) course of corticosteroids for prophylaxis 
(e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type 
hypersensitivity reaction caused by a contact allergen) is permitted.  
 
Regular concomitant use of bisphophosphonates and RANK-L inhibitors for prevention or 
reduction of skeletal-related events in patients with bone metastases is allowed if initiated prior 
to first dose of study therapy.  
 
Caution should be exercised when the following are administered with bevacizumab: 
• Aspirin and NSAIDs: Since the most serious toxicities observed with bevacizumab to 
date are hemorrhages, thrombosis, and gastrointestinal perforations, the use of aspirin and 
NSAIDs must be limited.  
o Participants who require long-term administration of aspirin (>325 mg/day) or 
non-steroidal anti-inflammatory drugs that inhibit platelet function at doses used 
to treat chronic inflammatory diseases will not be included in the study (see 
inclusion and exclusion criteria).  
o Administration of low doses of aspirin (≤325 mg/day), occasional administration 
of non-steroidal anti-inflammatory drugs or non-steroidal anti-inflammatory drugs 
inhibiting platelet function is authorized. Patients presenting with a venous 
thromboembolic accident during the trial will be withdrawn from bevacizumab 
treatment.  
 
5.3.2 Prohibited and/or Restricted Therapy 
 
The following medications are prohibited during the study, unless utilized to treat a drug-related 
adverse event: 
 
• Immunosuppressive agents; 
 
• Immunosuppressive doses of systemic corticosteroids, except as stated in Section 5.3.1; 
 
• Any concurrent anti-neoplastic therapy (i.e., chemotherapy, hormonal therapy, 
immunotherapy, extensive or non-palliative radiation therapy, or standard or 
investigational agents for the treatment of NSCLC). 
 


  
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For patients receiving bevacizumab, the following medications are prohibited during the study 
and for at least 14 days prior to initiation of the study treatment unless otherwise specified 
below.  
 
• Anticoagulants (e.g., LMWH, warfarin) are prohibited within 10 days of the first 
administration of bevacizumab and for the entire duration of treatment with bevacizumab.  
 
• Anti-platelet agents (e.g., ticlopidine, clopidogrel).  
 
Caution should be used regarding the use of herbal medications, as there may be as of yet 
unknown interactions with nivolumab. Discontinuation of the use of herbal medications prior to 
study enrollment is encouraged.  
 
Investigators should refer to the product labeling for carboplatin and pemetrexed for additional 
prohibited and restricted concomitant medications. Non-steroidal anti-inflammatory drugs 
(NSAIDs) can be administered with pemetrexed in patients with normal renal function, but 
caution should be used when administering NSAIDs concurrently with pemetrexed in patients 
with mild to moderate renal insufficiency. Further information is available in the Pemetrexed 
Package Insert.  
 
5.3.3 Supportive Care Guidelines 
 
Participants should receive full supportive care including transfusions of blood and blood 
products, antibiotics, analgesia, etc., according to local practice/institutional guidelines where 
appropriate. Anti-emetic medications should be prescribed according to local practice. 
 
Treatments received prior to the study entry and that are not prohibited by the protocol will be 
continued by the patients during the study, depending on their physician’s recommendations. All 
concomitant medication(s) must be reported in the Case Report Form.  
 
Palliative local radiation therapy will be permitted for participants with symptomatic bone 
metastases, skin lesions, or CNS lesions, provided that the participant continues to derive clinical 
benefit from the study drugs in the opinion of the investigator. Palliative radiation to lesions 
causing hemoptysis may also be permitted in subjects who do not have evidence of overall 
clinical or radiographic progression, provided that the lesions undergoing local therapy are not 
the only sites of measurable disease, upon discussion with the Principal Investigator.   
 
The potential for overlapping toxicities with radiotherapy and nivolumab is currently not known, 
although anecdotal data suggests that it is tolerable. In the absence of formal evaluation, in cases 
where palliative radiation is required for a tumor lesion, nivolumab should be withheld for at 
least 1 week before, during, and 1 week after radiation. Subjects should be closely monitored for 
any potential toxicity during and after receiving radiotherapy, and AEs should resolve to grade ≤ 
1 prior to resuming study drugs. For patients undergoing cerebral radiotherapy, bevacizumab 
should be held for 14 days following completion of radiation.  
 


  
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5.4 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue 
until one of the following criteria applies: 
 
• 
Disease progression.  
Note: In select cases, subjects may be continued on study drugs (including the 
chemotherapy agents pemetrexed and carboplatin) despite an initial investigator-
assessed, RECIST v1.1-defined progression, if they are tolerating the study drugs and 
deemed to be deriving clinical benefit by the investigator. The following criteria must 
be met in order to continue the study drug treatment through RECIST v1.1-defined 
radiological progression of disease: 
• Absence of clinical symptoms or signs indicating clinically significant 
disease progression; 
• No decline in performance status; 
• Absence of rapid disease progression or threat to vital organs or critical 
anatomical sites (e.g., progression in the central nervous system, respiratory 
failure due to tumor compression, spinal cord compression) requiring urgent 
alternative medical intervention; 
• No significant, unacceptable or irreversible toxicities related to study 
treatment. 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Unacceptable adverse event(s) 
 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
 
• 
Participant decides to withdraw from the protocol therapy 
 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
An ODQ Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the ODQ website or obtained from the ODQ 
registration staff. 
 


  
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In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Alice T. Shaw, MD, PhD, at 
.  
 
5.5 
Duration of Follow Up 
 
The follow-up period for a participant begins after the last completed assessment during the 
active study period. Any participant who discontinued study treatment for any reason other than 
disease progression, death, or withdrawal of consent will continue to have tumor assessments 
every 12 weeks (±14 days) until disease progression, death, or withdrawal of consent, whichever 
occurs first.  
 
All participants will be followed for safety on day 30 (±7 days) and on day 100 (±7 days) after 
the last dose of the study drugs with an office visit. The following laboratory tests will be 
performed on days 30 and 100 (±7 days) after the last dose of the study drugs: complete blood 
count (CBC) with differential, and chemistry panel including but not limited to sodium, 
potassium, calcium, chloride, BUN, creatinine, glucose, albumin, total protein, alkaline 
phosphatase, bilirubin (total and direct), AST/SGOT, ALT/SGPT, LDH, lipase, and TSH (reflex 
testing [T3 and free T4] to be done if TSH abnormal).   
 
All subjects will be followed for survival every 3 months (±7 days) following the last safety 
follow-up visit (on day 100) until death, withdrawal of consent from the study, or up to 2 years 
after the last participant is enrolled, whichever occurs first. Survival follow-up visits may be 
performed by record review (including public records), telephone contact (with the subject, 
family, or the subject’s treating physician), or office visit. Information on new anti-cancer 
therapies should be collected. New anti-cancer therapy includes (but is not limited to) any 
systemic or local medication, surgery, radiation, or any other therapy intended to treat the 
subject’s cancer.  
 
5.6 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
For Centralized Subject Registrations, the research team must submit a completed Off 
Treatment/Off Study form to ODQ when a participant comes off study. This form can be found 
on the ODQ website or obtained from the ODQ registration staff.  
 
For Decentralized Subject Registrations, the research team updates the relevant Off 
Treatment/Off Study information in OnCore.  
 


  
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6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and modifications will be made as specified below. For all cohorts, a ±3-day visit 
and treatment window is allowed. Per DF/HCC guidelines, delays for state/federal holidays, 
inclement weather, or circumstances beyond the control of the research team and/or participant 
are not considered protocol deviations. 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
6.1 
Dose Delay Criteria 
 
6.1.1 Dose Delays for Nivolumab Plus Carboplatin and Pemetrexed 
 
Nivolumab and carboplatin/pemetrexed administration should be delayed for the following: 
 
• Absolute neutrophil count (ANC) < 1500/µl 
• Platelets < 100,000/mm3 
• Any Grade ≥ 2 non-skin, non-hematologic, drug-related AE, except for fatigue and 
laboratory abnormalities 
• Any Grade ≥ 3 skin drug-related AE 
• Any Grade ≥ 3 drug-related laboratory abnormality with the following exceptions: 
o Grade 3 lymphopenia does not require a dose delay 
o If a subject has a baseline AST, ALT, or total bilirubin that is within normal 
limits, delay dosing for drug-related Grade ≥ 2 toxicity 
o 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 AE, laboratory abnormality or inter-current illness which, in the judgment of the 
investigator, warrants dose delays of the study medications. Investigator should consult 
local labeling for carboplatin and pemetrexed for additional guidance on dose delays.  
 
Of note, in subjects receiving carboplatin and pemetrexed with nivolumab, if any non-
hematologic AE meeting the dose delay criteria above is felt to be related to only one particular 
agent in the platinum-double chemotherapy, then that agent alone may be omitted for that cycle 
while the other agent(s) are given. In order to maintain synchronized dosing of the regimen, the 
omitted agent should be resumed with the next scheduled cycle once the AE has improved and 
re-treatment criteria are met.  
 
Subjects who require dosing delay should be re-evaluated weekly or more frequently if clinically 
indicated, and resume study treatment when re-treatment criteria are met, as specified in Section 
6.3.1.  
. 


  
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6.1.2 Toxicity Related to Bevacizumab 
 
Temporary suspension of bevacizumab must occur if a patient experiences a serious adverse 
event or a grade 3 or 4 non-serious adverse event assessed by the investigator as related to 
bevacizumab. If the event resolves to grade ≤1, bevacizumab may be restarted at the same dose 
level. If bevacizumab is delayed due to toxicity for >42 days beyond when the next dose should 
have been given, the patient must be permanently discontinued from bevacizumab. 
 
The appropriate interval between the last dose of bevacizumab and major surgery is unknown. 
Because bevacizumab has a half-life of approximately 21 days, elective surgery should be 
delayed whenever possible, but if necessary, bevacizumab should be held for ≥28 days prior to 
the procedure. Re-initiation of bevacizumab following surgery should not occur for ≥28 days and 
until wounds have fully healed. Re-initiation of bevacizumab after surgery requires documented 
approval from the sponsor.  
 
Infusion of bevacizumab should be interrupted in patients who develop dyspnea or clinically 
significant hypotension. Patients who experience an NCI CTCAE grade 3 or 4 allergic 
reaction/hypersensitivity, adult respiratory distress syndrome, or bronchospasm (regardless of 
grade) will be discontinued from bevacizumab treatment.  
 
Bevacizumab infusion should be slowed to ≤50% or interrupted for patients who experience any 
infusion-associated symptoms not specified above. If the infusion is interrupted, it may be 
resumed at ≤50% of the rate prior to the reaction after the patient’s symptoms have adequately 
resolved and increased in 50% increments up to the full rate if well tolerated. Infusions may be 
restarted at the full rate during the next cycle. 
 
Table 6.1.2-1: 
Bevacizumab Dose Management for Adverse Events 
 
CTCAE grade 
Action to be taken 
Hypertension 
Grade 1 or 2 
No treatment modifications. 
Grade 3 
If not controlled at ≤150 mm Hg with anti-hypertensive treatment, do 
not administer bevacizumab. 
Grade 4 
Discontinue bevacizumab. 
Sign of posterior reversible leukoencephalopathy syndrome (PRLS) 
Any grade (confirmed 
on an MRI) 
Discontinue bevacizumab. 
Hemorrhaging of the CNS 
Any grade 
Discontinue bevacizumab. 
Pulmonary hemorrhage 
Any grade 
Discontinue bevacizumab 
Non-pulmonary, non-CNS hemorrhage 
Grade 1 
No dose modifications. 
Grade ≥2 
Discontinue bevacizumab. 


  
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39 
Venous thrombosis 
Any grade 
Discontinue bevacizumab. 
Arterial thromboembolic event (angina pectoris, myocardial infarction, ischemic heart 
attack, arterial thromboembolic attack or any other arterial thromboembolic event) 
Any grade 
Discontinue bevacizumab. 
Proteinuria 
Grade 1 or 2 
No dose modifications. 
Grade 3 
Suspend bevacizumab until resolution of grade to ≤2. 
Grade 4 (nephrotic 
syndrome) 
Discontinue bevacizumab. 
GI perforation 
Grade ≥2 (requiring 
medical or surgical 
intervention) 
Discontinue bevacizumab. 
Intestinal obstruction 
Grade 1 
Continue bevacizumab for partial obstruction NOT requiring 
medical/surgical intervention. 
Grade 2 
Suspend bevacizumab for partial obstruction requiring 
medical/clinical intervention. The administration of treatment will 
resume after full resolution. 
Grade 3 or 4 
Discontinue bevacizumab for total obstruction. If surgical 
intervention is needed, the patient will resume treatment after wounds 
are healed and the assessment of investigator. 
Dehiscence of wounds requiring medical or surgical treatment (if the wound comes from 
incision of a cavity) 
Any grade 
Discontinue bevacizumab. 
Left ventricular systolic dysfunction 
Grade 1 or 2 
No dose modifications. 
Grade 3 
Suspend bevacizumab until resolution of grade to ≤1. 
Grade 4 
Discontinue bevacizumab. 
Fistula 
TE fistula 
Any grade 
Discontinue bevacizumab. 
Any other events of grade 3/4 that may be related to bevacizumab according to the 
investigator 
Grade 3  
Discontinue bevacizumab until resolution of grade to ≤1. 
Grade 4 
Discontinue bevacizumab.  
 
 
6.2 
Dose Reduction Criteria 
 
6.2.1 Dose Reductions for Nivolumab  
 
There will be no dose reductions for nivolumab.  


  
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6.2.2 Dose Reductions for Bevacizumab 
 
There will be no dose reductions for bevacizumab. Please refer to section 6.1.2 for criteria for 
treatment modification and guidelines for the management of bevacizumab-related toxicities.  
 
6.2.3 Dose Reductions for Carboplatin and Pemetrexed 
 
Carboplatin and pemetrexed chemotherapy may be dose reduced based on toxicities, according 
to Table 6.2.1-1. Once the dose of a chemotherapeutic agent is reduced, it may not be re-
escalated in subsequent cycles, except when starting the pemetrexed maintenance therapy. Any 
subject with two prior dose reductions who experiences a toxicity requiring a third dose 
reduction must be discontinued from the study drug. 
 
Table 6.2.3-1: 
Dose Reductions of Carboplatin and Pemetrexed 
 
Dose Level 
Carboplatin 
Pemetrexed 
Starting dose 
AUC 5 
500 mg/m2 
First dose reduction 
AUC 4 
375 mg/m2 
Second dose reduction 
AUC 3 
250 mg/m2 
Third dose reduction 
Discontinue 
Discontinue 
 
Dose modifications for toxicities according to CTCAE version 4.0 are summarized in Table 
6.2.1-2.  Dose level adjustments for carboplatin and pemetrexed are relative to that of the 
preceding administration. All dose reductions should be made based on the worst grade toxicity 
(and nadir blood counts as per local standards). Subjects experiencing any of the toxicities 
detailed in Table 6.2.1-2 during the previous cycle should have their chemotherapy delayed until 
re-treatment criteria are met, and then dose reduced for all subsequent cycles by one dose level 
or discontinued as appropriate.  
 
Dose levels for carboplatin and pemetrexed may be reduced independently for the non-
hematologic toxicities as summarized in the table. For hematologic toxicities, growth factors 
may be used after the first cycle to assist blood count recovery. Local standards of care in 
supportive measures should be utilized. Prophylactic antibiotics may also be used according to 
local standards of care. Any antibiotic or growth factor use should be reported on the eCRF.  
 
Table 6.2.3-2: 
Dose Modification Guidelines for Carboplatin and Pemetrexed Based 
on Toxicity 
 
Toxicity 
Carboplatin 
Pemetrexed 
Neutropenia 
Grade 4  
Reduce one dose level 
Reduce one dose level 
Thrombocytopenia 
Grade ≥ 3  
Reduce one dose level 
Reduce one dose level 
Thrombocytopenia Grade ≥ 3, 
Reduce two dose levels 
Reduce two dose levels 


  
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Grade ≥ 2 with bleeding 
Febrile Neutropenia 
Grade ≥ 3 
Reduce one dose level 
Reduce one dose level 
Diarrhea 
Grade ≥ 3 
No change 
Reduce one dose level 
Allergic reaction 
Grade ≥ 3 
Discontinue 
Discontinue 
Neuropathy 
Grade ≥ 3 
Discontinue 
Discontinue 
Transaminase elevation 
Grade 3 
Reduce one dose level 
Reduce one dose level 
Transaminase elevation 
Grade 4 
Discontinue 
Discontinue 
Calculated creatinine 
clearance < 20 mL/min 
Discontinue 
No change 
Mucositis 
Grade ≥ 3 
No change 
Reduce two dose levels 
Other Grade ≥ 3 toxicity  
(except for fatigue and transient 
arthralgia and myalgia) 
Adjust as medically indicated 
Adjust as medically indicated 
 
6.3 
Criteria to Resume Dosing 
 
6.3.1 Criteria to Resume Nivolumab Plus Carboplatin and Pemetrexed 
 
• ANC ≥ 1500/µl, platelet ≥ 100,000/mm3 
• All other drug-related toxicities returned to baseline or Grade ≤ 1, with exceptions as 
noted below. 
• Grade ≤ 2 alopecia and fatigue. 
• Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity.  
• 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 re-treatment if 
discussed with and approved by the Principal Investigator.  
• Subjects who received systemic corticosteroids for management of any drug-related 
toxicity must be off corticosteroids or have tapered down to an equivalent dose of 
prednisone ≤ 10 mg/day. 
• Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the Principal Investigator.  
• If a subject fails to meet criteria for re-treatment, then re-treatment should be delayed, 
and the subject should be re-evaluated weekly or more frequently as clinically indicated. 
Dose delay of nivolumab and/or carboplatin and pemetrexed which results in treatment 
interruption of > 6 weeks requires treatment discontinuation, with exceptions as noted in 


  
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Section 6.4.  
 
6.3.2 Criteria to Resume Bevacizumab 
 
Please refer to Section 6.1.2. 
 
6.4 
Criteria to Discontinue Treatment 
 
The assessment for discontinuation of nivolumab should be made separately from the assessment 
for discontinuation of carboplatin/pemetrexed or from the assessment for discontinuation of 
bevacizumab. If the investigator can attribute an adverse event to a specific agent and the criteria 
for discontinuation of that drug are met, then that agent can be discontinued and the other 
agent(s) continued until disease progression or unacceptable toxicity. If the investigator is unable 
to determine whether an adverse event is related to one drug only, then the subject should 
discontinue all drugs in the combination regimen and be taken off the treatment phase of the 
study.  
 
6.4.1 Criteria for Nivolumab Discontinuation 
 
• 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 ≥ 2 drug-related pneumonitis or interstitial lung disease that does not resolve 
to dose delay and systemic steroids. 
• Any Grade 3 drug-related bronchospasm, hypersensitivity reaction, or infusion reaction, 
regardless of duration. 
• Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic toxicity, 
hypersensitivity reactions, infusion reactions, endocrinopathies, and laboratory 
abnormalities: 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, 
neurologic toxicity, 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:  
 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 > 5-10x ULN for > 2 weeks 
• AST or ALT > 10x ULN 
• Total bilirubin > 5x ULN 
• Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN 


  
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• Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
o Grade 4 neutropenia ≤ 7 days 
o Grade 4 lymphopenia or leukopenia 
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. The Principal Investigator should be consulted for Grade 
4 amylase or lipase abnormalities.  
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 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 the Principal Investigator. 
• Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the Principal Investigator. Prior to re-initiating 
treatment in a subject with a dosing delay lasting > 6 weeks, the Principal Investigator 
must be consulted. Tumor assessments should continue per protocol even if the dosing is 
delayed. 
• 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.  
  
6.4.2 Criteria for Carboplatin/Pemetrexed Discontinuation 
 
Except where specified below, both agents (carboplatin and pemetrexed) should be discontinued 
for any of the following: 
 
• Any Grade ≥ 3 peripheral neuropathy. 
• Grade ≥ 3 drug-related thrombocytopenia associated with clinically significant bleeding. 
• Any drug-related liver function test (LFT) abnormality that meets the following criteria: 
o AST or ALT > 5-10x ULN for > 2 weeks 
o AST or ALT > 10x ULN 
o Total bilirubin > 5x ULN 
o Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN 
• Any drug-related adverse event which recurs after two prior dose reductions for the same 
drug-related adverse event requires discontinuation of the drug(s) which was/were 
previously dose reduced. 
• Any Grade ≥ 3 drug-related hypersensitivity reaction or infusion reaction requires 
discontinuation of the drug(s) felt to be causing the reaction. The drug not felt to be 
related to the hypersensitivity reaction or infusion reaction may be continued. 
• Any Grade 4 drug-related adverse event which the investigator deems is inappropriate to 
be managed by dose reduction(s) requires discontinuation of the drug(s) felt to be causing 


  
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the event. The drug not felt to be related to the event may be continued. 
• Any event that leads to delay in dosing of any study drug(s) for > 6 weeks from the 
previous dose requires discontinuation of that drug(s) with the following exception: 
o Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-
related reasons may be allowed if approved by the Principal Investigator. Prior to 
re-initiating treatment in a subject with a dosing delay lasting > 6 weeks, the 
Principal Investigator must be consulted.  
• 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 
carboplatin and pemetrexed dosing. Investigators should consult local labeling for the 
chemotherapy agents for additional guidance on dose discontinuation.  
 
6.4.3 Criteria for Bevacizumab Discontinuation 
 
Please refer to Section 6.1.2. 
 
6.5 
Management Algorithms for Immuno-Oncology Agents 
 
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 immune-oncology 
agent in this protocol. Early recognition and management of AEs associated with I-O 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 
• Endocrinopathy 
• Skin 
• Neurological 
 
The above algorithms are found in the nivolumab Investigator Brochure, as well as in Appendix 
B.  
 
6.6 
Treatment of Nivolumab 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 may manifest with fevers, chills, rigors, headache, rash, pruritus, arthralgias, hypo- or 
hypertension, bronchospasm or other symptoms. All Grade 3 or 4 infusion reactions should be 
reported within 24 hours to the Principal Investigator and 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 


  
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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 pre-medications are recommended for future infusions: diphenhydramine 50 
mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 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 (e.g., antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, intravenous fluids); prophylactic medications 
indicated for ≤ 24 hours): 
• Stop the nivolumab infusion. Begin an intravenous infusion of normal saline, and treat 
the subject with diphenhydramine 50 mg IV (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg. Remain at bedside and monitor subject until 
resolution of symptoms. Corticosteroid and/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). 
• For future infusions, the following prophylactic pre-medications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 
mg should be administered at least 30 minutes before nivolumab infusions. If necessary, 
corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used.  
 
For Grade 3 or 4 symptoms (severe reaction; Grade 3: prolonged (i.e., not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion), recurrence of symptoms 
following initial improvement, hospitalization indicated for other clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates); Grade 4: life-threatening, pressor or ventilator 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 1:1000 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 of the 
symptoms.  
 
In case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or 


  
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46 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (e.g., 
oral anti-histamine or corticosteroids). 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug and 
that does not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of investigational product, whether or not considered 
related to the investigational product. 
 
7.1 
Adverse Events 
 
7.1.1 Adverse Events for Nivolumab 
 
The following treatment-related adverse events (AEs) of any grade and of grade ≥ 3 were 
reported in patients with advanced NSCLC treated with nivolumab monotherapy at 3 mg/kg 
administered every 2 weeks, according to a pooled safety analysis (total 535 subjects) (44):  
 
Table 7.1.1: 
Summary of Adverse Events with Nivolumab Monotherapy in 
Subjects with Advanced NSCLC 
 
Event 
Any Grade, n (%) 
Grade 3-4, n (%) 
Drug-related AEs in ≥5% of subjects 
 
 
   Fatigue 
105 (19.6) 
9 (1.7) 
   Decreased appetite 
66 (12.3) 
1 (0.2) 
   Nausea 
64 (12.0) 
2 (0.4) 
   Asthenia 
56 (10.5) 
1 (0.2) 
   Rash 
45 (8.4) 
2 (0.4) 
   Diarrhea 
44 (8.2) 
5 (0.9) 
   Pruritus 
34 (6.4) 
1 (0.2) 
   Arthralgia 
28 (5.2) 
0 
   Hypothyroidism 
27 (5.0) 
0 
Drug-related AEs leading to discontinuation 
32 (6.0) 
25 (4.7) 
Drug-related AEs leading to discontinuation in > 1 
subject 
 
 
   Pneumonitis 
10 (1.9) 
7 (1.3) 


  
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47 
   Fatigue 
3 (0.6) 
1 (0.2) 
   Interstitial lung disease 
2 (0.4) 
1 (0.2) 
   Rash 
2 (0.4) 
1 (0.2) 
Drug-related SAEs 
42 (7.9) 
27 (5.0) 
Drug-related SAEs in >1 subject 
 
 
   Pneumonitis 
10 (1.9) 
7 (1.3) 
   Colitis 
2 (0.4) 
1 (0.2) 
   Diarrhea 
2 (0.4) 
2 (0.4) 
   Infusion-related reaction 
2 (0.4) 
0 
   Interstitial lung disease 
2 (0.4) 
1 (0.2) 
   Nausea 
2 (0.4) 
1 (0.2) 
   Pyrexia  
2 (0.4) 
0 
Select AEs 
 
 
   Drug-related endocrine select AEs 
39 (7.3) 
1 (0.2) 
     Thyroid disorder 
38 (7.1) 
0 
       Hypothyroidism 
27 (5.0) 
0 
       Blood TSH increased 
7 (1.3) 
0 
       Hyperthyroidism 
4 (0.7) 
0 
       Blood TSH decreased 
2 (0.4) 
0 
       Thyroiditis 
2 (0.4) 
0 
     Adrenal disorder 
1 (0.2) 
1 (0.2) 
       Adrenal insufficiency 
1 (0.2) 
1 (0.2) 
   Drug-related gastrointestinal select AEs 
45 (8.4) 
6 (1.1) 
     Diarrhea 
44 (8.2) 
5 (0.9) 
     Colitis 
3 (0.6) 
2 (0.4) 
   Drug-related hepatic select AEs 
21 (3.9) 
3 (0.6) 
     ALT increased 
12 (2.2) 
0 
     AST increased 
11 (2.1) 
1 (0.2) 
     Blood ALP increased 
5 (0.9) 
0 
     GGT increased 
2 (0.4) 
2 (0.4) 
     Transaminases increased 
2 (0.4) 
1 (0.2) 
     Blood bilirubin increased 
1 (0.2) 
0 
     Hepatotoxicity 
1 (0.2) 
0 
     Hyperbilirubinemia 
1 (0.2) 
0 
   Drug-related hypersensitivity/infusion reactions 
12 (2.2) 
2 (0.4) 
     Infusion-related reaction 
9 (1.7) 
0 
     Hypersensitivity 
3 (0.6) 
1 (0.2) 
     Anaphylactic reaction 
1 (0.2) 
1 (0.2) 
   Drug-related pulmonary select AEs 
22 (4.1) 
8 (1.5) 
     Pneumonitis 
19 (3.6) 
7 (1.3) 
     Interstitial lung disease 
2 (0.4) 
1 (0.2) 
     Lung infiltration 
1 (0.2) 
0 
   Drug-related renal select AEs 
15 (2.8) 
1 (0.2) 
     Blood creatinine increased 
11 (2.1) 
0 
     Renal failure 
2 (0.4) 
0 
     Renal failure acute 
2 (0.4) 
0 


  
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48 
     Tubulointerstitial nephritis 
1 (0.2) 
1 (0.2) 
   Drug-related skin select AEs 
81 (15.1) 
4 (0.7) 
   Drug-related skin select AEs in ≥ 1% of subjects 
 
 
     Rash 
45 (8.4) 
2 (0.4) 
     Pruritus 
34 (6.4) 
1 (0.2) 
     Rash, maculopapular 
8 (1.5) 
0 
 
Of note, “select AEs” were identified based on the following 4 principles: 
• AEs that may differ in type, frequency, and severity from AEs caused by non-
immunotherapies 
• AEs that may require immunosuppression (e.g., corticosteroids) as part of their 
management 
• AEs whose early recognition and management may mitigate severe toxicity 
• AEs for which multiple event terms may be used to describe a single type of AE, thereby 
necessitating the pooling of terms for full characterization.  
 
7.1.2 Adverse Events for Pemetrexed 
 
Table 7.1.3 provides the list of AEs reported in >5% of advanced NSCLC patients who received 
pemetrexed maintenance (a total of 333 patients) following platinum-based induction 
chemotherapy (56). 
 
 Table 7.1.3: 
Summary of Adverse Events with Pemetrexed Monotherapy in 
Subjects with Advanced NSCLC Following Platinum/Pemetrexed 
Induction Therapy 
 
Event 
Any Grade, % 
Grade 3-4, % 
Laboratory 
 
 
   Hematologic 
 
 
     Anemia 
15 
4.8 
     Neutropenia 
9 
3.9 
     Leukopenia 
6 
2 
 Clinical 
 
 
   Constitutional symptoms 
 
 
     Fatigue 
18 
4.5 
   Gastrointestinal 
 
 
     Nausea 
12 
0.3 
     Vomiting 
6 
0 
     Mucositis/stomatitis 
5 
0.3 
   General disorders 
 
 
     Edema 
5 
0 
 
The following additional grade 3 or 4 AEs were observed in patients with NSCLC who received 
pemetrexed: 
• Incidence of 1-5%: 


  
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49 
o Blood/bone marrow – Thrombocytopenia 
o General disorders – Febrile neutropenia 
• Incidence less than 1%: 
o Cardiovascular – Ventricular tachycardia, syncope 
o General disorders – Pain 
o Gastrointestinal – Gastrointestinal obstruction, ALT or AST elevation, diarrhea 
o Neurology – Depression, neuropathy 
o Renal – Renal failure 
o Vascular – Pulmonary embolism 
 
7.1.3 Adverse Events for Carboplatin 
 
The following list of AEs and their incidences have been described based on data from 1893 
patients with various types of tumors who received carboplatin as single-agent therapy (55): 
 
Table 7.1.4-1: 
Summary of Adverse Events with Carboplatin Monotherapy in 
Subjects with Various Tumors 
 
Event 
% 
Hematologic 
 
   Thrombocytopenia (platelet < 50,000/mm3) 
25 
   Neutropenia (ANC < 1000/mm3) 
16 
   Leukopenia (WBC < 2000/mm3) 
15 
   Anemia (Hgb < 11 g/dL) 
71 
Gastrointestinal 
 
   Vomiting 
65 
   Nausea alone 
10-15 
Neurologic 
 
   Peripheral neuropathy 
4 
Renal 
 
   Abnormal serum creatinine value 
6 
   Abnormal blood urea nitrogen value 
14 
   Decreased creatinine clearance 
27 
Hepatic 
 
   Abnormal total bilirubin 
5 
   Abnormal AST 
5 
   Abnormal alkaline phosphatase 
24 
Electrolyte changes 
 
   Low sodium 
29 
   Low potassium 
20 
   Low calcium 
22 
   Low magnesium  
29 
Allergic reactions 
 
   Hypersensitivity 
2 
 


  
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Other events that have been reported include injection site reactions, pain and asthenia, alopecia 
(3%). Malaise, anorexia, and hypertension have been reported as part of post-marketing 
surveillance. Cardiovascular, respiratory, genitourinary, and mucosal side effects have occurred 
in < 6% of the patients.  
 
Among patients with advanced NSCLC treated with carboplatin and pemetrexed combination 
chemotherapy for 6 or more cycles (total of 50 patients), the following AEs were noted (57): 
 
Table 7.1.4-2: 
Summary of Adverse Events with Carboplatin and Pemetrexed 
Combination Chemotherapy in Subjects with NSCLC 
  
Event 
Any Grade, n (%) 
Grade 3-4, n (%) 
Hematologic 
 
 
   Anemia 
42 (84) 
1 (2) 
   Neutropenia 
31 (62) 
13 (26) 
   Thrombocytopenia 
27 (54) 
1 (2) 
Non-hematologic 
 
 
   Nausea 
34 (68) 
1 (2) 
   Fatigue 
27 (54) 
2 (4) 
   Alopecia 
24 (48) 
0 
   Watery eyes 
21 (42) 
0 
   Stomatitis 
18 (36) 
0 
   Diarrhea 
14 (28) 
1 (2) 
   Vomiting 
14 (28) 
1 (2) 
   Dry eyes 
10 (20) 
0 
   Anorexia 
9 (18) 
0 
   Rash 
8 (16) 
0 
   Sensory neuropathy 
8 (16) 
0 
   Constipation 
7 (14) 
0 
   Pruritus 
4 (8) 
0 
   Thrush 
2 (4) 
0 
   Pneumonia 
1 (2) 
0 
   Upper respiratory tract infection 
1 (2) 
0 
 
7.1.4 
Adverse Events for Bevacizumab 
 
Hypertension: An increased incidence of hypertension has been observed in 
patients treated with bevacizumab. Grade 4 and 5 hypertensive events are rare. 
Clinical sequelae of hypertension are rare but have included hypertensive 
crisis, hypertensive encephalopathy, and reversible posterior 
leukoencephalopathy syndrome (RPLS). There is no information on the effect of 
bevacizumab in patients with uncontrolled hypertension at the time of 
initiating bevacizumab therapy. Therefore, caution should be exercised before 
initiating bevacizumab therapy in these patients. Monitoring of blood pressure 


  
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i s  r e c o m m e n d e d  d u r i n g  b e v a c i z u m a b  t h e r a p y .  O p t i m a l  c o n t r o l  o f  b l o o d  p r e s s u r e  
a c c o r d i n g  t o  s t a n d a r d  p u b l i c  h e a l t h  g u i d e l i n e s  i s  r e c o m m e n d e d  f o r  p a t i e n t s  o n  
t r e a t m e n t  w i t h  o r  w i t h o u t  b e v a c i z u m a b .  T e m p o r a r y  i n t e r r u p t i o n  o f  b e v a c i z u m a b  
t h e r a p y  i s  r e c o m m e n d e d  i n  p a t i e n t s  w i t h  h y p e r t e n s i o n  r e q u i r i n g  m e d i c a l  t h e r a p y  
u n t i l  a d e q u a t e  c o n t r o l  i s  a c h i e v e d .  I f  h y p e r t e n s i o n  c a n n o t  b e  c o n t r o l l e d  w i t h  
m e d i c a l  t h e r a p y ,  b e v a c i z u m a b  t h e r a p y  s h o u l d  b e  p e r m a n e n t l y  d i s c o n t i n u e d .  
B e v a c i z u m a b  s h o u l d  b e  p e r m a n e n t l y  d i s c o n t i n u e d  i n  p a t i e n t s  w h o  d e v e l o p  
h y p e r t e n s i v e  c r i s i s  o r  h y p e r t e n s i v e  e n c e p h a l o p a t h y .  
 
Pr otei n uri a :  A n  i n c r e a s e d  i n c i d e n c e  o f  p r o t e i n u r i a  h a s  b e e n  o b s e r v e d  i n  
p a t i e n t s  t r e a t e d  w i t h  b e v a c i z u m a b  c o m p a r e d  w i t h  c o n t r o l  a r m  p a t i e n t s .  I n  t h e  
b e v a c i z u m a b - c o n t a i n i n g  t r e a t m e n t  a r m s  o f  c l i n i c a l  t r i a l s  ( a c r o s s  a l l  
i n d i c a t i o n s ) ,  t h e  i n c i d e n c e  o f  p r o t e i n u r i a  ( r e p o r t e d  a s  a n  a d v e r s e  e v e n t )  w a s  
u p  t o  3 8 %  ( m e t a s t a t i c  C R C  S t u d y  A V F 2 1 9 2 g ) .  T h e  s e v e r i t y  o f  p r o t e i n u r i a  h a s  
r a n g e d  f r o m  a s y m p t o m a t i c  a n d  t r a n s i e n t  e v e n t s  d e t e c t e d  o n  r o u t i n e  d i p s t i c k  
u r i n a l y s i s  t o  n e p h r o t i c  s y n d r o m e ;  t h e  m a j o r i t y  o f  p r o t e i n u r i a  e v e n t s  h a v e  b e e n  
g r a d e  1 .  N C I - C T C  G r a d e  3  p r o t e i n u r i a  w a s  r e p o r t e d  i n  u p  t o  3 %  o f  b e v a c i z u m a b -
t r e a t e d  p a t i e n t s ,  a n d  G r a d e  4  i n  u p  t o  1 . 4 %  o f  b e v a c i z u m a b - t r e a t e d  p a t i e n t s .  
T h e  p r o t e i n u r i a  s e e n  i n  b e v a c i z u m a b  c l i n i c a l  t r i a l s  w a s  n o t  a s s o c i a t e d  w i t h  
r e n a l  i m p a i r m e n t  a n d  r a r e l y  r e q u i r e d  p e r m a n e n t  d i s c o n t i n u a t i o n  o f  b e v a c i z u m a b  
t h e r a p y .  B e v a c i z u m a b  s h o u l d  b e  d i s c o n t i n u e d  i n  p a t i e n t s  w h o  d e v e l o p  G r a d e  4  
p r o t e i n u r i a  ( n e p h r o t i c  s y n d r o m e ) .  P a t i e n t s  w i t h  a  h i s t o r y  o f  h y p e r t e n s i o n  m a y  
b e  a t  i n c r e a s e d  r i s k  f o r  t h e  d e v e l o p m e n t  o f  p r o t e i n u r i a  w h e n  t r e a t e d  w i t h  
b e v a c i z u m a b .  T h e r e  i s  e v i d e n c e  f r o m  t h e  d o s e - f i n d i n g ,  P h a s e  I I  t r i a l s  
( A V F 0 7 8 0 g ,  A V F 0 8 0 9 s ,  a n d  A V F 0 7 5 7 g )  s u g g e s t i n g  t h a t  
G r a d e  1  p r o t e i n u r i a  m a y  b e  r e l a t e d  t o  b e v a c i z u m a b  d o s e .   
 
T hr o m b oe m b olic E ve nts :  B o t h  v e n o u s  a n d  a r t e r i a l  t h r o m b o e m b o l i c  ( T E )  e v e n t s ,  
r a n g i n g  i n  s e v e r i t y  f r o m  c a t h e t e r - a s s o c i a t e d  p h l e b i t i s  t o  f a t a l  e v e n t s ,  h a v e  
b e e n  r e p o r t e d  i n  p a t i e n t s  t r e a t e d  w i t h  b e v a c i z u m a b  i n  t h e  c o l o r e c t a l  c a n c e r  
t r i a l s  a n d ,  t o  a  l e s s e r  e x t e n t ,  i n  p a t i e n t s  t r e a t e d  w i t h  b e v a c i z u m a b  i n  N S C L C  
a n d  b r e a s t  c a n c e r  t r i a l s .  
 
Ve n o us t hr o m b oe m b olis m (i ncl u di n g dee p ve n o us t hr o m b osis, p ul m o n ar y e m b olis m, a n d 
t hr o m b o p hle bitis):  I n  t h e  p i v o t a l  P h a s e  I I I  t r i a l  i n  m e t a s t a t i c  C R C ,  t h e r e  w a s  
a  s l i g h t l y  h i g h e r  r a t e  o f  v e n o u s  T E  e v e n t s  i n  p a t i e n t s  t r e a t e d  w i t h  
b e v a c i z u m a b  p l u s  c h e m o t h e r a p y  c o m p a r e d  w i t h  c h e m o t h e r a p y  a l o n e  ( 1 9 %  v s .  1 6 % ) .  
I n  S t u d y  A V F 2 1 0 7 g ,  a  P h a s e  I I I ,  p i v o t a l  t r i a l  i n  m e t a s t a t i c  C R C ,  V T E  e v e n t s ,  
i n c l u d i n g  d e e p  v e n o u s  t h r o m b o s i s ,  p u l m o n a r y  e m b o l i s m ,  a n d  t h r o m b o p h l e b i t i s ,  
o c c u r r e d  i n  1 5 . 2 %  o f  p a t i e n t s  r e c e i v i n g  c h e m o t h e r a p y  a l o n e  a n d  1 6 . 6 %  o f  
p a t i e n t s  r e c e i v i n g  c h e m o t h e r a p y  a n d b e v a c i z u m a b .  


  
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5 2  
 
T h e  i n c i d e n c e  o f  N C I - C T C  G r a d e  ≥3  v e n o u s  V T E  e v e n t s  i n  o n e  N S C L C  t r i a l  
( E 4 5 9 9 )  w a s  h i g h e r  i n  t h e  b e v a c i z u m a b - c o n t a i n i n g  a r m  c o m p a r e d  t o  t h e  
c h e m o t h e r a p y  c o n t r o l  a r m  ( 5 . 6 %  v s .  3 . 2 % ) .  O n e  e v e n t  ( 0 . 2 % )  w a s  f a t a l  i n  t h e  
b e v a c i z u m a b - c o n t a i n i n g  a r m ;  n o  f a t a l  e v e n t s  w e r e  r e p o r t e d  i n  t h e  
c a r b o p l a t i n / p a c l i t a x e l  a r m  ( s e e  b e v a c i z u m a b  I n v e s t i g a t o r  B r o c h u r e ) .   
 
I n  m e t a s t a t i c  C R C  c l i n i c a l  t r i a l s ,  t h e  i n c i d e n c e  o f  V T E  e v e n t s  w a s  s i m i l a r  i n  
p a t i e n t s  r e c e i v i n g  c h e m o t h e r a p y  p l u s  b e v a c i z u m a b  a n d  t h o s e  r e c e i v i n g  t h e  
c o n t r o l  c h e m o t h e r a p y  a l o n e .  I n  c l i n i c a l  t r i a l s  a c r o s s  a l l  i n d i c a t i o n s  t h e  
o v e r a l l  i n c i d e n c e  o f  V T E  e v e n t s  w a s  2 . 8  -  1 7 . 3 %  i n  t h e  b e v a c i z u m a b - c o n t a i n i n g  
a r m s  c o m p a r e d  w i t h  3 . 2  -  1 5 . 6 %  i n  t h e  c h e m o t h e r a p y  c o n t r o l  a r m s .  T h e  u s e  o f  
b e v a c i z u m a b  w i t h  c h e m o t h e r a p y  d o e s  n o t  s u b s t a n t i a l l y  i n c r e a s e  t h e  r i s k  o f  V T E  
e v e n t  c o m p a r e d  w i t h  c h e m o t h e r a p y  a l o n e .  H o w e v e r ,  p a t i e n t s  w i t h  m e t a s t a t i c  C R C  
w h o  r e c e i v e  b e v a c i z u m a b  a n d  e x p e r i e n c e d  a  V T E  e v e n t  m a y  b e  a t  h i g h e r  r i s k  f o r  
r e c u r r e n c e  o f  V T E  e v e n t .  
 
Arteri al T hr o m b oe m b olic E ve nts: A n  i n c r e a s e d  i n c i d e n c e  o f  A T E  e v e n t s  w a s  
o b s e r v e d  i n  p a t i e n t s  t r e a t e d  w i t h  b e v a c i z u m a b  c o m p a r e d  w i t h  t h o s e  r e c e i v i n g  
c o n t r o l  t r e a t m e n t .  A T E  e v e n t s  i n c l u d e  c e r e b r o v a s c u l a r  a c c i d e n t s ,  m y o c a r d i a l  
i n f a r c t i o n ,  t r a n s i e n t  i s c h e m i c  a t t a c k s  ( T I A s ) ,  a n d  o t h e r  A T E  e v e n t s .  I n  a  
p o o l e d  a n a l y s i s  o f  d a t a  f r o m  f i v e  r a n d o m i z e d  P h a s e  I I  a n d  I I I  t r i a l s  ( m C R C  
[ A V F 2 1 0 7 g ,  A V F 2 1 9 2 g ,  A V F 0 7 8 0 g ] ;  l o c a l l y  a d v a n c e d  o r  m e t a s t a t i c  N S C L C  
[ A V F 0 7 5 7 g ] ;  a n d  m e t a s t a t i c  b r e a s t  c a n c e r  [ A V F 2 1 1 9 g ] ) ,  t h e  i n c i d e n c e  o f  A T E  
e v e n t s  w a s  3 . 8 %  ( 3 7  o f  9 6 3 )  i n  p a t i e n t s  w h o  r e c e i v e d  c h e m o t h e r a p y  a n d  
b e v a c i z u m a b  c o m p a r e d  w i t h  1 . 7 %  ( 1 3  o f  7 8 2 )  i n  p a t i e n t s  t r e a t e d  w i t h  
c h e m o t h e r a p y  a l o n e .  A T E  e v e n t s  l e d  t o  a  f a t a l  o u t c o m e  i n  0 . 8 %  ( 8  o f  9 6 3 )  o f  
p a t i e n t s  t r e a t e d  w i t h  c h e m o t h e r a p y  a n d  b e v a c i z u m a b  a n d  0 . 5 %  ( 4  o f  7 8 2 )  o f  
p a t i e n t s  t r e a t e d  w i t h  c h e m o t h e r a p y  a l o n e .  C e r e b r o v a s c u l a r  a c c i d e n t s  ( i n c l u d i n g  
T I A s )  o c c u r r e d  i n  2 . 3 %  o f  p a t i e n t s  t r e a t e d  w i t h  c h e m o t h e r a p y  a n d  b e v a c i z u m a b  
a n d  0 . 5 %  o f  p a t i e n t s  t r e a t e d  w i t h  c h e m o t h e r a p y  a l o n e .  M y o c a r d i a l  i n f a r c t i o n  
o c c u r r e d  i n  1 . 4 %  o f  p a t i e n t s  t r e a t e d  w i t h  c h e m o t h e r a p y  p l u s  b e v a c i z u m a b  
c o m p a r e d  w i t h  0 . 7 %  o f  p a t i e n t s  t r e a t e d  w i t h  c h e m o t h e r a p y  a l o n e  ( s e e  t h e  
b e v a c i z u m a b  I n v e s t i g a t o r  B r o c h u r e  f o r  a d d i t i o n a l  d e t a i l s ) .  
 
A s p i r i n  i s  a  s t a n d a r d  t h e r a p y  f o r  p r i m a r y  a n d  s e c o n d a r y  p r o p h y l a x i s  o f  
a r t e r i a l  t h r o m b o e m b o l i c  e v e n t s  i n  p a t i e n t s  a t  h i g h  r i s k  o f  s u c h  e v e n t s ,  a n d  
t h e  u s e  o f  a s p i r i n  ≤ 3 2 5  m g  d a i l y  w a s  a l l o w e d  i n  t h e  f i v e  r a n d o m i z e d  s t u d i e s  
d i s c u s s e d  a b o v e .  U s e  o f  a s p i r i n  w a s  a s s e s s e d  r o u t i n e l y  a s  a  b a s e l i n e  o r  
c o n c o m i t a n t  m e d i c a t i o n  i n  t h e s e  t r i a l s ,  t h o u g h  s a f e t y  a n a l y s e s  s p e c i f i c a l l y  


  
Pr ot oc ol # 1 7 -0 1 1  
Versi o n Date:  J ul y 2 0, 2 0 1 8 
 
5 3  
r e g a r d i n g  a s p i r i n  u s e  w e r e  n o t  p r e p l a n n e d .  D u e  t o  t h e  r e l a t i v e l y  s m a l l  n u m b e r s  
o f  a s p i r i n  u s e r s  a n d  a r t e r i a l  t h r o m b o e m b o l i c  e v e n t s ,  r e t r o s p e c t i v e  a n a l y s e s  o f  
t h e  a b i l i t y  o f  a s p i r i n  t o  a f f e c t  t h e  r i s k  o f  s u c h  e v e n t s  w e r e  i n c o n c l u s i v e .  
H o w e v e r ,  s i m i l a r l y  r e t r o s p e c t i v e  a n a l y s e s  s u g g e s t e d  t h a t  t h e  u s e  o f  u p  t o  3 2 5  
m g  o f  a s p i r i n  d a i l y  d o e s  n o t  i n c r e a s e  t h e  r i s k  o f  g r a d e  1 - 2  o r  g r a d e  3 - 4  
b l e e d i n g  e v e n t s ,  a n d  s i m i l a r  d a t a  w i t h  r e s p e c t  t o  m e t a s t a t i c  c o l o r e c t a l  c a n c e r  
p a t i e n t s  w e r e  p r e s e n t e d  a t  A S C O  2 0 0 5  ( H a m b l e t o n  e t  a l . ,  2 0 0 5 ) .  F u r t h e r  
a n a l y s e s  o f  t h e  e f f e c t s  o f  c o n c o m i t a n t  u s e  o f  b e v a c i z u m a b  a n d  a s p i r i n  i n  
c o l o r e c t a l  a n d  o t h e r  t u m o r  t y p e s  a r e  o n g o i n g .  
 
G astr oi nt esti n al perf or ati o n: P a t i e n t s  w i t h  m e t a s t a t i c  c a r c i n o m a  m a y  b e  a t  
i n c r e a s e d  r i s k  f o r  t h e  d e v e l o p m e n t  o f  g a s t r o i n t e s t i n a l  p e r f o r a t i o n  a n d  f i s t u l a  
w h e n  t r e a t e d  w i t h  b e v a c i z u m a b  a n d  c h e m o t h e r a p y .  B e v a c i z u m a b  s h o u l d  b e  
p e r m a n e n t l y  d i s c o n t i n u e d  i n  p a t i e n t s  w h o  d e v e l o p  g a s t r o i n t e s t i n a l  p e r f o r a t i o n .  
A  c a u s a l  a s s o c i a t i o n  o f  i n t r a - a b d o m i n a l  i n f l a m m a t o r y  p r o c e s s e s  a n d  
g a s t r o i n t e s t i n a l  p e r f o r a t i o n  t o  b e v a c i z u m a b  t r e a t m e n t  h a s  n o t  b e e n  e s t a b l i s h e d .  
N e v e r t h e l e s s ,  c a u t i o n  s h o u l d  b e  e x e r c i s e d  w h e n  t r e a t i n g  p a t i e n t s  w i t h  i n t r a -
a b d o m i n a l  i n f l a m m a t o r y  p r o c e s s e s  w i t h  b e v a c i z u m a b .  G a s t r o i n t e s t i n a l  
p e r f o r a t i o n  h a s  b e e n  r e p o r t e d  i n  o t h e r  t r i a l s  i n  n o n - c o l o r e c t a l  c a n c e r  
p o p u l a t i o n s  ( e . g . ,  o v a r i a n ,  r e n a l  c e l l ,  p a n c r e a s ,  b r e a s t ,  a n d  N S C L C )  a n d  m a y  
b e  h i g h e r  i n  i n c i d e n c e  i n  s o m e  t u m o r  t y p e s .  
 
Fist ul a :  B e v a c i z u m a b  u s e  h a s  b e e n  a s s o c i a t e d  w i t h  s e r i o u s  c a s e s  o f  f i s t u l a e  
i n c l u d i n g  e v e n t s  r e s u l t i n g  i n  d e a t h .  F i s t u l a e  i n  t h e  G I  t r a c t  a r e  c o m m o n  ( 1 % –
1 0 %  i n c i d e n c e )  i n  p a t i e n t s  w i t h  m e t a s t a t i c  C R C ,  b u t  u n c o m m o n  ( 0 . 1  -  1 % )  o r  
r a r e  ( 0 . 0 1 % – 0 . 1 % )  i n  o t h e r  i n d i c a t i o n s .  I n  a d d i t i o n ,  f i s t u l a e  t h a t  i n v o l v e  
a r e a s  o f  t h e  b o d y  o t h e r  t h a n  t h e  G I  t r a c t  ( e . g . ,  t r a c h e o e s o p h a g e a l ,  
b r o n c h o p l e u r a l ,  u r o g e n i t a l ,  b i l i a r y )  h a v e  b e e n  r e p o r t e d  u n c o m m o n l y  ( 0 . 1 % – 1 % )  
i n  p a t i e n t s  r e c e i v i n g  b e v a c i z u m a b  i n  c l i n i c a l  s t u d i e s  a n d  p o s t m a r k e t i n g  
r e p o r t s .  E v e n t s  w e r e  r e p o r t e d  a t  v a r i o u s  t i m e p o i n t s  d u r i n g  t r e a t m e n t ,  r a n g i n g  
f r o m  1  w e e k  t o  > 1  y e a r  f o l l o w i n g  i n i t i a t i o n  o f  b e v a c i z u m a b ,  w i t h  m o s t  e v e n t s  
o c c u r r i n g  w i t h i n  t h e  f i r s t  6  m o n t h s  o f  t h e r a p y .  B e v a c i z u m a b  s h o u l d  b e  
p e r m a n e n t l y  d i s c o n t i n u e d  i n  p a t i e n t s  w i t h  t r a c h e o e s o p h a g e a l  f i s t u l a e  o r  a n y  
G r a d e  4  f i s t u l a .  L i m i t e d  i n f o r m a t i o n  i s  a v a i l a b l e  o n  t h e  c o n t i n u e d  u s e  o f  
b e v a c i z u m a b  i n  p a t i e n t s  w i t h  o t h e r  f i s t u l a e .  I n  c a s e s  o f  i n t e r n a l  f i s t u l a  n o t  
a r i s i n g  i n  t h e  G I  t r a c t ,  d i s c o n t i n u a t i o n  o f  b e v a c i z u m a b  s h o u l d  b e  c o n s i d e r e d .  
 
W o u n d he ali n g c o m plic ati o ns: W o u n d  h e a l i n g  c o m p l i c a t i o n s  s u c h  a s  w o u n d  
d e h i s c e n c e  h a v e  b e e n  r e p o r t e d  i n  p a t i e n t s  r e c e i v i n g  b e v a c i z u m a b .  I n  a n  
a n a l y s i s  o f  p o o l e d  d a t a  f r o m  t w o  t r i a l s  i n  m e t a s t a t i c  c o l o r e c t a l  c a n c e r ,  
p a t i e n t s  u n d e r g o i n g  s u r g e r y  2 8 - 6 0  d a y s  b e f o r e  s t u d y  t r e a t m e n t  w i t h  5 - F U / L V  


  
Protocol #17-011  
Version Date: July 20, 2018 
 
54 
plus bevacizumab did not appear to have an increased risk of wound healing 
complications compared to those treated with chemotherapy alone. Surgery in 
patients currently receiving bevacizumab is not recommended. No definitive 
data are available to define a safe interval after bevacizumab exposure with 
respect to wound healing risk in patients receiving elective surgery; however, 
the estimated half life of bevacizumab is 21 days. Bevacizumab should be 
discontinued in patients with severe wound healing complications. 
 
If patients receiving treatment with bevacizumab require elective major 
surgery, it is recommended that bevacizumab be held for 4–8 weeks prior to the 
surgical procedure. Patients undergoing a major surgical procedure should not 
begin or restart bevacizumab until 4 weeks after that procedure (in the case 
of high-risk procedures such as liver resection, thoracotomy, or neurosurgery, 
it is recommended that chemotherapy be restarted no earlier than 6 weeks and 
bevacizumab no earlier than 8 weeks after surgery). 
 
Hemorrhage: Overall, Grade 3 and 4 bleeding events were observed in 4.0% of 
1132 patients treated with bevacizumab in a pooled database from eight Phase I, 
II, and III clinical trials in multiple tumor types (bevacizumab Investigator 
Brochure). The hemorrhagic events that have been observed in bevacizumab 
clinical studies were predominantly tumor-associated hemorrhage (see below) 
and minor mucocutaneous hemorrhage. 
 
Tumor-Associated Hemorrhage: Major or massive pulmonary hemorrhage or 
hemoptysis has been observed primarily in patients with NSCLC. Life-
threatening and fatal hemoptysis was identified as a bevacizumab-related 
adverse event in NSCLC trials. These events occurred suddenly and presented as 
major or massive hemoptysis. Among the possible risk factors evaluated 
(include squamous cell histology, treatment with anti-rheumatic/anti-
inflammatory drugs, treatment with anticoagulants, prior radiotherapy, 
bevacizumab therapy, previous medical history of atherosclerosis, central 
tumor location, and cavitation of tumors during therapy), the only variables 
that showed statistically significant correlations with bleeding were 
bevacizumab therapy and squamous cell histology.  
 
Of patients experiencing pulmonary hemorrhages requiring medical intervention, 
many had cavitation and/or necrosis of the tumor, either preexisting or 
developing during bevacizumab therapy. Patients developing lung cavitation on 
treatment should be assessed by the treating physician for risk-benefit. In 


  
Pr ot oc ol # 1 7 -0 1 1  
Versi o n Date:  J ul y 2 0, 2 0 1 8 
 
5 5  
S t u d y  E 4 5 9 9 ,  i n  w h i c h  s q u a m o u s  c e l l  c a r c i n o m a  w a s  e x c l u d e d ,  t h e  r a t e  o f  a n y  
t y p e  o f  G r a d e  ≥3  h e m o r r h a g e  w a s  1 . 0 %  i n  t h e  c o n t r o l  a r m  ( c a r b o p l a t i n  a n d  
p a c l i t a x e l )  v e r s u s  4 . 1 %  i n  t h e  c a r b o p l a t i n  a n d  paclita x el pl us b e v a c i z u m a b  a r m .   
 
G I  h e m o r r h a g e s ,  i n c l u d i n g  r e c t a l  b l e e d i n g  a n d  m e l e n a  h a v e  b e e n  r e p o r t e d  i n  
p a t i e n t s  w i t h  C R C ,  a n d  h a v e  b e e n  a s s e s s e d  a s  t u m o r - a s s o c i a t e d  h e m o r r h a g e s .  
 
T u m o r - a s s o c i a t e d  h e m o r r h a g e s  w e r e  a l s o  s e e n  r a r e l y  i n  o t h e r  t u m o r  t y p e s  a n d  
l o c a t i o n s ,  i n c l u d i n g  a  c a s e  o f  C N S  b l e e d i n g  i n  a  p a t i e n t  w i t h  h e p a t o m a  w i t h  
o c c u l t  C N S  m e t a s t a s e s  a n d  a  p a t i e n t  w h o  d e v e l o p e d  c o n t i n u o u s  o o z i n g  o f  b l o o d  
f r o m  a  t h i g h  s a r c o m a  w i t h  n e c r o s i s .  A  r e c e n t  r e v i e w  e x a m i n e d  t h e  r i s k  o f  C N S  
h e m o r r h a g e  i n  a s s o c i a t i o n  w i t h  a n t i - V E G F  t h e r a p y .  A m o n g  6 6 9  p a t i e n t s  t r e a t e d  
o n  P h a s e  I  a n d  I I  s t u d i e s  o f  b e v a c i z u m a b  t h a t  e x c l u d e d  b r a i n  m e t a s t a s e s ,  o n l y  
1  c a s e  ( 0 . 2 % )  o f  C N S  b l e e d i n g  w a s  r e p o r t e d .   
 
M uc oc ut a ne o us He m orr h a ge: A c r o s s  a l l  b e v a c i z u m a b  c l i n i c a l  t r i a l s ,  
m u c o c u t a n e o u s  h e m o r r h a g e  h a s  b e e n  s e e n  i n  2 0 % - 4 0 %  o f  p a t i e n t s  t r e a t e d  w i t h  
b e v a c i z u m a b .  T h e s e  w e r e  m o s t  c o m m o n l y  N C I - C T C  G r a d e  1  e p i s t a x i s  t h a t  l a s t e d  
l e s s  t h a n  5  m i n u t e s ,  r e s o l v e d  w i t h o u t  m e d i c a l  i n t e r v e n t i o n  a n d  d i d  n o t  r e q u i r e  
a n y  c h a n g e s  i n  b e v a c i z u m a b  t r e a t m e n t  r e g i m e n .  T h e r e  h a v e  a l s o  b e e n  l e s s  c o m m o n  
e v e n t s  o f  m i n o r  m u c o c u t a n e o u s  h e m o r r h a g e  i n  o t h e r  l o c a t i o n s ,  s u c h  a s  g i n g i v a l  
b l e e d i n g  a n d  v a g i n a l  b l e e d i n g .  
 
Re versi ble P ost eri or Le u k oe nce p h al o p at h y S y n dr o me: T h e r e  h a v e  b e e n  r a r e  r e p o r t s  
o f  b e v a c i z u m a b - t r e a t e d  p a t i e n t s  d e v e l o p i n g  s i g n s  a n d  s y m p t o m s  t h a t  a r e  
c o n s i s t e n t  w i t h  R P L S ,  a  r a r e  n e u r o l o g i c a l  d i s o r d e r  t h a t  c a n  p r e s e n t  w i t h  t h e  
f o l l o w i n g  s i g n s  a n d  s y m p t o m s  ( a m o n g  o t h e r s ) :  s e i z u r e s ,  h e a d a c h e ,  a l t e r e d  
m e n t a l  s t a t u s ,  v i s u a l  d i s t u r b a n c e ,  o r  c o r t i c a l  b l i n d n e s s ,  w i t h  o r  w i t h o u t  
a s s o c i a t e d  h y p e r t e n s i o n .  B r a i n  i m a g i n g  i s  m a n d a t o r y  t o  c o n f i r m  t h e  d i a g n o s i s  
o f  R P L S .  I n  p a t i e n t s  w h o  d e v e l o p  R P L S ,  t r e a t m e n t  o f  s p e c i f i c  s y m p t o m s ,  
i n c l u d i n g  c o n t r o l  o f  h y p e r t e n s i o n ,  i s  r e c o m m e n d e d  a l o n g  w i t h  d i s c o n t i n u a t i o n  
o f  b e v a c i z u m a b .  T h e  s a f e t y  o f  r e i n i t i a t i n g  b e v a c i z u m a b  t h e r a p y  i n  p a t i e n t s  
p r e v i o u s l y  e x p e r i e n c i n g  R P L S  i s  n o t  k n o w n .   
 
C o n gesti ve he art f ail ure: I n  c l i n i c a l  t r i a l s ,  C H F  w a s  o b s e r v e d  i n  a l l  c a n c e r  
i n d i c a t i o n s  s t u d i e d  t o  d a t e ,  b u t  p r e d o m i n a n t l y  i n  p a t i e n t s  w i t h  m e t a s t a t i c  
b r e a s t  c a n c e r .  I n  t h e  P h a s e  I I I  c l i n i c a l  t r i a l  o f  m e t a s t a t i c  b r e a s t  c a n c e r  
( A V F 2 1 1 9 g ) ,  7  ( 3 % )  b e v a c i z u m a b - t r e a t e d  p a t i e n t s  e x p e r i e n c e d  C H F ,  c o m p a r e d  w i t h  
t w o  ( 1 % )  c o n t r o l  a r m  p a t i e n t s .  T h e s e  e v e n t s  v a r i e d  i n  s e v e r i t y  f r o m  
a s y m p t o m a t i c  d e c l i n e s  i n  l e f t  v e n t r i c u l a r  e j e c t i o n  f r a c t i o n  ( L V E F )  t o  


  
Pr ot oc ol # 1 7 -0 1 1  
Versi o n Date:  J ul y 2 0, 2 0 1 8 
 
5 6  
s y m p t o m a t i c  C H F  r e q u i r i n g  h o s p i t a l i z a t i o n  a n d  t r e a t m e n t .  A l l  t h e  p a t i e n t s  
t r e a t e d  w i t h  b e v a c i z u m a b  w e r e  p r e v i o u s l y  t r e a t e d  w i t h  a n t h r a c y c l i n e s  
( d o x o r u b i c i n  c u m u l a t i v e  d o s e  o f  2 4 0 3 6 0  m g / m 2) .  M a n y  o f  t h e s e  p a t i e n t s  a l s o  
h a d  p r i o r  r a d i o t h e r a p y  t o  t h e  l e f t  c h e s t  w a l l .  M o s t  o f  t h e s e  p a t i e n t s  s h o w e d  
i m p r o v e d  s y m p t o m s  a n d / o r  l e f t  v e n t r i c u l a r  f u n c t i o n  f o l l o w i n g  a p p r o p r i a t e  
m e d i c a l  t h e r a p y .  
 
I n  a  r a n d o m i z e d ,  P h a s e  I I I  t r i a l  o f  p a t i e n t s  w i t h  p r e v i o u s l y  u n t r e a t e d  
m e t a s t a t i c  b r e a s t  c a n c e r  ( E 2 1 0 0 ) ,  t h e  i n c i d e n c e  o f  L V E F  d e c r e a s e  ( d e f i n e d  a s  
N C I - C T C  G r a d e  3  o r  4 )  i n  t h e  p a c l i t a x e l  b e v a c i z u m a b  a r m  w a s  0 . 3 %  v e r s u s  0 %  
f o r  t h e  p a c l i t a x e l  a l o n e  a r m .  N o  i n f o r m a t i o n  i s  a v a i l a b l e  o n  p a t i e n t s  w i t h  
p r e e x i s t i n g  C H F  o f  N e w  Y o r k  H e a r t  A s s o c i a t i o n  ( N Y H A )  C l a s s  I I I V  a t  t h e  t i m e  
o f  i n i t i a t i n g  b e v a c i z u m a b  t h e r a p y ,  a s  t h e s e  p a t i e n t s  w e r e  e x c l u d e d  f r o m  
c l i n i c a l  t r i a l s .  P r i o r  a n t h r a c y c l i n e s  e x p o s u r e  a n d / o r  p r i o r  r a d i o t h e r a p y  t o  
t h e  c h e s t  w a l l  m a y  b e  p o s s i b l e  r i s k  f a c t o r s  f o r  t h e  d e v e l o p m e n t  o f  C H F .  
C a u t i o n  s h o u l d  b e  e x e r c i s e d  b e f o r e  i n i t i a t i n g  b e v a c i z u m a b  t h e r a p y  i n  p a t i e n t s  
w i t h  t h e s e  r i s k  f a c t o r s .  A  P h a s e  I I  t r i a l  i n  p a t i e n t s  w i t h  r e f r a c t o r y  a c u t e  
m y e l o g e n o u s  l e u k e m i a  r e p o r t e d  5  c a s e s  o f  c a r d i a c  d y s f u n c t i o n  ( C H F  o r  L V E F  
d e c r e a s e  t o  < 4 0 % )  a m o n g  4 8  p a t i e n t s  t r e a t e d  w i t h  s e q u e n t i a l  c y t a r a b i n e ,  
m i t o x a n t r o n e ,  a n d  b e v a c i z u m a b .  A l l  b u t  1  o f  t h e s e  p a t i e n t s  h a d  s i g n i f i c a n t  
p r i o r  e x p o s u r e  t o  a n t h r a c y c l i n e s  a s  w e l l .   
 
T w o  a d d i t i o n a l  s t u d i e s  i n v e s t i g a t e d  c o n c u r r e n t  a d m i n i s t r a t i o n  o f  
a n t h r a c y c l i n e s  a n d  b e v a c i z u m a b .  I n  2 1  p a t i e n t s  w i t h  i n f l a m m a t o r y  b r e a s t  c a n c e r  
t r e a t e d  w i t h  n e o a d j u v a n t  d o c e t a x e l ,  d o x o r u b i c i n ,  a n d  b e v a c i z u m a b ,  n o  p a t i e n t s  
d e v e l o p e d  c l i n i c a l l y  a p p a r e n t  C H F ;  h o w e v e r ,  p a t i e n t s  h a d  a s y m p t o m a t i c  
d e c r e a s e s  i n  L V E F  t o  <  4 0 % .  I n  a  s m a l l  P h a s e  I I  s t u d y  i n  p a t i e n t s  w i t h  s o f t  
t i s s u e  s a r c o m a ,  2  o f  t h e  1 7  p a t i e n t s  t r e a t e d  w i t h  b e v a c i z u m a b  a n d  h i g h - d o s e  
d o x o r u b i c i n  ( 7 5  m g / m 2)  d e v e l o p e d  C H F  ( o n e  G r a d e  3  e v e n t  a f t e r  a  c u m u l a t i v e  
d o x o r u b i c i n  d o s e  o f  5 9 1  m g / m 2,  o n e  G r a d e  4  e v e n t  a f t e r  a  c u m u l a t i v e  
d o x o r u b i c i n  d o s e  o f  4 2 0  m g / m 2) ;  a n  a d d i t i o n a l  4  p a t i e n t s  h a d  a s y m p t o m a t i c  
d e c r e a s e s  i n  L V E F .  O t h e r  s t u d i e s  i n  p a t i e n t s  w i t h  v a r i o u s  t u m o r  t y p e s  a n d  
e i t h e r  a  h i s t o r y  o f  a n t h r a c y c l i n e  e x p o s u r e  o r  c o n c o m i t a n t  u s e  w i t h  b e v a c i z u m a b  
a r e  o n g o i n g .  P a t i e n t s  r e c e i v i n g  c o n c o m i t a n t  a n t h r a c y c l i n e s  o r  w i t h  p r i o r  
e x p o s u r e  t o  a n t h r a c y c l i n e s  s h o u l d  h a v e  a  b a s e l i n e  M U G A  s c a n s  o r  
e c h o c a r d i o g r a m s  ( E c h o ’ s )  w i t h  a  n o r m a l  L V E F .  
 
Ne utr o pe ni a: I n c r e a s e d  r a t e s  o f  s e v e r e  n e u t r o p e n i a ,  f e b r i l e  n e u t r o p e n i a ,  o r  
i n f e c t i o n  w i t h  s e v e r e  n e u t r o p e n i a  ( i n c l u d i n g  s o m e  f a t a l i t i e s )  h a v e  b e e n  


  
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observed in patients treated with some myelotoxic chemotherapy regimens plus 
bevacizumab in comparison to chemotherapy alone. 
 
Additional Adverse Events: See the bevacizumab Investigator Brochure for 
additional details regarding the safety experience with bevacizumab. 
 
7.2 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Serious adverse event (SAE): 
- A Serious Adverse Event (SAE) is any untoward medical occurrence that, at any dose: 
- 
results in death 
- 
is life-threatening (defined as an event in which the participant was at risk of 
death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe) 
- 
requires inpatient hospitalization or causes prolongation of existing 
hospitalization (see NOTE below) 
- 
results in persistent or significant disability/incapacity 
- 
is a congenital anomaly/birth defect 
- 
is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based 
upon appropriate medical and scientific judgment, may jeopardize the subject 
or may require intervention [eg, medical, surgical] to prevent one of the other 
serious outcomes listed in the definition above.) Examples of such events 
include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.)  
- 
Suspected transmission of an infectious agent (eg, pathogenic or 
nonpathogenic) via the study drug is an SAE.  
- Although pregnancy, overdose, potential drug-induced liver injury (DILI) and cancer 
are not always serious by regulatory definition, these events must be handled as SAEs. 




  
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• If an ongoing SAE changes in its intensity or relationship to study drug 
or if new information becomes available, a follow-up SAE report 
should be sent within 24 hours to BMS using the same procedure used 
for transmitting the initial SAE report. All SAEs should be followed to 
resolution or stabilization.  
 
7.3.4 DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office 
for Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
7.4 
Pregnancy 
 
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 5 half-lives after product administration, the investigational 
product will be permanently discontinued in an appropriate manner (e.g,, dose tapering if 
necessary for participant).  
 
The investigator must immediately notify 
 of this event via the 
Pregnancy Surveillance Form in accordance with SAE reporting procedures.  
 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant. 
 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form [provided upon request from BMS]. 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. In 
order for Sponsor or designee to collect any pregnancy surveillance information from the female 
partner, the female partner must sign an informed consent form for disclosure of this 
information.  
 
7.5 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
7.6 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 


  
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safety reports or sentinel events that require reporting according to institutional policy.  
 
7.7 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
Investigators should report to the responsible regulatory authority as appropriate. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the study agents can be found in 
Section 7.1. 
 
8.1 
Nivolumab 
 
8.1.1 Description 
 
Nivolumab (BMS-936558, MDX-1106, ONO-4538) anti-PD-1 monoclonal antibody is a 
soluble protein consisting of 4 polypeptide chains, including 2 identical heavy chains and 
2 identical light chains. Its molecular weight is 146,221 daltons.  
 
8.1.2 Form 
 
Nivolumab is provided as solution for injection, 10 mL per vial (100 mg per vial). It is a 
clear to opalescent, colorless to pale yellow liquid, which may contain light (few) 
particulates. The drug product is a sterile, non-pyrogenic, single-use, isotonic aqueous 
solution formulated at 10 mg/mL in sodium citrate, sodium chloride, mannitol, 
diethylenetriaminepentacetic acid (pentetic acid), and polysorbate 80 (TweenTM 80), pH 
6.0, and includes an overfill to account for vial, needle, and syringe holdup. It is supplied 
in 10-cc Type I flint glass vials, stoppered with butyl rubber stoppers and sealed with 
aluminum seals. 
 
8.1.3 Storage and Stability 
 
Nivolumab vials must be stored at 2°C to 8°C (36°F to 46°F) and protected from light 
and freezing.  
 
The administration of nivolumab infusion must be completed within 24 hours of 
preparation. If not used immediately, the infusion solution may be stored under 
refrigeration conditions (2°C to 8°C, 36°F to 46°F) for up to 24 hours, and a maximum of 


  
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4 hours of the total 24 hours can be at room temperature (20°C to 25°C, 68°F to 77°F) 
and room light. The maximum 4-hour period under room temperature and room light 
conditions includes the product administration period.  
 
8.1.4 Compatibility 
 
Nivolumab can be diluted with 0.9% sodium chloride injection, USP or 5% dextrose 
injection, USP to protein concentrations. No incompatibilities between nivolumab and 
polyvinyl chloride (PVC) and non-PVC/non-DEHP (di(2-ethylhexyl)phthalate) 
containers/IV components or glass bottles have been observed.  
 
8.1.5 Handling 
 
During drug product preparation and handling, vigorous mixing or shaking is to be 
avoided. Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the study agent in a self-contained and protective environment.  
 
8.1.6 Availability 
 
Nivolumab will be provided by Bristol-Myers Squibb. 
 
8.1.7 Preparation 
 
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 
0.35 mg/mL. During drug product preparation and handling, vigorous mixing or shaking 
is to be avoided. Care must be taken to assure sterility of the prepared solution as the 
product does not contain any antimicrobial preservative or bacteriostatic agent.  
 
8.1.8 Administration 
 
See Section 5.2. Nivolumab is to be administered as an IV infusion through a 0.2-micron 
to 1.2-micron pore size, low-protein binding in-line filter at the protocol-specified doses 
and infusion times. It is not to be administered as an IV push or bolus injection.  
 
8.1.9 Ordering 
 
Investigative site(s) will order nivolumab directly through Bristol-Myers Squibb. 
Shipments will be at appropriate intervals, depending on patient accrual. The site(s) must 
use an appropriate accountability form provided by the Sponsor, or an acceptable 
substitute provided by the Sponsor.  
 
8.1.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a 


  
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62 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.1.11 Destruction and Return 
 
If the study agent is to be destroyed on site, it is the investigator’s responsibility to ensure 
that arrangements have been made for disposal, and that procedures for proper disposal 
have been established according to applicable regulations, guidelines, and institutional 
procedures. Appropriate records of the disposal must be maintained. Please consult with 
the Principal Investigator for instructions on the disposal of unused nivolumab. 
 
8.2 
Bevacizumab 
 
8.2.1 Description 
 
Bevacizumab is a recombinant monoclonal antibody targeting vascular endothelial 
growth factor (VEGF). 
 
8.2.2 Form 
 
Pharmaceutical form: solution for dilution for infusion  
Bevacizumab 25 mg per mL 
Trehalose dihydrate  
Sodium phosphate 
Polysorbate 20 
Water for injection 
Clear to slightly opalescent liquid, colourless to pale brown.  
 
8.2.3 Storage and Stability 
 
Chemical and physical stability during use has been demonstrated for 48 hours between 
2°C and 30°C in an injectable solution of sodium chloride at 9 mg/mL (0.9%). From a 
microbiological point of view, immediate use is recommended. If the product is not used 
immediately after reconstitution, the storage period and conditions are the responsibility 
of the user and must not normally exceed 24 hours in the refrigerator between 2°C and 
8°C, unless the dilution has been performed in controlled, aseptic conditions.  
Do not freeze.  
Store the vial in the outer packaging away from light.  
 
8.2.4 Compatibility 
 


  
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No incompatibility between bevacizumab and infusion bags or devices made of polyvinyl 
chloride or polyolefin has been observed. 
 
8.2.5 Handling 
 
Procedures for proper handling and disposal of anticancer drugs should 
be considered. 
Bevacizumab must be prepared by a health professional observing aseptic precautions. 
Take the volume of bevacizumab needed for the preparation of one dose of 15 mg/kg of 
body weight every 3 weeks and dilute it with an injectable solution of sodium chloride at 
9 mg/mL (0.9%) up to a total volume of 100 mL. Dispose of any unused amount 
remaining in the vial, since the product does not contain a preservative. Medicinal 
products intended for parenteral route must be visually examined, looking for particles 
and colour deviations, before their administration. 
No incompatibility between bevacizumab and infusion bags or devices made of polyvinyl 
chloride or polyolefin has been observed. 
When bevacizumab has been mixed with a sterile saline solution bag, the solution must 
be administered within 8 hours. 
Bevacizumab must not be administered or mixed with glycated solutions (see 
investigator’s brochure). 
A mechanism regulating the speed of the infusions will be used for all infusions. When 
the bag is empty, a volume of 50 mL of sodium at 0.9% will be added or another bag will 
be added, and the infusion will be continued for a volume equal to that of the tube in 
order to ensure the complete administration of bevacizumab. Saline solution, which will 
then be injected to empty the tube, will not influence the infusion time of the study 
treatment.  
 
8.2.6 Availability 
 
Bevacizumab will be provided by the local site supplier. This medication is not funded by 
the study, and will be charged to the patient’s insurance. 
 
8.2.7 Administration 
 
See Section 5.2.  
 
8.2.8 Ordering 
 
Investigative site(s) will order pemetrexed directly through the local supplier. Shipments 
will be at appropriate intervals, depending on patient accrual.  
 


  
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8.2.9 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.2.10 Destruction and Return 
 
If the study agent is to be destroyed on site, it is the investigator’s responsibility to ensure 
that arrangements have been made for disposal, and that procedures for proper disposal 
have been established according to applicable regulations, guidelines, and institutional 
procedures. Appropriate records of the disposal must be maintained. Please consult with 
the Principal Investigator for instructions on the disposal of unused bevacizumab. 
 
8.3 
Pemetrexed 
 
8.3.1 Description 
 
Pemetrexed (Alimta) is an antifolate anti-neoplastic agent.  
 
[Chemical name] L-glutamic acid, N-[4-2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-
d]pyrimidin-5-yl)ethyl]benzoyl]-,disodium salt, heptahydrate. 
 
[Molecular formula] C20H19N5O6•2Na•7H2O. 
 
8.3.2 Form 
 
Pemetrexed is supplied as lysophilized powder in glass vials (100 mg in a 10-mL size 
vial, or 500 mg in a 50-mL size vial). The product vials contain pemetrexed and mannitol 
in a 1:1 ratio. Sodium hydroxide and/or hydrochloric acid solution may have been added 
during processing to adjust the pH. The product is a white to either light-yellowish or 
green-yellow lysophilized solid.  
 
8.3.3 Storage and Stability 
 
The drug product is stable when stored at room temperature, not to exceed 30°C, and 
normal lighting conditions. Chemical and physical stability of reconstituted and infusion 
solutions of pemetrexed were demonstrated for up to 24 hours following initial 
reconstitution, when stored refrigerated, 2-8°C. 
 
8.3.4 Compatibility 
 
Pemetrexed can be reconstituted in 0.9% sodium chloride solution, without preservative, 
for injection. No incompatibilities between pemetrexed and polyvinyl chloride (PVC) and 


  
Protocol #17-011  
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65 
polyolefin line administration sets and infusion bags have been observed. Pemetrexed is 
physically incompatible with diluents containing calcium, including Lactated Ringer’s 
injection and Ringer’s Injection. Co-administration of pemetrexed with other drugs and 
diluents has not been studied, and therefore, is not recommended. 
 
8.3.5 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the study agent in a self-contained and protective environment.  
 
8.3.6 Availability 
 
Pemetrexed will be provided by the local site supplier. This medication is not funded by 
the study, and will be charged to the patient’s insurance. 
 
8.3.7 Preparation 
 
Pemetrexed vial must be reconstituted with 0.9% sodium chloride solution for injection, 
without preservative, resulting in a solution containing 10 mg/mL to 50 mg/mL. Gently 
swirl each vial until the powder is completely dissolved. The resulting solution is clear 
and ranges in color from colorless to yellow or green-yellow without adversely affecting 
product quality. The pH of the reconstituted solution is between 6.6 and 7.8. Further 
dilution is required. 
 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration. If particulate matter or dark green color is observed, 
do not administer. 
 
The appropriate volume of reconstituted pemetrexed solution should be further diluted to 
75 to 125 mL with 0.9% sodium chloride solution without preservative for injection.  
 
8.3.8 Administration 
 
See Section 5.2. Pemetrexed is to be administered as an IV infusion over 10 minutes.  
 
8.3.9 Ordering 
 
Investigative site(s) will order pemetrexed directly through the local supplier. Shipments 
will be at appropriate intervals, depending on patient accrual.  
 
8.3.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  


  
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66 
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.3.11 Destruction and Return 
 
If the study agent is to be destroyed on site, it is the investigator’s responsibility to ensure 
that arrangements have been made for disposal, and that procedures for proper disposal 
have been established according to applicable regulations, guidelines, and institutional 
procedures. Appropriate records of the disposal must be maintained. Please consult with 
the Principal Investigator for instructions on the disposal of unused pemetrexed. 
 
8.4 
Carboplatin 
 
8.4.1 Description 
 
Carboplatin (Paraplatin) is a platinum coordination compound. It produces DNA cross-
links to have a cell-cycle non-specific, anti-neoplastic effect.   
 
[Chemical name] platinum, diammine [1,1-cyclobutane-dicarboxylato(2-)-0,0’]-,(SP-4-
2). 
 
[Molecular formula] C6H12N2O4Pt   
 
8.4.2 Form 
 
Carboplatin is supplied as a sterile 10 mg/mL aqueous solution in vials. 
 
8.4.3 Storage and Stability 
 
Unopened vials of carboplatin aqueous solution injection are stable to the date indicated 
on the package when stored at 25°C (77°F); excursions permitted from 15°C to 30 °C. 
Carboplatin must be protected from light. When diluted further, aqueous solutions are 
stable for 8 hours at room temperature (25°C). 
 
8.4.4 Compatibility 
 
Carboplatin can be further diluted with 5% dextrose in water or 0.9% sodium chloride 
injection, USP. 
 
8.4.5 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the study agent in a self-contained and protective environment.  
 


  
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8.4.6 Availability 
 
Carboplatin will be provided by the local site supplier. This medication is not funded by 
the study, and will be charged to the patient’s insurance. 
 
8.4.7 Preparation 
 
Carboplatin vial is a pre-mixed aqueous solution of 10 mg/mL. It can be further diluted to 
concentrations as low as 0.5 mg/mL with 5% dextrose in water or 0.9% sodium chloride 
injection, USP.  
 
8.4.8 Administration 
 
See Section 5.2. Carboplatin is to be administered as an IV infusion over 60 minutes with 
standard anti-emetics per local practice guidelines.  
 
8.4.9 Ordering 
 
Investigative site(s) will order carboplatin directly through the local supplier. Shipments 
will be at appropriate intervals, depending on patient accrual.  
 
8.4.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.4.11 Destruction and Return 
 
If the study agent is to be destroyed on site, it is the investigator’s responsibility to ensure 
that arrangements have been made for disposal, and that procedures for proper disposal 
have been established according to applicable regulations, guidelines, and institutional 
procedures. Appropriate records of the disposal must be maintained. Please consult with 
the Principal Investigator for instructions on the disposal of unused carboplatin. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Tumor Tissue Collection 
 
Archival or fresh FFPE tumor tissue collected within 6 months prior to enrollment must be 
submitted for determination of the PD-L1 status using the analytically validated IHC assay. PD-
L1 stained tissue samples will be assessed by a pathologist at a lab identified by the Principal 
Investigator, and scored as PD-L1 expressing if membrane staining is observed in ≥ 1% tumor 




  
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69 
evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. 
Assessments must be performed prior to administration of any study agent. Study visits and 
agents should be administered within ± 3 days of the protocol-specified date, unless otherwise 
noted. For tumor assessments with scans and survival follow-up, a ±7-day window is allowed. 
Please note that once the participant’s screening labs meet the eligibility criteria, the cycle 1 day 
1 labs do not need to re-meet the eligibility criteria. 


70 
 
Table 10-1: 
Study Calendar  
 
Screening 
Period 
Treatment Period 
Every 21-day cycle1 
Follow-Up Period 
Assessment 
Screening 
Cycle 1 
Day 1 
Cycle 1 
Day 8 
Subsequent Cycles 
Day 1 
EOT 
30 Day 
Follow-Up 
100 Day 
Follow-Up 
Survival  
Follow-Up 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Relevant medical history & 
current medical conditions 
X 
 
 
 
 
 
 
 
Diagnosis/extent of cancer 
X 
 
 
 
 
 
 
 
Prior antineoplastic therapy 
X 
 
 
 
 
 
 
 
Documentation of EGFR or 
ALK status 
X 
 
 
 
 
 
 
 
Smoking history 
X 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
 
Antineoplastic therapies  
 
 
 
 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
 
Hematology/chemistry 
X 
X 
X 
X 
X 
X 
X 
 
TSH 
X 
X2 
 
X 
X 
 
 
 
Urinalysis 
X 
X 
 
X 
X 
 
 
 
Hepatitis B and C testing3 
X 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
X 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
Disease assessments4 
X 
X4 
X 
 
 
 
Tumor Biopsy5 
X 
 
 
 
 
 
 
 
Blood for germline DNA 
 
X 
 
 
 
 
 
 
Adverse events  
X 
X 
X 
X 
X 
X 
X 
 
Survival follow-up6 
 
 
 
 
 
 
 
X6 
Nivolumab (IV) 
 
X 
 
X 
 
 
 
 
Carboplatin and 
Pemetrexed (IV)7 
 
X 
 
X7 
 
 
 
 
Bevacizumab (IV) 8 
 
X 
 
X8 
 
 
 
 
 


  
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1. Each cycle is 21 consecutive days. A ±3-day window period will be authorized throughout the study period. 
 
2. Thyroid function testing is to be done at screening and every 6 weeks (TSH only, unless abnormal in which case reflex free T3 and free T4 
testing is to be performed). Infusion administrations can begin as long as the thyroid function test has been drawn.  The thyroid function test 
needs not have resulted prior to the infusions. 
 
3. Hepatitis B and C testing consist of HBV sAg and HCV Ab or HCV RNA.  
 
4. Disease assessments will include CT/MRI of the chest and abdomen (and pelvis if clinically indicated) every 6 weeks (± 7 days) for the first 6 
months, followed by every 12 weeks until disease progression, lost to follow-up, withdrawal of consent or study termination, whichever 
occurs first. MRI of brain will be performed at the same time intervals in patients with known metastatic disease in the brain per the baseline 
screening MRI brain. In patients without known metastatic intracranial disease on the baseline screening MRI brain, repeat MRI brain will be 
performed every 6 months. For all disease assessments, a ±7-day window is allowed.  
 
5. Tumor tissue sample may be fresh, or archival if obtained within 6 months prior to enrollment. If a tissue sample is available but it has been >6 
months and there has been no intervening therapy, the Principal Investigator may approve the sample after discussion. PD-L1 IHC testing will 
be performed on the tumor tissue, but positivity on the PD-L1 IHC testing is not required to enroll in the study. 
 
6. Survival follow-up may be conducted by phone or visit, every 3 months (± 7 days) until death, lost to follow-up, withdrawal of study consent 
or up to 2 years from the enrollment of the last subject, whichever occurs first. 
 
7. Patients will receive nivolumab with carboplatin and pemetrexed on Day 1 of every cycle for 4 cycles. Starting with cycle 5, patients will 
receive pemetrexed with nivolumab on Day 1 of every cycle. A ±3-day window is allowed for the study treatment. 
 
8. Patients in Cohorts E and F only (NOT cohorts G and H) will receive bevacizumab on Day 1 of every cycle.  A ±3-day window is allowed for 
the study treatment. 
 
 


72 
 
 
10.1 
Study Assessments 
 
• Informed consent: Informed consent, documented by a signed consent form, must be 
obtained prior to any screening activities not otherwise part of the participant’s care. A 
note documenting the informed consent procedure should be included in the participant’s 
medical record. 
 
• Demographics: Demographic information consists of the participant’s age, gender, race, 
and ethnicity (as allowed by local law and regulations). 
 
• Relevant medical history and current medical conditions: Medical and surgical 
history includes diagnoses, therapies, and medical/surgical treatments. 
 
• Diagnosis and extent of cancer: The initial cancer diagnosis and the current cancer 
diagnosis at the time of screening (if different), along with dates of diagnosis need to be 
recorded. 
 
• Prior antineoplastic therapy: Prior cancer therapy history consists of the specific 
oncologic regimens a patient has received, the dates of the regimen and the best response 
to the regimen, and the reason for failure or intolerance to each regimen. Stem cell 
transplant or experimental or investigational therapy history must also be recorded.  
 
o Documentation of an EGFR mutation or ALK rearrangement: Documentation of an 
EGFR activating gene mutation (e.g., L858R, exon 19 deletion) is required per local 
testing. ALK status is to be determined using ALK FISH, IHC, or next generation 
sequencing (NGS). For ALK FISH, positivity will be defined as > 15% positive tumor 
cells. Local ALK testing is acceptable, provided that archival tissue is available for 
patients deemed ALK positive on the basis of NGS. 
 
• Concomitant medications: Concomitant medications for all ongoing medical conditions 
or AEs must be reported from the date the informed consent is signed until at least 30 
days after the end of treatment, and for all concomitant medications related to serious or 
study drug-related toxicities until the medication is no longer taken or until the patient 
contact discontinues.  
 
• Vital signs: Vital signs include temperature, pulse, respiratory rate, and blood pressure 
(when patient is seated). In addition, screening assessment includes height and weight. 
 
• ECOG performance status: The participant’s performance status must be assessed 
using the ECOG performance scale (Appendix A).  
 
• Physical exam: A physical examination will be performed, the extent of which should be 
consistent with the medical history and the participant’s underlying disease.  
 


  
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• Hematology: Hematology assessments of the parameters listed in Table 10.1-1 will be 
tested as per the schedule of assessments (Table 10-1).  
 
Table 10.1-1: 
Local Clinical Laboratory Parameters Collection Plan 
 
Test Category 
Test Name 
Hematology 
Hemoglobin (Hgb), platelets, white blood cells (WBC), red blood cells 
(RBC), differential (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils (% or absolute)) 
Chemistry 
Albumin, ALT, AST, calcium, creatinine, total bilirubin, direct bilirubin 
(only if total bilirubin is ≥ grade 2), blood urea nitrogen (BUN) or urea, 
magnesium, potassium, sodium, glucose, phosphate (inorganic 
phosphorus), alkaline phosphatase, lipase, and LDH 
Thyroid function 
test 
TSH 
Free T4 and free T3 by reflex if TSH is abnormal 
Urinalysis 
Macroscopic panel (color, total bilirubin, blood, glucose, ketones, 
leukocyte esterase, nitrite, pH, protein, specific gravity, urobilinogen) 
Microscopic panel (RBC, WBC, casts, crystals, bacteria, epithelial cells) 
Pregnancy test 
Serum pregnancy test 
 
• Chemistry: Clinical chemistry assessments of the parameters listed in Table 10.1-1 will 
be tested as per the schedule of assessments (Table 10-1). 
 
• Thyroid function testing: Thyroid function assessment listed in Table 10.1-1 will be 
tested as per the schedule of assessments (Table 10-1). 
 
• Urinalysis: Urine measurements will be performed as per Table 10.1-1 and according to 
the schedule of assessments (Table 10-1).  
 
• Electrocardiogram: 12-lead ECGs will be performed at baseline during the screening 
visit, and again at the end of treatment. Additional ECGs may be performed as clinically 
indicated throughout the study. 
 
• Pregnancy test: A serum pregnancy test will be completed at baseline during the 
screening. 
 
• Disease assessments: Tumor assessments will take place in accordance with the schedule 
outlined in Table 10-1. A ±7-day window is permitted. At screening, disease assessment 
must include imaging of the chest and abdomen. Imaging of the pelvis should also be 
performed if clinically indicated. Contrast-enhanced CT with PO/IV contrast or contrast-
enhanced MRI are the preferred imaging modalities for assessing radiographic tumor 
response. If a subject has a known allergy to contrast material, local prophylaxis standard 
should be used to obtain the assessment with contrast if at all possible. In cases where 
contrast is strictly contraindicated, a non-contrast scan will suffice. Should a subject have 
a contraindication for CT IV contrast, a non-contrast CT of the chest and a contrast-


  
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enhanced MRI of the abdomen may be obtained. Every attempt should be made to image 
each subject using an identical acquisition protocol on the same scanner for all imaging 
time points.  
 
MRI of the brain is required at screening in order to rule out active metastatic disease. If 
disease is identified, then MRI of the brain should be repeated as outlined in Table 10-1. 
If no brain disease is identified on screening MRI brain, participants will undergo repeat 
MRI brain every 6 months as surveillance.  
 
Target and non-target lesions must be selected at study start and followed throughout the 
course of treatment for response assessment according to RECIST version 1.1 guidelines 
(See Section 11). Imaging assessment is also required to be performed at the End of 
Treatment. 
 
• Tumor biopsy: Tumor tissue sample is within 6 months prior to enrollment. Tissue 
sample may be fresh, or archival if obtained within 6 months prior to enrollment.  
 
• Adverse events: Participants must be followed for all adverse events (AEs) from the start 
of study treatment until the safety follow-up phase (day 30 and day 100 since end of 
treatment), and for all serious or study drug-related toxicities until the AEs are resolved 
and are considered chronic or stable or until patient contact discontinues. Serious adverse 
events (SAEs) should be monitored and reported. Type, incidence, severity (graded in 
accordance with the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) version 4.0), timing, seriousness and relatedness, 
outcome, action taken with the study drug, and treatment will be assessed and 
documented by the investigator throughout the study. Malignancy-related signs and 
symptoms noted at study entry will be recorded as AEs during the trial if they worsen in 
severity or increase in frequency.  
 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, participants should be re-evaluated for response every 6 weeks for 
the first 6 months, and then every 12 weeks thereafter. Response and progression will be 
evaluated in this study using the new international criteria proposed by the Response Evaluation 
Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
 
11.1.1 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 


  
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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.) 
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥10 mm with CT 
scan or MRI (excluding lymph nodes – see below).  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area are not eligible for 
measurable disease unless there is objective evidence of progression of the lesion prior to 
study enrollment. Lesions in previously irradiated areas must be clearly identified as 
such.  
 
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. 
 
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 


  
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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.  
 
11.1.3 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.  
 
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).   
 
11.1.4 Response Criteria 
 
11.1.4.1 
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 


  
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increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 
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. 
 
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). 
 
11.1.4.3 
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. 
 
11.1.4.4 
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) 


  
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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** 
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. 
 
11.1.5 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). 
 
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 


  
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11.1.6 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 
the day treatment starts to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation. 
 
Time to Progression: Time to Progression (TTP) is defined as the time from the day 
treatment starts to progression, or censored at date of last disease evaluation for those 
without progression reported. 
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on 
the data for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the Office of Data Quality in accordance with DF/HCC SOPs. 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Board (DSMB) will review and monitor study 
progress, toxicity, safety and other data from this study. The board is chaired by a medical 
oncologist from outside of DF/HCC and has external and internal representation. Information 
that raises any questions about participant safety or protocol performance will be addressed by 
the Overall PI, statistician and study team. Should any major concerns arise, the DSMB will 
offer recommendations regarding whether or not to suspend the study. 
 
The DSMB will meet twice a year to review accrual, toxicity, response and reporting 
information. Information to be provided to the DSMB may include: participant accrual; 
treatment regimen information; adverse events and serious adverse events reported by category; 
summary of any deaths on study; audit results; and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request.  


  
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13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This is a phase II trial evaluating the efficacy and safety of nivolumab administered in 
combination with platinum-doublet chemotherapy, with or without bevacizumab, in TKI-pre-
treated, chemotherapy-naïve, EGFR-mutant or ALK-positive patients. The patients must have 
advanced EGFR-mutant NSCLC which progressed on a third-generation EGFR TKI, or 
advanced ALK-rearranged NSCLC which progressed on at least one next-generation ALK TKI. 
 
• Eligible patients who are chemotherapy-naïve and bevacizumab–eligible will receive 
nivolumab plus carboplatin and pemetrexed plus bevacizumab for 4 cycles, followed by 
nivolumab plus bevacizumab plus pemetrexed maintenance therapy at the pre-specified 
doses (Cohorts E and F).  
 
• Eligible patients who are chemotherapy-naïve and bevacizumab–ineligible will receive 
nivolumab plus carboplatin and pemetrexed for 4 cycles, followed by nivolumab plus 
pemetrexed maintenance therapy at the pre-specified doses (Cohorts G and H).  
 
Our primary objective will be to evaluate the efficacy of these combinations using an objective 
response rate (ORR). ORR will be determined using efficacy assessments (CT chest/abdomen) 
performed every 6 weeks for the first 6 months, after which assessments will be performed every 
12 weeks until disease progression, unacceptable toxicity, patient withdrawal, death or 
discontinuation from the study for any other reason, or study termination, whichever comes first. 
ORR is defined as the number of subjects with the best overall response (BOR) of complete 
response (CR) or partial response (PR) divided by the number of treated subjects in each cohort. 
The BOR is assessed per RECIST 1.1. For subjects who continue study medication beyond 
progression, the BOR should be determined based on response designations recorded at the time 
of the initial RECIST 1.1-defined progression.  
 
Secondary endpoints that will be investigated include the disease control rate (DCR), duration of 
response (DOR), duration on treatment, progression-free survival (PFS) (including PFS rates at 6 
months and at 12 months), and overall survival (OS) (including OS rates at 1 year and at 2 
years). Safety and tolerability of the combination regimen will also be assessed. Exploratory 
analysis will include evaluation of the efficacy endpoints in subjects with PD-L1-expressing or 
non-expressing tumors. Baseline tumor tissue and peripheral blood samples will be evaluated for 
biomarkers of response or resistance to the combination therapy (e.g., PD-L1, PD-L2, CD4, 
CD8, FOXP3, cytokines, T-cell subsets, genetic sequencing).   
 
13.2 
Sample Size, Accrual Rate and Study Duration 
 
This study will be comprised of four cohorts as specified above. Each cohort will be considered 
as independent for efficacy and will be analyzed independently. The study will be conducted 
using a two-stage design.   


  
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For each cohort, in the first stage, 9 patients will be enrolled in each cohort. Enrollment to the 
second stage will proceed in each cohort only if at least 3 of the evaluable patients were to have 
CR or PR. Should the study proceed to the second stage, 16 more patients will be enrolled for a 
total of 25 in each cohort. If 12 (or more) of 25 evaluable patients were to have a confirmed CR 
or PR, the combination of nivolumab plus carboplatin and pemetrexed would be considered to 
have a promising anti-tumor activity. This design is associated with 80% power if 55% of the 
patients truly were to have a response to nivolumab plus carboplatin and pemetrexed. The overall 
type 1 error rate is 4.2% if the underlying rate of responses were 30% or less. The probability of 
early termination is 0.463. The null hypothesis is based on the data from prior studies suggesting 
that platinum-based doublet chemotherapy following progression on a prior TKI in oncogene-
driven NSCLC generally leads to responses in 20-30% of patients (2, 15, 16).  
 
Accrual Rate and Study Duration: 
EGFR mutations and ALK rearrangements are identified in approximately 10-15% and 3-7% of 
patients with NSCLC, respectively. At MGH alone, approximately 500 patients with NSCLC 
undergo genotyping annually. Additionally, DF/HCC is a referral center for patients with EGFR-
mutant and ALK-positive NSCLC. Therefore, across the participating institutions, we expect to 
enroll 3-4 subjects per month. Therefore, we expect to complete enrollment in approximately 25-
33 months.  
 
All subjects will be followed for survival every 3 months (± 7 days) for up to 2 years after the 
last participant is enrolled.  
 
13.3 
Interim Monitoring Plan   
 
Please refer to Section 13.2 for the two-stage study design with an early termination rule based 
on efficacy.  
 
13.4 
Analysis of Primary Endpoints 
 
See Section 13.1. Analysis of the primary endpoint will follow the trial design. Response rates 
will be calculated at each stage, and the decision to continue will be based on the criteria 
specified in Section 13.1. In addition, 95% exact binomial CI will be reported. Response rates 
will be reported by cohort and for the pooled groups of E+F and G+H to obtain a tighter CI for 
the ORR estimate. 
 
13.5 
Analysis of Secondary Endpoints 
 
Secondary endpoints will be analyzed for exploratory purposes only. These analyses are 
applicable to the entire cohort as well as PD-L1 expressing (staining positive for PD-L1 in ≥1% 
of tumor cells) and PD-L1 non-expressing subset cohorts.  
 
Disease control rate (DCR) – DCR is defined as the percentage of subjects who have either a 
complete response (CR), partial response (PR), or stable disease (SD) as assessed by RECIST 
v1.1.  


  
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Duration of response (DOR) – DOR is measured from the first time measurement criteria are 
met for CR or PR (whichever is recorded first), based on RECIST 1.1 guidelines, until the first 
date that progressive disease (PD) is objectively documented. The duration of CR is measured 
from the time measurement criteria are first met for CR until the first date that PD is objectively 
documented. Subjects who are non-responders (i.e., do not achieve at least a PR) will be 
excluded from the analysis of the endpoint of interest for DOR. Subjects who have achieved at 
least a PR and do not have disease progression as of the data cutoff date for statistical analysis 
will be censored at the date of the last radiographic assessment prior to the data cutoff date.  
 
Duration on therapy (DOT) – DOT is measured from the date of initiation on study therapy 
until study drug discontinuation, death, or withdrawal of consent, whichever occurs first.  
 
Progression-free survival (PFS) – PFS is defined as the time from the start date of the study 
drug treatment to the date of first documented progression or death due to any cause. Subjects 
who do not have disease progression and are alive as of the data cutoff date for the statistical 
analysis will be censored at the date of the last radiographic assessment prior to the data cutoff 
date. PFS will be summarized in each treatment cohort using the Kaplan-Meier method with 
median PFS time (including two-sided 95% CI). The PFS rates at 6 months and at 12 months 
will be estimated with two-sided 95% CIs.  
 
Overall survival (OS) – OS is defined as the time from the start date of the study drug treatment 
to death due to any cause. All subjects who are lost to follow-up prior to the end of the study or 
who have withdrawn from the study will be censored at the time of last contact. Subjects who are 
still receiving treatment as of the data cutoff date will be censored at the cutoff date. OS will be 
summarized for each treatment cohort using the Kaplan-Meier method with median OS time 
(including two-sided 95% CI). The OS rates at 1 year and at 2 years will be estimated with two-
sided 95% CIs.  
 
Safety – All participants who receive any study drug will be evaluable for toxicity. Toxicities 
(including laboratory parameter abnormalities) will be assessed using CTCAE v4.0. Summary 
tables of adverse events and serious adverse events will be created. The number and percentage 
of participants who experience any AE, SAE, treatment-related AE, and treatment-related SAE 
will be summarized according to worst toxicity grades. The incidence and reasons for dose 
reductions, interruptions, and discontinuations will be recorded.  
 
Frequency, management, and resolution of select (immunologic) AEs will be analyzed (e.g., 
pneumonitis IMAEs, diarrhea/colitis IMAEs, hepatitis IMAEs, nephritis and renal dysfunction 
IMAEs, rash IMAEs, endocrine IMAEs). A tabular summary of overall immunologic AEs and 
serious immunologic AEs will be provided. Time-to-onset, severity, duration of IMAEs, action 
taken with the study drug, dosing delays, corticosteroid details and re-challenge information will 
be described. 
 
Exploratory biomarker analyses – Exploratory analyses will be performed to correlate any 
findings from the various potential biomarker studies listed in Section 9 with the study endpoints 
above.  
 
The goal of the biomarker/correlative studies is to establish the relationship between PD-L1 


  
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83 
expression level (and potentially other biomarkers, such as the presence of tumor infiltrating 
lymphocytes or tumor mutational burden) and response to the study drugs. The rationale for 
these studies is outlined in Section 2.6. In the recent large randomized trials of checkpoint 
inhibitors including KEYNOTE-024 (103), patients with EGFR-mutant or ALK-rearranged 
metastatic NSCLC were excluded. Thus, it will be important to investigate the potential 
biomarkers of response to immunotherapies among the EGFR-mutant or ALK-rearranged 
NSCLC patients in a systematic manner.  
 
PD-L1 expression level will be estimated and binned into a binary variable of positive 
(expressed in ≥ 1% of tumor cells) or negative (expressed in <1% of tumor cells). A Fisher’s 
Exact Test will be used to test the relationship between response and PD-L1 status, and p-values 
will be calculated to test for statistical significance. All analyses will be done by cohort and also 
by treatment groups (cohorts E+F and cohorts G+H). A sample of 25 subjects will have a 95% 
one-sided lower limit of 74.3% for a desired sensitivity rate of 90%; for a sample of 50 subjects, 
the lower limit is 80%. 
 
 
14. PUBLICATION PLAN 
 
It is anticipated that the results of this study will first be reported in abstract form, followed by 
presentation in a peer-reviewed manuscript.  
 


  
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
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). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 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. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 


  
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APPENDIX B 
MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY AGENTS 
 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immune-oncology agents and regimens. 
 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non inflammatory etiologies should be considered and appropriately 
treated.  
 
Corticosteroids are a primary therapy for immune-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
 
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immune-oncology agent or regimen being used.  


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