Clinical trial NCT03158129
Conditions: Stage I Lung Non-Small Cell Cancer AJCC v7 Stage IA Lung Non-Small Cell Carcinoma AJCC v7 Stage IB Lung Non-Small Cell Carcinoma AJCC v7 Stage II Lung Non-Small Cell Cancer AJCC v7 Stage IIA Lung Non-Small Cell Carcinoma AJCC v7 Stage IIB Lung Non-Small Cell Carcinoma AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7
Sponsor: M.D. Anderson Cancer Center
Start date: 2017-06-16; Completion date: 2024-11-13
Enrollment: 101 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies how well nivolumab works when given alone and in combination with ipilimumab or chemotherapy in treating patients with previously untreated stage I-IIIA non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cisplatin, docetaxel, and pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab with ipilimumab or chemotherapy may work better in treating patients with non-small cell lung cancer compared to chemotherapy alone.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine the major pathologic response rate (MPRR) in patients treated with induction nivolumab, nivolumab plus ipilimumab, and nivolumab plus platinum-based chemotherapy.

SECONDARY OBJECTIVES:

I. Toxicity (assessed by the National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version 4).

II. Peri-operative morbidity and mortality. III. CD8 positive (+) tumor infiltrating lymphocytes (TILs) in resected tumor tissues of patients treated with nivolumab alone and nivolumab plus ipilimumab and nivolumab plus platinum-based chemotherapy.

IV. Quantification of CD8+ TILs will be assessed by counting the cells positive for staining with an anti-CD8 antibody by immunohistochemistry in five random square areas (1 mm\^2 each) in both intratumoral and peritumoral compartments using the automated Aperio system.

V. Response rates to induction treatment (by Response Evaluation Criteria in Solid Tumors \[RECIST\] version 1.1).

VI. Recurrence-free survival. VII. Overall survival. VIII. To correlate major pathologic response with recurrence-free and overall survival.

IX. Complete resection (R0) rate. X. Pathologic complete response (pCR) in resected tumor specimens. XI. To correlate response assessed by imaging studies with outcomes (both major pathologic response to treatment and long-term recurrence-free survival).

XII. To correlate blood, tissue, and stool-based biomarkers with efficacy and toxicity.

EXPLORATORY OBJECTIVES:

I. To identify novel prognostic and predictive markers present at diagnosis. II. To determine modulation of markers by induction immunotherapy and/or immunotherapy plus platinum-based chemotherapy in order to inform future translational studies.

OUTLINE: Patients are randomized to Arms A and B and enrolled in Arm C or D after completion of enrollment to Arms A and B.

ARM A: Patients receive nivolumab intravenously (IV) over 60 minutes on days 1, 15, and 29 in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive nivolumab as in Arm A and receive ipilimumab IV over 90 minutes on day 1 in the absence of disease progression or unacceptable toxicity.

ARM C: Patients receive nivolumab IV over 30 minutes and cisplatin IV over 2 hours on days 1, 22, and 43 in the absence of disease progression or unacceptable toxicity. Patients also receive docetaxel IV over 1 hour or pemetrexed IV over 10 minutes on days 1, 22, and 43 in the absence of disease progression or unacceptable toxicity.

ARM D: Patients receive ipilimumab IV over 90 minutes on day 1, nivolumab IV over 30 minutes on days 1, 22, and 43, and cisplatin (or carboplatin) IV over 2 hours on days 1, 22, and 43 in the absence of disease progression or unacceptable toxicity. Patients also receive docetaxel IV over 1 hour or pemetrexed IV over 10 minutes on days 1, 22, and 43 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment and surgery, patients are followed up at 8 weeks.

Arms: arm 1: Participants receive nivolumab IV over 60 minutes on days 1, 15, and 29 in the absence of disease progression or unacceptable toxicity. arm 2: Participants receive nivolumab as in Arm A and receive ipilimumab IV over 90 minutes on day 1 in the absence of disease progression or unacceptable toxicity. arm 3: Patients receive nivolumab IV over 30 minutes and cisplatin IV over 2 hours on days 1, 22, and 43 in the absence of disease progression or unacceptable toxicity. Patients also receive docetaxel IV over 1 hour or pemetrexed IV over 10 minutes on days 1, 22, and 43 in the absence of disease progression or unacceptable toxicity. arm 4: Patients receive ipilimumab IV over 90 minutes on day 1, nivolumab IV over 30 minutes on days 1, 22, and 43, and cisplatin (or carboplatin) IV over 2 hours on days 1, 22, and 43 in the absence of disease progression or unacceptable toxicity. Patients also receive docetaxel IV over 1 hour or pemetrexed IV over 10 minutes on days 1, 22, and 43 in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Carboplatin intervention 2: Cisplatin intervention 3: Docetaxel intervention 4: Ipilimumab intervention 5: Nivolumab intervention 6: Pemetrexed
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Given IV intervention 6: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
11 January 2022 
Protocol: 2016-0982 
 
 
 
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MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2016-0982 
Protocol Title 
PHASE II STUDY OF INDUCTION CHECKPOINT BLOCKADE FOR UNTREATED 
STAGE I-IIIA NON-SMALL CELL LUNG CANCERS AMENABLE FOR SURGICAL 
RESECTION 
 
Phase 
Phase II 
Protocol Version 
14 
Version Date 
01/11/2022 
 
Protocol PI 
Tina Cascone, MD 
Department 
Thoracic, Head and Neck Medical Oncology 
Investigational 
Products 
Nivolumab and Ipilimumab  
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
134,837 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol: 2016-0982 
 
 
 
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PHASE II STUDY OF INDUCTION CHECKPOINT BLOCKADE FOR UNTREATED 
STAGE I-IIIA NON-SMALL CELL LUNG CANCERS AMENABLE FOR SURGICAL 
RESECTION 
 
 
BMS Protocol #: CA209-926 
Principal Investigator and study center: 
Tina Cascone, MD, PhD 
Department of Thoracic/Head and Neck Medical Oncology 
1515 Holcombe Blvd. Unit 432 
Houston, TX 77030 
 
Protocol History 
Version 0-03JAN2017 
Version 1-24JAN2017 
Version 3-21APR2017 
Version 4-15MAY2017 
Version 5 -05JUL2017 
Version 6-18JAN2018 
Version 7-20JUN2018 
 
Version 8-17JAN2019 
Version 9-7JUN2019 
Version 10-04SEP2019 
Version 11-02DEC2019 
Version 12-02MAR2020 
Version 13 - 11DEC2020 
Verison 14 – 11JAN2022 
 
 


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Table of Contents 
 
 
1 
BACKGROUND ...................................................................................................... 7 
2 
STUDY OBJECTIVES ........................................................................................... 14 
2.1 
Hypotheses ............................................................................................................ 14 
2.2 
Study Endpoints ...................................................................................................... 14 
2.2.1 Primary endpoint ............................................................................................................. 14 
2.2.2 Secondary endpoints ......................................................................................................... 15 
2.2.3 Exploratory endpoints ....................................................................................................... 16 
2.2.4 Additional assessments ....................................................................................................... 17 
3 
ETHICAL CONSIDERATIONS ............................................................................... 18 
4 
ELIGIBILITY CRITERIA ....................................................................................... 18 
4.1 
Inclusion Criteria .................................................................................................... 18 
4.2 
Exclusion Criteria ................................................................................................... 21 
5 
STUDY DESIGN AND PLAN ................................................................................. 23 
6 
TREATMENT ....................................................................................................... 25 
6.1 
Induction Treatment ................................................................................................ 25 
6.2 
Surgery ................................................................................................................. 26 
6.3 
Post-operative (Adjuvant) Systemic Therapy............................................................... 26 
6.4 
Post-operative (Adjuvant) Radiation Therapy ............................................................. 27 
7 
PRODUCT INFORMATION .................................................................................. 28 
7.1 
Drug Ordering and Accountability ............................................................................ 28 
7.1.1 Nivolumab and Ipilimumab (Immune-Oncology [I-O] Agents) .............................................. 28 
7.1.2 Other agent(s) .................................................................................................................. 28 
7.2 
Product Description and Dosage Form ...................................................................... 29 


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7.2.1 Nivolumab and ipilimumab (I-O Agents) ............................................................................. 29 
7.2.2 Other agent(s) .................................................................................................................. 30 
7.3 
Handling and Dispensing ......................................................................................... 30 
7.3.1 Nivolumab and Ipilimumab (I-O Agents) ............................................................................ 30 
7.3.2 Other agent(s) .................................................................................................................. 31 
7.4 
Destruction ............................................................................................................ 31 
7.5 
Dose Administration ................................................................................................ 32 
7.5.1 Nivolumab and ipilimumab (I-O Agents) ............................................................................. 32 
7.5.2 Other agent(s) .................................................................................................................. 33 
7.5.3 General Concomitant Medication and Supportive Care Guidelines ....................................... 34 
8 
DOSE MODIFICATIONS AND TOXICITY MANAGEMENT ................................... 36 
8.1 
Management Algorithms for Immuno-oncology (I-O) Agents ........................................ 36 
8.1.1 Dose delay criteria for I-O agents ....................................................................................... 37 
8.1.2 Criteria to resume treatment with I-O agents ........................................................................ 38 
8.1.3 Treatment of nivolumab or ipilimumab-related infusion reactions ............................................ 39 
8.2 Management Algorithms for Platinum-based Chemotherapy ..................................................... 39 
8.2.1 Dose Modifications and Discontinuation Criteria of Platinum-based Chemotherapy .............. 40 
8.2.2 Re-treatment Criteria for Platinum-based Chemotherapy ..................................................... 47 
8.2.3 Dose Delay Criteria for Platinum-based Chemotherapy ....................................................... 48 
8.2.4 Discontinuation criteria for I-O agents ................................................................................ 48 
9 STUDY ASSESSMENTS AND PROCEDURES ........................................................................ 52 
9.1 Description of Study Assessments ........................................................................................... 58 
9.1.1 Performance status ........................................................................................................... 58 
9.1.2 Clinical laboratory tests .................................................................................................... 59 
9.1.3 Symptoms and toxicity assessment ..................................................................................... 59 
9.1.4 Radiology assessments ...................................................................................................... 59 


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9.1.5 Mediastinal staging .......................................................................................................... 59 
9.1.6 Tumor tissue samples ........................................................................................................ 60 
9.1.7 Blood-based biomarkers .................................................................................................... 62 
9.1.8 Stool-based biomarkers ..................................................................................................... 62 
9.1.9 CT imaging-based biomarkers ........................................................................................... 63 
9.1.10 Long-term follow-up ........................................................................................................ 63 
9.1.11 Assessments for premature discontinuation from study ......................................................... 63 
10 TISSUE AND BLOOD SAMPLE REPOSITORY ..................................................................... 63 
11 ADVERSE EVENT COLLECTION AND REPORTING ........................................................... 65 
11.1 Definitions ........................................................................................................................ 65 
11.1.1 Adverse events ................................................................................................................. 65 
11.1.2 Serious adverse events .................................................................................................... 67 
11.2 Serious Adverse Event and Pregnancy Reporting ................................................................... 69 
11.2.1 Serious Adverse Event Reporting ...................................................................................... 69 
11.2.2 Pregnancy and Reporting ................................................................................................ 71 
11.2.3 Potential Drug Induced Liver Injury ................................................................................. 72 
11.2.4 Nonserious adverse events ............................................................................................... 72 
11.3 Laboratory test abnormalities ............................................................................................... 73 
11.4 Overdose ........................................................................................................................... 74 
11.5 Other Safety Considerations ................................................................................................ 74 
12 
RECORDING AND COLLECTION OF DATA ......................................................... 75 
12.1 Case Report Forms ............................................................................................................. 75 
13  
SAMPLE AND DATA SHARING .................................................................................. 75 
14 STATISTICAL CONSIDERATIONS ..................................................................................... 76 
15 STUDY MONITORING AND EARLY STOPPING RULES ................................................... 79 
16 APPENDICES ...................................................................................................................... 81 


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Appendix 1 Sample of Drug Ordering and Pharmacy Reference Material ........................................ 81 
Appendix 2 Management Algorithms ........................................................................................... 86 
17 REFERENCES .................................................................................................................... 93 
 
 
 


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1 BACKGROUND 
 
 
Surgical resection remains the preferred treatment approach for patients with stage I, II, and 
selected stage III non-small cell lung cancers. Nonetheless, a substantial number of patients 
will recur after surgical resection alone. As such, the use of peri-operative cytotoxic therapy 
has been developed to improve outcomes in this setting. 
 
 
Adjuvant chemotherapy. Cisplatin-based adjuvant chemotherapy has become the standard of 
care treatment following surgical resection of patients with lymph node positive non-small cell 
lung cancer, based on data from three randomized controlled studies (1-3). A meta- analysis 
including 4584 patients and 5 trials demonstrated a hazard ratio (HR) for death of 
0.89 in favor of adjuvant chemotherapy compared to surgery alone (95% confidence interval 
[CI] 0.82-0.96, p=0.005), which translates to an absolute improvement in 5-year overall 
survival of 5.4% (4). 
 
 
Neoadjuvant (induction) systemic therapy. Early randomized, single-institution, small scale 
studies evaluating the role of induction chemotherapy in patients with stage III NSCLC 
provided evidence for potential benefits from systemic therapy prior to surgical resection. 
Despite the small sample size, Roth et al., and Rosell et al. found statistically significant 
improvements in overall survival for patients assigned to receive induction treatment, 
compared to the control arm of surgery alone (5, 6). Following this experience, several multi- 
institutional, randomized, phase III studies were launched to evaluate the effects of induction 
chemotherapy in patients with stage I-III NSCLC (7-11). Collectively, these studies 
demonstrated that (1) induction treatment had activity in NSCLC and elicited objective 
responses in at least 40% of the patients; (2) there was no significant increase in peri- operative 
mortality; (3) induction chemotherapy did not seem to negatively impact disease resectability. 
Furthermore, a meta-analysis including seven induction randomized trials (988 patients), 
demonstrated a HR for death of 0.82 (95% CI 0.69-0.97, p=0.002) in favor of induction 
treatment, translating into an absolute improvement of overall survival at 5 years of 6% (12). 
Since these figures are very similar to the benefits seen in the adjuvant chemotherapy meta-
analysis, one could argue that chemotherapy, either before or after surgery, are reasonable 
treatment options in patients that are candidate for peri-operative systemic therapy.  
 
Potential advantages of neoadjuvant compared to adjuvant treatment include: (1) the ability to 
deliver treatment with higher dose intensity, due to better tolerability (10); (2) the ability to 
demonstrate sensitivity to treatment in vivo (since one can follow response to therapy by 
imaging studies, and assess pathologic response in the resected specimen) – the in vivo 


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assessment of treatment efficacy provides important prognostic information, since patients with 
a partial or complete radiographic response to treatment (13), and patients with lymph node 
pathologic downstaging after therapy have been shown to have improved survival (14-16); (3) 
the ability to study biomarker modulation in response to therapy, and correlate them with 
short- term (i.e., response rates), and long-term (i.e., disease-free or overall survival) efficacy 
outcomes, thus streamlining translational research. 
Induction systemic therapy may be particularly important in the setting of immune checkpoint 
inhibitor use. One might postulate that, in contrast to the adjuvant setting (in which only 
micro-metastatic disease is present), the higher tumor burden present at the time of induction 
treatment may be necessary for abundant antigen release and presentation to the immune 
system, and consequently, development of a robust immune response. The possible 
superiority of induction immune therapy, as compared to adjuvant immune therapy, is 
currently being investigated in pre-clinical models at MD Anderson (Cascone et al, 
manuscript in preparation). 
 
Nivolumab. Nivolumab (also referred to as BMS-936558 or MDX1106) is a human 
monoclonal antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the 
programmed death-1 (PD-1) cluster of differentiation 279 (CD279) cell surface membrane 
receptor. PD-1 is a negative regulatory molecule expressed by activated T and B lymphocytes. 
Binding of PD-1 to its ligands, programmed death–ligands 1 (PD-L1) and 2 (PD- L2), results 
in the down-regulation of lymphocyte activation. Inhibition of the interaction between PD-1 
and its ligands promotes immune responses and antigen-specific T-cell responses to both 
foreign antigens as well as self-antigens. Please refer to the Investigator’s brochure for further 
information on nivolumab. 
 
 
Ipilimumab. Ipilimumab is a fully human monoclonal IgG1κ that binds to the CTLA-4 antigen 
expressed on a subset of T cells from human and nonhuman primates. CTLA-4 is a negative 
regulator of T-cell activity. Ipilimumab is a monoclonal antibody that binds to CTLA-4 and 
blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been 
shown to augment T-cell activation and proliferation, including the activation and proliferation 
of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce Treg 
function, which may contribute to a general increase in T-cell responsiveness, including the 
anti-tumor response. Please refer to the Investigator’s brochure for further information on 
ipilimumab. 
 
 
Nivolumab for NSCLC. The results of two phase III trials led to the FDA approval of 
nivolumab for patients with advanced squamous and non-squamous NSCLC who had disease 
recurrence after one prior platinum-based chemotherapy regimen. The CheckMate 017 was a 


11 January 2022 
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randomized, open-label, multinational, phase III trial comparing the efficacy and safety of 
nivolumab 3 mg/kg every 2 weeks versus docetaxel 75 mg/m2 every 3 weeks in patients with 
advanced, squamous NSCLC. The median OS was 9.2 months with nivolumab and 6.0 
months with docetaxel, with 1-year OS rates of 42 and 24 %, respectively, and 18-month OS 
rates of 28 and 13% respectively. The HRs for OS favored nivolumab versus docetaxel across 
various pre-specified subgroups, apart from the ‘rest-of-world’ geographic region and patients 
aged ≥75 years. The confirmed ORR was significantly higher in nivolumab than in docetaxel 
recipients. A CR was seen in 1 % of nivolumab recipients and 0 % of docetaxel recipients and 
a PR occurred in 19 and 9 % of patients in the corresponding treatment groups. The median 
PFS was 3.5 months with nivolumab and 2.8 months with docetaxel (17). The CheckMate 057 
was a randomized, open-label, international phase 3 study, in which patients with non-
squamous NSCLC that had progressed during or after platinum-based doublet chemotherapy 
were randomized to receive nivolumab at a dose of 3 mg/kg every 2 weeks or docetaxel (75 
mg/m2) every 3 weeks. In this trial, the median OS was 12.2 months among  292 patients in 
the nivolumab group and 9.4 months among 290 patients in the docetaxel group (hazard ratio 
for death, 0.73; P=0.002). At 1 year, the overall survival rate was 51% with nivolumab versus 
39% with docetaxel. The RR was 19% with nivolumab versus 12% with docetaxel (18). The 
preliminary results of a small scale phase 2 study evaluating the safety and feasibility of 
neoadjuvant nivolumab for early stage NSCLC patients were recently published (19). 
Neoadjuvant nivolumab induced major pathologic response in 45% (9/20) of evaluable 
patients, which is markedly increased relative to the one noted following neoadjuvant 
chemotherapy (19%) (20). Furthermore, the authors showed a correlation between both pre-
treatment tumor mutation and predicted neo-antigen loads with pathologic response. 
Immunohistochemical analysis of pre- and post-treatment tumors showed an influx of PD-
1+CD8+ T cells into responding tumors. These results indicate that nivolumab is safe and 
neither delays surgery nor induces surgical complications when given preoperatively. 
 
 
Combination of nivolumab and ipilimumab for NSCLC. CheckMate 012 compared 
several dosing schedules for combining nivolumab and ipilimumab for front-line use in 
treating advanced NSCLC to explore the safety and efficacy of dual checkpoint therapy in the 
metastatic setting. Initially, the combination with ipilimumab mirrored the dose and schedules 
used in metastatic melanoma (nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 
weeks or nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks). Response rates 
with these combinations were 13% and 20%, respectively. Grade 3/4 treatment-related 
adverse event rates were 58% and 44%, and 37% of patients discontinued this combination 
due to toxicity. Given the toxicities encountered in the initial experience of the combination of 
ipilimumab and nivolumab in metastatic NSCLC, modified dose schedules have been studied: 
 
• 
Nivolumab at 1 mg/kg every 3 weeks × 4 plus ipilimumab at 1 mg/kg every 3 weeks 


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Protocol: 2016-0982 
 
 
 
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× 4 plus nivolumab at 3 mg/kg every 2 weeks (n = 31) 
 
• 
Nivolumab at 1 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks (n 
= 40) 
 
• 
Nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 12 weeks (n 
= 38) 
 
• 
Nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks (n 
= 39). 
 
 
Efficacy and safety results of the Checkmate 012 study were recently published by Hellmann 
et al. (21). The combination was well tolerated in all the cohorts. Only 11-13% of patients 
discontinued treatment due to adverse events. This compares favorably to what was seen with 
first-line nivolumab monotherapy (10%). Grade 3/4 treatment-related adverse events occurred 
in 33% to 37% of patients and were manageable. There were no treatment-related deaths. The 
study also demonstrated a high level of clinical activity characterized by deep and durable 
responses. Objective responses were confirmed in 43% in the overall population (≥50% PD-
L1, ≥1% PD-L1, and <1% PD-L1), and ranged from 47% to 39% in the cohorts receiving 
nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 12 weeks or every 6 
weeks, respectively. Median duration of response was not reached in any arm, regardless of 
PD-L1 expression, with median follow-up times of 12.8 months in the ipilimumab every 12 
weeks cohort and 11.8 months in the ipilimumab every 6 weeks cohort (21). 
 
Combination of nivolumab and platinum-based chemotherapy for NSCLC. The PD-1 
inhibitor pembrolizumab has shown superior efficacy as monotherapy in previously untreated 
patients with advanced NSCLC and a PD-L1 tumor proportion score ≥50% compared with 
standard platinum-based chemotherapy, with fewer toxicities (22). Based on this results, the 
investigators of the Keynote-021 phase II study assessed the efficacy of pembrolizumab 
added to platinum-doublet chemotherapy as first line therapy for advanced non-squamous 
NSCLC patients (23). The objective response rate was 55% in the pembrolizumab plus 
chemotherapy group compared with 29% in the chemotherapy alone group (p=0.0016) with 
an overall tolerable toxicity profile. More recently, the IMpower150 phase 3 trial is 
evaluating the addition of the PD-L1 inhibitor atezolizumab (atezo) to carboplatin (C) + 
paclitaxel (P) ± bevacizumab (bev) in chemo-naive patients with metastatic non-squamous 
NSCLC. The initial results of this trial has been recently presented by Reck et al at the ESMO 
Immuno-Oncology Congress 2017 (24) . Median PFS in atezo + bev 15 mg/kg + C + P (Arm 
B) vs. bev + C + P (Arm C)  was 8.3 months vs 6.8 months and 11.3 months vs 6.8 months in 
the ITT-wild type (WT) and in WT pts with expression of a tumor T-effector gene signature, 


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respectively. PFS benefit was seen regardless of PD-L1 IHC status, including PD-L1–
negative pts. Arm B had a comparable safety profile to Arm C; treatment-related serious 
adverse events were 25% vs 19%, respectively. This is the first phase III trial to show a 
statistically significant and clinically meaningful PFS benefit with atezo + bev + chemo as 
compared with bev + chemo in previously untreated pts with non-squamous metastatic 
NSCLC. 
 
The phase III trial, KEYNOTE-189, was a randomized, double blind, placebo controlled, 
study investigating pembrolizumab in combination with pemetrexed and cisplatin or 
carboplatin compared with pemetrexed and cisplatin or carboplatin alone in previously 
untreated patients with wild type (WT) advanced or metastatic nonsquamous NSCLC, 
regardless of PD-L1 expression (NCT02578680). The results of this phase 3 trial have been 
recently reported and demonstrated that in patients with previously untreated metastatic 
nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to 
standard pemetrexed plus platinum-based chemotherapy resulted in significantly longer OS 
and PFS than chemotherapy alone. After a median follow-up of 10.5 months, the 12-month 
OS rate was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-
combination group vs. 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (HR 
for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Median PFS was 8.8 months (95% CI, 7.6 to 
9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the 
placebo-combination group (HR for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; 
P<0.001) (25). Another phase III trial, CheckMate 227, compared nivolumab, or nivolumab 
plus ipilimumab, or nivolumab plus platinum-based chemotherapy versus platinum-based 
chemotherapy in patients with chemotherapy-naïve stage IV recurrent NSCLC 
(NCT02477826). Results have been recently reported and demonstrated that PFS among 
patients with a high tumor mutational burden was significantly longer with nivolumab plus 
ipilimumab than with chemotherapy. The 1-year PFS rate was 42.6% with nivolumab plus 
ipilimumab vs. 13.2% with chemotherapy, and the median PFS was 7.2 months (95% 
confidence interval [CI], 5.5 to 13.2) vs. 5.5 months (95% CI, 4.4 to 5.8) (HR for disease 
progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P<0.001). The ORR was 45.3% with 
nivolumab plus ipilimumab and 26.9% with chemotherapy (26). 
Collectively, these results and the ongoing studies support investigation of checkpoint 
inhibitors with or without platinum-based chemotherapy in the pre- operative setting. 
 
Combination of nivolumab plus ipilimumab (dual ICI) and platinum-based chemotherapy 
plus dual ICI for advanced/metastatic NSCLC. CheckMate 568 was an open-label phase II 
trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-
line treatment of advanced/metastatic NSCLC patients (27). Two hundred eighty-eight 
patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 
mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was 


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objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 
expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end 
point. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 
1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 
10 or more mutations/megabase (mut/Mb). Grade 3 to 4 treatment-related adverse events 
occurred in 29% of patients. Nivolumab plus low-dose ipilimumab was effective and 
tolerable as a first-line treatment of advanced/metastatic NSCLC. In the second phase of this 
study, 36 previously untreated stage IV/recurrent stage IIIb NSCLC patients without the 
presence of a known tumor genomic driver (PD-L1 TPS all comers), have been treated with 
2 cycles of nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks plus 
platinum doublet chemotherapy followed by nivolumab 360 mg every 3 weeks plus 
ipilimumab 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity for a 
maximum of 2 years.   With a median follow up time of 15.5 months, 1 case of dose limiting 
toxicity (DLT) was observed with one patient experiencing a Grade 3 ALT/AST elevation 
that resulted in ipilimumab discontinuation after cycle 1. Patient continued treatment with 
nivolumab plus platinum doublet chemotherapy with a 50% tumor size reduction. Overall 
92% of treated patients experienced treatment-related AEs of any grade (Grade 3-4 61%, 
Grade 5 0), and in 19% of patients treatment had to be discontinued to  drug-related 
toxicities, which included 2 cases of pneumonitis, 2 colitis, 2 cases of encephalopathy, 1 case 
of acute kidney injury and 1 adrenal insufficiency. Most patients received the pre-planned 2 
cycles of chemo (1/36 stopped therapy due to vomiting and febrile neutropenia). In 
summary, the initial safety profile of the first 36 patients treated with the combination of 
nivolumab, low dose ipilimumab and 2 cycles of platinum doublet chemotherapy was 
manageable and consistent with the known profile of combination (unpublished data). No 
new safety issues were identified and lower frequency of potential chemotherapy- related 
toxicities was noted as compared to historical standard of care controls with 4 cycles of 
chemotherapy platinum doublet +/- pembrolizumab in the first line setting for metastatic 
NSCLC patients, suggesting that the combination of nicolumab, low dose ipilimumab and 
platinum doublet chemotherapy may be a safe and more potent therapeutic strategy in the 
neoadjuvant setting for resectable NSCLC patients.  
 
Major pathologic response as a marker of induction chemotherapy efficacy. Several small 
studies have suggested that the degree of tumor regression after induction therapy, as 
determined by histopathologic findings in the resected tumor, may be an objective criterion of 
chemotherapy response and may correlate with long-term treatment outcomes (28-31). This 
issue was comprehensively evaluated recently by Pataer et al. in a retrospective study with 192 
patients treated with induction chemotherapy and 166 patients treated with surgery upfront at 
M. D. Anderson (20).Using a score system that quantifies the percentage of viable tumor cells 
in at least 1 section per cm of tumor greatest diameter (5-30 slides examined for each case), the 
authors demonstrated that in patients that received induction treatment, there is a statistically 


11 January 2022 
Protocol: 2016-0982 
 
 
 
13 
 
significant correlation between higher percentage of viable cells and shorter disease-free and 
overall survival. This correlation was not evident in patients treated with surgery upfront. In 
this cohort, 89% of the neoadjuvant treated patients received a platinum and a taxane-based 
regimen, and a pathologic response (defined as ≤ 10% viable tumor cells) occurred in 19% of 
the patients. The 5-year recurrence-free survival for patients with and without a pathologic 
response were 78% and 35%, respectively (p < 0.001). The 5-year overall survival for patients 
with and without a pathologic response were 85% and 40%, respectively (p < 0.0001). Taken 
together, these results support the use of major pathologic response as a surrogate endpoint for 
recurrence-free and overall survival in patients with NSCLC treated with neoadjuvant 
chemotherapy.  
 
Neoadjuvant Immune checkpoint blockade in resectable NSCLC 
Recently published results of a small, pilot study evaluating the safety and feasibility of 
neoadjuvant nivolumab as monotherapy for a limited number of patients with resectable 
NSCLC has demonstrated that nivolumab is safe, does not delay surgery, and induces a 
major pathological response in 9 of 20 resected tumors (45%) (19). Translational analyses 
revealed a significant correlation between the pathological response and the pretreatment 
tumor mutational burden, and the number of T-cell clones that were found in both the tumor 
and peripheral blood expanded  significantly after neoadjuvant nivolumab therapy in 8/9 
patients evaluated. These remarkable results highlights the need to test additional 
immunotherapy-based combination in the neoadjuvant setting to discover efficacy signal of 
compounds to be tested in larger trials.  
 
 
TCD8+ TILs as a prognostic marker. Several studies have demonstrated that TCD8+ TILs 
are associated with improved outcomes in resected NSCLCs (32-34). PD-1 and/or CTLA4 
blockade are expected to recruit antigen-specific TCD8+ cells to the tumor microenvironment, 
and therefore contribute to an enhanced immune response. As such, automated quantification 
of TCD8+ cells in resected specimens following induction immunotherapy may provide 
evidence for its role as a surrogate marker of efficacy of these drugs, and is included as a 
secondary endpoint in this study. Additionally, phenotypic characterization of the immune 
infiltrate (such as evaluation of exhausted T cells) may also be important to evaluate potential 
differences in outcomes to single agent versus combined immune checkpoint blockade (35). 
 
 
 


11 January 2022 
Protocol: 2016-0982 
 
 
 
14 
 
2 
STUDY OBJECTIVES 
 
2.1 Hypotheses 
 
 
The primary hypothesis to be tested in this study is that, in patients with stage I-IIIA 
NSCLC amenable for surgical resection, induction immunotherapy with nivolumab alone 
and/or nivolumab plus ipilimumab and/or single or combined immunotherapy  plus 
platinum-based chemotherapy will produce major pathologic responses of at least 40%, a 
target response that is superior to the one observed following induction platinum-based 
chemotherapy alone, as compared to the MD Anderson historical controls. 
 
 
The secondary hypothesis to be tested in this study is that immunotherapy with nivolumab 
and/or nivolumab plus ipilimumab and/or single or combined immunotherapy plus 
platinum-based chemotherapy will induce immune responses (as assessed by CD8+ TILs), 
tumor shrinkage (as assessed by CT), and improve recurrence-free survival (RFS) and 
overall survival (OS) in a subset of patients; analysis of correlative studies in these patients 
will assist in developing biomarkers predictive of response to immunotherapeutic agents in 
NSCLC and will assist in determining immune modulation by nivolumab alone and/or 
nivolumab plus ipilimumab and/or single or combined immunotherapy plus platinum-
based chemotherapy . 
 
 
2.2 Study Endpoints 
 
 
2.2.1 Primary endpoint 
 
• 
Major pathologic response rate in patients treated with  induction nivolumab, nivolumab 
plus ipilimumab, and single or combined immunotherapy  plus platinum-based 
chemotherapy. 
 
 
Major pathologic response is defined as ≤ 10% viable tumor cells in the resected specimen 
using the methods described by Pataer et al (20). Briefly, at least 1 section per cm of tumor 
greatest diameter is evaluated, with a minimum of 5 slides. The percentage of residual 
tumor is determined by comparing the estimated cross sectional area of the viable tumor 
foci to estimated cross sectional areas of necrosis, fibrosis and inflammation on each slide. 
The results for all slides are averaged together to determine a mean value of viable tumor 


11 January 2022 
Protocol: 2016-0982 
 
 
 
15 
 
cells for each patient. 
 
 
2.2.2 Secondary endpoints 
 
 
• 
Toxicity (assessed by the NCI CTCAE version 4) 
 
 
• 
Peri-operative morbidity and mortality 
 
 
• 
CD8+ TILs in resected tumor tissues of patients treated with nivolumab alone and 
nivolumab plus ipilimumab and single or combined immunotherapy plus platinum-based 
chemotherapy. 
 
• 
Quantification of CD8+ TILs will be assessed by counting the cells positive for 
staining with an anti-CD8 antibody by immunohistochemistry in five random square areas 
(1 mm2 each) in both intratumoral and peritumoral compartments using the automated 
Aperio system. 
 
• 
Response rates to induction treatment (by RECIST version 1.1) (36)  
 
• 
Recurrence-free survival 
 
 
• 
Overall survival 
 
 
• 
To correlate major pathologic response with recurrence-free and overall survival 
 
 
• 
Complete resection (R0) rate 
 
• 
Pathologic complete response (pCR) in resected tumor specimens 
 
 
• 
To correlate response assessed by imaging studies with outcomes (both major 
pathologic response to treatment and long-term recurrence-free survival) 
 


11 January 2022 
Protocol: 2016-0982 
 
 
 
16 
 
 
• 
To correlate blood, tissue, and stool-based biomarkers with efficacy and toxicity 
 
2.2.3 Exploratory endpoints 
 
An important aspect of this trial is to identify novel prognostic and predictive markers present 
at diagnosis, and to determine modulation of markers by induction immunotherapy and/or 
immunotherapy plus platinum-based chemotherapy in order to inform future translational 
studies. As such, blood, stools and tumor tissue will be collected throughout the study period. 
The markers to be assessed in these specimens (likely with the use of high throughput 
technology) will be determined according to the best scientific knowledge and technology 
available at the time of batch analysis. Correlative studies will be interpreted as hypothesis- 
generating data, to be validated in subsequent trials. Candidate markers to be evaluated 
include (but are not restricted to): 
 
• 
PD-L1 expression in tumor tissue 
 
 
• 
Multi-region next generation DNA and/or RNA sequencing in tumor tissue 
(including whole exome and/or whole genome sequencing) and in blood/normal tissue, so 
that tumor heterogeneity and mutational load can be correlated with efficacy of 
immunotherapy and/or other correlative markers 
 
• 
Immunophenotyping or characterization of the immune cell subsets in tumor tissue, 
including markers of T cell exhaustion (CD3, PD-1, CD4, CD8, CTLA-4, CD45), T cell 
activation (CD3, CD28, CD44, CD8, CD62L, CD45), T regulatory cells (CD3, FOXP3, 
CD8, CD4, CD25, CD45), T cell function (CD3, IFN-gamma, CD4, CD8, IL10, CD45), 
antigen presenting cells (CD11B, CD11C, GR-1, CD86, PD-L1, CD45), as well as CD20, 
Ki67, granzyme B, IFN-γ, TGF-beta, GATA-3, RORgt, BCL2 (thus allowing for estimation 
of T cell activation, and Th1/Th2/Th17 bias), as well as CD68 and other markers relevant to 
immune profiling. 
 
• 
Expression of immunoregulatory and co-stimulatory markers in TILs by flow 
cytometry, including, but not limited to, PD1, CTLA4, LAG3, 41BB, and TCR zeta chain 
 
 
• 
RNA and protein expression in tumor and adjacent normal tissue, 
including assessment of immune/inflammatory pathways 
 
• 
Immunophenotyping or characterization of the immune cell subsets in the periphery, 


11 January 2022 
Protocol: 2016-0982 
 
 
 
17 
 
including, but not limited to, T cells, B cells, NK cells, or subpopulations of the 
aforementioned immune cell types 
 
• 
Single cell genomics in tumor and adjacent normal tissue 
 
• 
Serum soluble factors, including IFN-gamma and interferon inducible factors (such as 
CXCL9 and CXCL10), PD-L1, PD-1, anti-tumor antibodies, microRNAs (such as miR-513, 
and miR19b), IL-12, TNFα, IL-10, TGF-β, VEGF, IL-6, IL-8, IL-17, IL-18, C-reactive protein 
and, as well as other cytokines, chemokines, inflammatory factors and immune mediators 
 
 
• 
T cell receptor repertoire sequencing in tumor tissue and the periphery 
 
 
• 
Next generation sequencing of cell-free circulating DNA 
 
 
• 
Immunopeptidome analysis 
 
 
• 
Enteric microbiome analysis 
 
 
• 
CT imaging analysis 
 
 
2.2.4 Additional assessments 
 
 
In addition to the endpoints described above, post-treatment TILs will also be isolated, 
expanded and evaluated for anti-tumor activity in vitro. TILs may also be stored for future re- 
infusion into patients that develop disease recurrence as part of a separate clinical trial. We 
hypothesize that the efficiency of TIL isolation and efficacy of adoptive T-cell therapy will be 
improved when cells are collected post exposure to checkpoint inhibitors, thus providing 
further rationale for developing induction immunotherapy strategies in resectable NSCLCs. 
 
 
We may also establish cell cultures and patient-derived xenografts in rodents from tissues 
obtained under this protocol for future pre-clinical studies. Procedures for establishing and 
maintaining xenografts will be contemplated in a separate animal protocol. 


11 January 2022 
Protocol: 2016-0982 
 
 
 
18 
 
 
 
 
3 
ETHICAL CONSIDERATIONS 
 
 
The study will be conducted in accordance with Good Clinical Practice (GCP), as defined 
by the International Conference on Harmonization (ICH), WHO and any local directives, 
and In compliance with the protocol. 
 
 
The protocol, any amendments, and the subject informed consent will receive Institutional 
Review Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion 
before initiation of the study. 
 
 
4 
ELIGIBILITY CRITERIA 
 
 
All eligibility criteria must be met prior to initiating treatment. 
 
 
4.1 Inclusion Criteria 
 
 
1. 
Age > 18 years 
 
 
2. 
Histologically or cytologically confirmed previously untreated non-small cell lung 
cancer. If a diagnostic biopsy is available, a pre-treatment biopsy is not required. 
Patients with a suspected lung cancer are eligible, but pathology must be 
confirmed prior to initiating treatment on study. Neuroendocrine carcinomas are 
not eligible. Carcinomas with neuroendocrine differentiation are eligible. 
 
 
3. 
 Patients with stage IA or stage IB < 4 cm (according to AJCC 7th edition) are 
eligible for randomization into arms A and B only. Patients with stage IB ≥ 4cm, IIA, IIB, 
or IIIA disease (according to AJCC 7th edition) are eligible for randomization into arms 
A and B, and for enrollment into arms C and D. 


11 January 2022 
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19 
 
 
4. 
Patients with stage IIIA must not have more than one mediastinal lymph node 
station involved by tumor. 
5. 
All patients must have lymph node evaluation of contralateral stations 2 and/or 4 
to exclude N3 disease (see section 9.1.5). 
 
 
6. 
The patient must be a suitable candidate for surgery, in the opinion of the 
treating physician. 
 
 
7. 
Signed and dated written informed consent must be provided by the patient prior 
to admission to the study in accordance with ICH-GCP guidelines and to the local 
legislation 
 
 
8. 
ECOG performance status score 0-1 
 
 
9. 
Patients must have organ and marrow function as defined below: 
 
System 
Laboratory Values 
Hematologic 
Absolute neutrophil count (ANC) 
Hemoglobin 
Platelets 
≥1.5 X 109/L 
≥8.0 g/dL 
≥100 X 109/L 
Hepatic 


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Protocol: 2016-0982 
 
 
 
20 
 
Total bilirubin 
AST and ALT 
≤ 1.5 X ULN (except subjects with Gilbert 
Syndrome, who can have total bilirubin < 3.0 
mg/dL) 
≤3 X ULN 
Renal 
Creatinine 
OR 
Calculated creatinine clearance1 
OR 
24-hour urine creatinine clearance 
≤1.5 X ULN 
≥ 50 mL/min 
≥ 50 mL/min 
 
 
1Cockcroft-Gault formula for creatinine clearance calculation:  
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 


11 January 2022 
Protocol: 2016-0982 
 
 
 
21 
 
 
4.2 Exclusion Criteria 
 
1. 
Prior systemic therapy or radiation therapy for treatment of the current lung cancer 
 
2. 
Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, 
or biologic therapy) or investigational anti-cancer drug 
3. 
Pregnant or lactating female 
 
 
• 
Women of childbearing potential (WOCB) must have a negative serum or urine 
• 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 
hours prior to the start of nivolumab 
• 
Women of childbearing potential is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 
months of amenorrhea in a woman over 45 in the absence of other biological or 
physiological causes 
 
4. 
Unwillingness or inability to follow the procedures required in the protocol 
5. 
Patients with pre-existing sensorineural hearing impairment/loss or newly diagnosed 
as documented by an audiology assessment performed prior to study enrollment may 
not be eligible for cisplatin and may be dispositioned to carboplatin, as determined 
by the treating physician.  
 
6. 
Patients with a history of severe hypersensitivity reaction to Taxotere® and or 
polysorbate 80 must be excluded 
7. 
Any serious or uncontrolled medical disorder that, in the opinion of the investigator, 
may increase the risk associated with study participation or study drug administration, 
impair the ability of the subject to receive protocol therapy, or interfere with the 
interpretation of study results. Prior malignancy active within the previous 2 years. 
Patients with locally curable cancers that have been apparently cured, such as basal or 
squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the 
prostate, cervix, or breast with local control measures (surgery, radiation) are eligible. 
8. 
Subjects with active, known or suspected autoimmune disease. Subjects with 
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune 
condition only requiring hormone replacement, psoriasis not requiring systemic 
treatment, or conditions not expected to recur in the absence of an external trigger are 
permitted to enroll 
9. 
Subjects with a condition requiring systemic treatment with either corticosteroids (> 


11 January 2022 
Protocol: 2016-0982 
 
 
 
22 
 
10 mg daily prednisone equivalents) or other immunosuppressive medications within 
14 days of study drug administration. Inhaled or topical steroids and adrenal 
replacement doses > 10 mg daily prednisone equivalents are permitted in the absence 
of active autoimmune disease. 
 
 
• 
Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Physiologic replacement doses of 
systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A 
brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment 
of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by 
contact allergen) is permitted. 
 
 
10. 
Prior treatment with an anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody 
 
 
 
11. 
Known positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus 
ribonucleic acid indicating acute or chronic infection 
 
 
12. 
Known history of testing positive for human immunodeficiency virus or known acquired 
immunodeficiency syndrome 
 
 
13. 
History of severe hypersensitivity reaction to any monoclonal antibody and/or to study drug 
components 
 
 
14. 
Serious illness or concomitant non-oncological disease such as neurologic, psychiatric, 
infectious disease or laboratory abnormality that may increase the risk associated with study 
participation or study drug administration and in the judgment of the investigator would make 
the patient inappropriate for entry into the study. 
 
 
15. 
Patients who are sexually active, with preserved reproductive capacity, and unwilling to use 
a medically acceptable method of contraception (e.g. such as implants, injectables, combined 
oral contraceptives, some intrauterine devices or vasectomized partner for participating 
females, condoms for participating males) during and after the trial as detailed below 


11 January 2022 
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23 
 
 
 
• 
WOCBP should use an adequate method to avoid pregnancy for 23 weeks after the 
last dose of investigational drug(s). 
• 
Men who are sexually active with WOCBP must use any contraceptive method with a 
failure rate of less than 1% per year. 
• 
Men receiving nivolumab and who are sexually active with WOCBP will be instructed 
to adhere to contraception for a period of 31 weeks after the last dose of investigational 
product. 
• 
Women who are not of childbearing potential as well as azoospermic men do not 
require contraception 
 
16. 
Psychological, familial, sociological or geographical factors potentially hampering 
compliance with the study protocol and follow-up schedule. 
 
5 
STUDY DESIGN AND PLAN 
 
 
Modular design of neoadjuvant signal-finding study platform  
Given the promising activity and safety demonstrated by neoadjuvant nivolumab, several 
immunotherapy-based regimens are now being tested in the neoadjuvant setting in phase 2 
studies using the MPR as primary endpoint of efficacy. It follows that the best approach to 
expedite the evaluation of novel and active therapeutic strategies that merit further 
investigation in larger randomized trials, would be a modular platform clinical trial of single 
arm, signal-finding and efficacy-testing studies. Based on this design, upon completion of a 
proposed single arm study, a follow-on evaluation could result in a randomized comparison, 
if a signal of activity is observed, or the launch of another single arm study evaluating a new 
immunotherapy combination, if the proposed study fails to demonstrate a signal of activity.  
 
Study Plan 
This is an open label, phase 2 multi-arm study with modular design of nivolumab, nivolumab 
plus ipilimumab, single or combined  immunotherapy plus platinum-based chemotherapy 
induction treatment in patients with resectable NSCLC, with the primary objective to 
determine the MPR in each arm, and compare it not between arms, but to the benchmark 
from historical controls of neoadjuvant chemotherapy. After confirmation of eligibility 
criteria, patients will be stratified by stage (I vs. II vs. III) and randomized to Arm A or Arm 
B using a minimization technique. Upon completion of enrollment in these two arms, 
eligible patients will be enrolled to Arm C or D.  
 
 


11 January 2022 
Protocol: 2016-0982 
 
 
 
24 
 
Arm A — nivolumab single agent 
 
 
Arm B — nivolumab plus ipilimumab 
 
 
       Arm C — nivolumab plus platinum-based chemotherapy 
 
 
     Arm D — nivolumab plus ipilimumab plus platinum-based chemotherapy 
 
 
 
 
For patients accrued to Arms A and B, randomization will be performed via a centralized, web-
based randomization system – the Clinical Trial Conduct (CTC) application in the 
Department of Biostatistics. Patients who are randomized will be assigned to a treatment arm 
and given a unique patient number by the centralized, web-based system. 
 
 
 
 


11 January 2022 
Protocol: 2016-0982 
 
 
 
25 
 
6 
TREATMENT 
 
6.1 Induction Treatment 
Patients will receive induction treatment according to the randomization arm, as 
follows:  
Arm A: 
 
• 
Nivolumab 3 mg/kg intravenously on days 1, 15, and 29  
 
Arm B: 
• 
Ipilimumab 1 mg/kg intravenously on day 1, and 
 
 
• 
Nivolumab 3 mg/kg intravenously on days 1, 15, and 29  
 
Upon completion of randomization to Arms A and B, patients will be accrued to Arm C: 
• 
Nivolumab 360 mg IV every 3 weeks (D1, D22, D43) plus Cisplatin and Docetaxel 
IV administered every 3 weeks (D1, D22, D43), up to a maximum of 3 cycles for 
squamous histology NSCLCs, or Nivolumab 360 mg IV every 3 weeks (D1, D22, 
D43) plus Cisplatin and Pemetrexed IV administered every 3 weeks (D1, D22, D43), 
up to a maximum of 3 cycles for non-squamous histology NSCLCs. For carcinomas 
with neuroendocrine features and/or differentiation either regimen with Cisplatin and 
Docetaxel plus Nivolumab or Ciplatin and Pemetrexed plus Nivolumab may be used 
based on treating physician’s preference.  
 
Upon completion of enrollment to Arm C, patients will be accrued to Arm D: 
• 
Ipilimumab 1 mg/kg intravenously on day 1 only plus Nivolumab 360 mg IV every 3 
weeks (D1, D22, D43) plus Cisplatin (or Carboplatin) and Docetaxel IV administered 
every 3 weeks (D1, D22, D43), up to a maximum of 3 cycles for squamous histology 
NSCLCs, or Ipilimumab 1 mg/kg intravenously on day 1 only plus Nivolumab 360 mg 
IV every 3 weeks (D1, D22, D43) plus Cisplatin (or Carboplatin) and Pemetrexed IV 
administered every 3 weeks (D1, D22, D43), up to a maximum of 3 cycles for non-
squamous histology NSCLCs. For carcinomas with neuroendocrine features and/or 
differentiation Cisplatin (or Carboplatin) and Docetaxel or Cisplatin (or Carboplatin) 
and Pemetrexed regimens plus Ipilimumab and Nivolumab may be used based on the 
treating physician’s preference. 
 
 
 


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26 
 
6.2 Surgery 
 
 
Surgery will be performed after completion of induction therapy. It is strongly 
recommended that 3 doses of nivolumab (arms A and B) or 3 cycles of platinum-based 
chemotherapy plus nivolumab (arm C), or 3 cycles of platinum-based chemotherapy plus 
ipilimumab and nivolumab (arm D) are administered prior to surgery. However, less than 
3 doses of nivolumab or 3 cycles of platinum-based chemotherapy plus nivolumab, or 3 
cycles of platinum-based chemotherapy plus pilimumab and nivolumab will be allowed in 
case of excessive toxicities or other reasons identified by the treating physician that may 
lead to an unfavorable benefit/risk ratio of proceeding with therapy as planned per protocol, 
after discussing the case with the principal investigator. 
 
 
There must be at least a 21-day nivolumab-free or platinum-based chemotherapy plus 
nivolumab-free interval before surgery (i.e., surgery will only be performed at least 21 days 
after the last dose of nivolumab or platinum-based chemotherapy plus nivolumab, unless 
there is a strong clinical indication to perform surgery sooner, in the opinion of the treating 
physician). It is strongly recommended that surgery be performed within 3 to 6 weeks after the 
last dose of nivolumab or nivolumab plus platinum-based chemotherapy. 
 
The operative approach (thoracoscopy versus thoracotomy) and the extent of surgical 
resection will be based on the treating surgeon’s judgment and may include wedge resection, 
segmentectomy, lobectomy, or pneumonectomy with mediastinal lymph node dissection of 
nodal stations 4, 7, 8, 9,10, 11-14 for right sided resections, and nodal stations 5, 6, 7, 8, 9, 
10, 11-14 for left sided resection. 
 
 
6.3 Post-operative (Adjuvant) Systemic Therapy 
 
Since the primary efficacy endpoint of this study is major pathologic response (which will be 
assessed at the time of surgery), mandatory use or mandatory prohibition of post-operative 
(adjuvant) systemic therapy will not be defined by this protocol. Patients may receive adjuvant 
systemic therapy at the discretion of the treating physician. In general, if patients have 
completed 3 cycles of induction platinum-based chemotherapy, no adjuvant systemic therapy 
is recommended. For patients who did not receive induction platinum-based chemotherapy, and 
with stage IB (with tumor size 4 cm or greater), II, and III, at least 3 cycles of adjuvant 
cisplatin- based chemotherapy are recommended. In case adjuvant systemic therapy is used, 
this information will be captured by retrospective chart review and may be used for 
interpretation of analysis of long-term treatment outcomes. 


11 January 2022 
Protocol: 2016-0982 
 
 
 
27 
 
6.4 Post-operative (Adjuvant) Radiation Therapy 
 
 
Since the primary efficacy endpoints of this study is major pathologic response (which will be 
assessed at the time of surgery), mandatory use or mandatory prohibition of post-operative 
(adjuvant) radiation therapy will not be defined by this protocol. Post-operative radiation 
therapy will be delivered according to institutional guidelines and the treating physician’s best 
judgement, preferably within 6 weeks of surgical resection or completion of adjuvant systemic 
therapy (whichever is longer). While radiation therapy is not formally required per protocol, it 
is strongly suggested that the following principles of radiation therapy be followed: 
 
• 
Consider post-operative radiation therapy in patients with pathologic confirmation 
of mediastinal lymph node involvement by cancer either before or after induction 
treatment. 
 
• 
Consider post-operative radiation therapy in patients with positive margins at surgical 
resection. 
 
• 
When recommended, deliver either photon- or proton-based external beam radiation 
therapy between 50-66 Gy depending on the completeness of tumor resection. 
Typically 50 Gy in 25 fractions is given for R0 resection, 60 Gy in 30 fractions for R1, 
and 66 Gy in 33 fractions for R2 resection. The final dose will be left up to the 
treating radiation oncologist. 
 
In case adjuvant radiation therapy is used, this information will be captured by retrospective 
chart review and may be used for interpretation of analysis of long-term treatment outcomes. 
 
 
 
 


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7 
PRODUCT INFORMATION 
 
 
7.1 Drug Ordering and Accountability 
 
 
Only product supplied and designated for this protocol should be used for this study. 
 
 
7.1.1 Nivolumab and Ipilimumab (Immune-Oncology [I-O] Agents) 
 
 
 
BMS will supply study drugs nivolumab and ipilimumab used for this investigational study 
by ordering through a completed Drug Request Form provided by BMS for this specific 
trial. 
• 
Please see Appendix 1 for information on provisions for ordering study drug from 
BMS. The investigator is responsible for ensuring that the investigational product is stored 
under the appropriate environmental conditions (temperature, light, and humidity) 
 
 
• 
If concerns regarding the quality or appearance of the investigational product arise, 
do not dispense the investigational product, and contact BMS immediately. If 
commercial investigational product is used, it should be stored in accordance with 
the appropriate local labeling 
 
• 
If the study drug(s) are 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 
 
 
 
7.1.2 Other agent(s) 
 
Commercially available pemetrexed, cisplatin, carboplatin and docetaxel will be supplied by the 
study center (or according to local regulations). Pemetrexed, cisplatin, carboplatin and docetaxel 
should be stored as directed in the product package insert (or equivalent documentation). 
Medication should be kept in a secured locked area at the study site in accordance with applicable 
regulatory requirements. 


11 January 2022 
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29 
 
7.2 Product Description and Dosage Form 
 
7.2.1 Nivolumab and ipilimumab (I-O Agents) 
 
 
Product 
Description and 
Dosage Form 
Potency 
Primary 
Packaging 
(Volume)/ Label 
Type 
Appearance 
Storage 
Conditions 
(per label) 
Nivolumab BMS- 
936558-01 
Solution 
for 
Injectiona 
100 mg 
(10 
mg/mL) 
10 mL vial 
Clear to 
opalescent 
colorless to pale 
yellow liquid. 
May contain 
particles 
2 to 8 C. 
Protect 
form light 
and freezing 
Ipilimumab 
Solution for 
Injection 
200 mg 
(5 mg/mL) 
40 mL vial 
Clear, colorless to 
pale yellow liquid. 
May contain 
particles 
2 to 8°C. 
Protect from 
light and 
freezing. 
aNivolumab may be labeled as BMS-936558-01 Solution for Injection 
 
 
 
If stored in a glass front refrigerator, vials should be stored in the carton. 
Recommended safety measures for preparation and handling of nivolumab and 
ipilimumab include laboratory coats and gloves. 
 
For additional details on prepared drug storage and use time of nivolumab or 
ipilimumab under room temperature/light and refrigeration, please refer to the 
BMS- 936558 (nivolumab) and Ipilimumab Investigator Brochure section for 
“Recommended Storage and Use Conditions” 
 
 
 


11 January 2022 
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30 
 
7.2.2 Other agent(s) 
 
 
Pemetrexed 
Commercially available pemetrexed will be supplied by the study center (or according to 
local regulations). 
 
 
Cisplatin 
Commercially available cisplatin will be supplied by the study center (or according to 
local regulations). 
 
 
Carboplatin 
Commercially available carboplatin will be supplied by the study center (or according to local 
regulations). 
 
Docetaxel 
Commercially available docetaxel will be supplied by the study center (or according to local 
regulations). 
 
 
7.3 Handling and Dispensing 
 
 
7.3.1 Nivolumab and Ipilimumab (I-O Agents) 
 
 
The investigator should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as per product information and the 
Investigator Brochure and per local regulations. It is the responsibility of the investigator to 
ensure that investigational product is only dispensed to study subjects. The investigational 
product must be dispensed only from official study sites by authorized personnel according to 
local regulations. If concerns regarding the quality or appearance of the study drug arise, the 
study drug should not be dispensed and contact BMS immediately. 
 
Please refer to the current version of the Investigator Brochure for additional information on 
storage, handling, dispensing, and infusion information for nivolumab and ipilimumab. 
 
 


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31 
 
7.3.2 Other agent(s) 
 
 
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents. 
 
Cisplatin 
 
Cisplatin will be reconstituted as directed in the product package insert (or 
equivalent documentation). 
 
 
Carboplatin 
Carboplatin will be reconstituted as directed in the product package insert (or equivalent 
documentation). 
 
Pemetrexed 
 
Pemetrexed will be reconstituted as directed in the product package insert (or equivalent 
documentation). 
 
 
Docetaxel 
 
Docetaxel will be reconstituted as directed in the product package insert (or 
equivalent documentation). 
 
 
7.4 Destruction 
 
Sponsor/Investigator drug destruction is allowed provided the following minimal standards 
are met: 
 
 
• 
On-site disposal practices must not expose humans to risks from the drug. 
 
• 
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances. 
 


11 January 2022 
Protocol: 2016-0982 
 
 
 
32 
 
• 
Written procedures for on-site disposal are available and followed. 
 
• 
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. 
The method of disposal, i.e., incinerator, licensed sanitary landfill, or licensed waste 
disposal vendor must be documented. 
 
 
• 
Accountability and disposal records are complete, up-to-date, and available for BMS 
to review throughout the clinical trial period as per the study agreement. 
 
 
If conditions for destruction cannot be met, please contact BMS. 
 
 
It is the Investigator’s responsibility to arrange for disposal of all empty containers, provided 
that procedures for proper disposal have been established according to applicable federal, 
state, local, and institutional guidelines and procedures, and provided that appropriate records 
of disposal are kept. 
 
 
7.5 Dose Administration 
 
 
7.5.1 Nivolumab and ipilimumab (I-O Agents) 
 
 
For preparation and administration details, please refer to the Investigator Brochure. When study 
drugs (ipilimumab or nivolumab) are to be administered on the same day, separate infusion bags 
and filters must be used for each infusion. It is recommended that nivolumab be administered first. 
The second infusion will always be ipilimumab, and will start approximately 30 minutes after 
completion of the nivolumab infusion 
 
 
 
BMS-936558 (nivolumab) is to be administered as a 60 minute IV infusion. Ipilimumab 
should be administered as a 90 minute infusion following. 
 
Ipilimumab and nivolumab may be diluted in 0.9% Sodium Chloride Solution or 5% 
Dextrose solution. 


11 January 2022 
Protocol: 2016-0982 
 
 
 
33 
 
 
The dosing calculations should be based on the actual body weight. If the subject’s weight on 
the day of dosing differs by > 10% from the weight used to calculate the dose, the dose must 
be recalculated. All doses should be rounded up or down per institutional standard. 
 
Patients may be dosed no less than 9 days from the previous dose of drug; and dosed up to 7 
days after the scheduled date if necessary. 
 
 
7.5.2 Other agent(s) 
 
 
Body surface area (BSA) for chemotherapy dose calculation will be determined according 
the following formula:       
BSA (m2) = (height (cm) x weight (kg)/3600)½  
or  BSA (m2) = square root of (height (cm) x weight (kg)/3600)  
        
 
The actual body weight will be used for BSA calculation, but the investigators will consider 
using adjusted or ideal body weight if the BSA exceeds 2.0 m2. BSA should be recalculated 
prior to the start of every cycle of therapy. 
 
 
 
Agent(s) 
Starting 
Dose 
Route 
Schedule 
Docetaxel 
Cisplatin 
Or Carboplatin 
75 mg/m2 
 
75 mg/m2 
 
 
AUC 5 or 6 
IV 
IV 
 
IV 
      Day 1 q 21 days + 7 days/-3 days a 
 
Day 1 q 21 days + 7 days/-3 days a 
 
 
Day 1 q 21 days + 7 days/-3 days a 
a For a maximum of 3 cycles. 
 
 


11 January 2022 
Protocol: 2016-0982 
 
 
 
34 
 
Agent(s) 
Starting 
Dose 
Route 
Schedule 
Pemetrexed 
 
Cisplatin 
Or Carboplatin 
 500 mg/m2 
 
75 mg/m2 
 
AUC 5 or 6 
   IV 
IV 
IV 
   Day 1 q 21 days + 7 days/-3 days a 
 
Day 1 q 21 days + 7 days/-3 days a 
 
Day 1 q 21 days + 7 days/-3 days a 
 
a For a maximum of 3 cycles. 
Docetaxel and cisplatin or carboplatin, or pemetrexed and cisplatin or carboplatin will be 
prepared and administered according to local practice and in accordance with the most recent 
Package Inserts/Data Sheets. 
For participants who are unable to tolerate cisplatin, the reasons for intolerability should 
be documented and the investigator can use a carboplatin-based regimen. 
 
 
7.5.3 General Concomitant Medication and Supportive Care Guidelines 
 
Prophylactic G-CSF support is strongly recommended and should be administered at least 24 
hours after infusion of chemotherapy, beginning at cycle 1 and continued for the duration of 
treatment with chemotherapy. Treating physicians may consider discontinuing G-CSF 
administration at cycles ≥ 2 provided that the patient did not have febrile neutropenia or 
grade4 neutropenia lasting ≥ 7 days on previous cycles, and provided that the patient is 
experiencing adverse events associated with G-CSF administration. 
 
Management of nausea and vomiting during platinum-based chemotherapy (including 
cisplatin and/or docetaxel and/or pemetrexed and/or carboplatin dose reductions) with the use 
of prophylactic anti-emetics will be implemented at the discretion of the treating physician. 
 
To reduce the severity of fluid retention and hypersensitivity reactions related to docetaxel, 
all patients will be considered for pre-medication with corticosteroids, such as oral 
dexamethasone 16 mg per day (e.g., 8 mg BID) for 3 days starting 1 day prior to docetaxel 
administration. Considerations for modification of the corticosteroid regimen (including 
schedule and dose reductions) should be made in patients receiving the prophylactic anti- 
emetics fosaprepitant or aprepitant. 
 
 


11 January 2022 
Protocol: 2016-0982 
 
 
 
35 
 
In order to reduce treatment-related hematologic and GI toxicities related to pemetrexed, 
patients will also be required to take folic acid, 350-1000 ug orally daily beginning 
approximately 5 days before the first dose of pemetrexed and continuing daily until 3 
weeks after the last dose of pemetrexed. In addition, Vitamin B12, 1000 ug, will be 
injected intramuscularly on day 1 of the first dose of pemetrexed and will be repeated 
approximately every 9 weeks until discontinuation of chemotherapy. 
 
 
 


11 January 2022 
Protocol: 2016-0982 
 
 
 
36 
 
8 DOSE MODIFICATIONS AND TOXICITY MANAGEMENT 
 
 
The toxicity management outlined herein is considered a general guideline. The investigator 
should use his or her best judgment when determining treatment interruptions. For example, 
some grade 2 non-hematologic toxicities may require treatment delays, and some grade 3 or 4 
organ toxicities (e.g., hepatic, renal, cardiac, central nervous system) may require a permanent 
treatment discontinuation. 
 
 
8.1 Management Algorithms for Immuno-oncology (I-O) Agents 
 
 
There will be no dose modifications permitted. Dose reductions or dose escalations are not 
permitted. 
 
Immuno-oncology (IO) agents are associated with adverse events that can differ in severity and 
duration than adverse events caused by other therapeutic classes. Nivolumab and ipilimumab are 
considered immuno-oncology agents in this protocol. Management algorithms have been 
developed to assist investigators in assessing and managing the following groups of adverse 
events: Gastrointestinal, Renal, Pulmonary, Hepatic, Endocrinopathies, Skin, and Neurological. 
 
 
Early recognition and intervention are recommended according to the management 
algorithms; and in addition include ophthalmologic evaluations for any visual symptoms in 
order to evaluate for nivolumab or ipilimumab related uveitis. 
 
 
The algorithms recommended for utilization are attached as Appendix 2. 
 
 
 
For subjects expected to require more than 4 weeks of corticosteroids or other 
immunosuppressant to manage an adverse event, consider the following recommendations 
 
 
• 
Antimicrobial/antifungal prophylaxis per institutional guidelines to prevent 
opportunistic infections such as Pneumocystis jiroveci and fungal infections. 
 
 


11 January 2022 
Protocol: 2016-0982 
 
 
 
37 
 
• 
Early consultation with an infectious disease specialist should be considered. 
 
 
Depending on the presentation, consultation with a pulmonologist for bronchoscopy or 
a gastroenterologist for endoscopy may also be appropriate. 
 
 
• 
In patients who develop recurrent adverse events in the setting of ongoing or prior 
immunosuppressant use, an opportunistic infection should be considered in the 
differential diagnosis. 
 
 
Additional details on the safety of nivolumab and ipilimumab, including results from 
clinical studies, are available in the Investigator’s Brochure. 
 
 
8.1.1 Dose delay criteria for I-O agents 
 
 
Dose delay criteria apply for all drug-related adverse events (regardless of whether or not the 
event is attributed to nivolumab, ipilimumab or both). All study drugs must be delayed until 
treatment can resume. 
Nivolumab administration should be delayed for the following: 
 
 
• 
Any Grade ≥ 2 non-skin, drug-related adverse event, with the following exceptions: 
 
 
• 
Grade 2 drug-related fatigue or laboratory abnormalities that do not require a 
treatment delay 
 
• 
Any Grade 3 skin, drug-related adverse event 
 
 
• 
Any Grade 3 drug-related laboratory abnormality, with the following exceptions 
for asymptomatic amylase or lipase, AST, ALT, or total bilirubin: 
 
• 
Grade 3 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis do not require a dose delay. It is recommended 
to consult with the principle investigator for Grade 3 amylase or lipase abnormalities. 


11 January 2022 
Protocol: 2016-0982 
 
 
 
38 
 
 
• 
If a subject has a baseline AST, ALT, or total bilirubin that is within 
normal limits, delay dosing for drug-related Grade ≥ 2 toxicity 
 
• 
If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 
toxicity range, delay dosing for drug-related Grade ≥ 3 toxicity 
 
 
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in 
the judgment of the investigator, warrants delaying the dose of study 
medication. 
 
 
 
8.1.2 Criteria to resume treatment with I-O agents 
 
 
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to Grade 
 
≤1 or baseline value, with the following exceptions: 
 
 
• 
Subjects may resume treatment in the presence of Grade 2 fatigue 
 
 
• 
Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity 
 
• 
Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays 
for reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume 
treatment in the presence of Grade 2 AST/ALT OR total bilirubin 
 
• 
Subjects with combined Grade 2 AST/ALT AND total bilirubin values 
meeting discontinuation parameters (Section 8.4) should have treatment 
permanently discontinued 
 
• 
Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to 
baseline before treatment is resumed 
 
• 
Drug-related endocrinopathies adequately controlled with only physiologic 


11 January 2022 
Protocol: 2016-0982 
 
 
 
39 
 
hormone replacement may resume treatment 
 
 
 
If the criteria to resume treatment are met, the subject should restart treatment at the next 
scheduled time point per protocol. However, if the treatment is delayed past the next 
scheduled time point per protocol, the next scheduled time points will be delayed until 
dosing resumes. 
 
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study 
therapy, except as specified in discontinuation section. 
 
 
 
 
8.1.3 Treatment of nivolumab or ipilimumab-related infusion reactions 
 
 
 
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such 
a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. 
 
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. 
Infusion reactions should be graded according to NCI CTCAE version 4 guidelines. 
 
Treatment of infusion reactions will follow Institutional standards. 
 
 
8.2 Management Algorithms for Platinum-based Chemotherapy 
 
 
Toxicities will be graded by using the NCI CTCAE version 4.0. Refer to the following 
website for the CTCAE manual or the CTCAE document: 
 
http://ctep.cancer.gov 
 
The dose modifications outlined below are considered general guidelines. The investigator 
should use his or her best judgment when determining treatment interruptions and dose 


11 January 2022 
Protocol: 2016-0982 
 
 
 
40 
 
modifications. For example, some grade 2 non-hematologic toxicities may require treatment 
delays and/or dose reductions, and some grade 3 or 4 organ toxicities (e.g., hepatic, renal, 
cardiac, central nervous system) may require a permanent treatment discontinuation. If one 
chemotherapy agent (docetaxel/pemetrexed or cisplatin) needs to be discontinued/delayed, the 
other chemotherapy agent (cisplatin or docetaxel/pemetrexed) or nivolumab may be continued 
or delayed at the discretion of the treating physician. In the event that both cisplatin and 
docetaxel or cisplatin and pemetrexed need to be permanently discontinued, nivolumab will 
also be permanently discontinued. Docetaxel or pemetrexed or cisplatin doses will not be re- 
escalated once they have been reduced for toxicity. 
 
 
8.2.1 Dose Modifications and Discontinuation Criteria of Platinum-based Chemotherapy 
 
Dose reductions of platinum doublet regimens may be required and will be performed 
according to Table 8.2A below. 
 
Table 8.2A: Dose Modifications for Platinum-Based Chemotherapy 
 
Dose Level 
Docetaxel 
Pemetrexed 
Cisplatin 
Carboplatin 
Starting dose 
75 mg/m2 
500 mg/m² 
75 mg/m² 
AUC 5 or 6 
First dose 
reduction 
75% of 
starting dose 
75% of starting 
dose 
75% of 
starting dose 
AUC 4 or 5 
Second dose 
reduction 
50% of 
starting dose 
50% of starting 
dose 
50% of 
starting dose 
AUC 3 or 4 
Third dose 
reduction 
Discontinue 
Discontinue 
Discontinue 
 Discontinue 
 
 
Any participants with 2 prior dose reductions for 1 agent who experiences a toxicity that 
would cause a third dose reduction must be discontinued from that agent. 
 
Dose Modifications for Docetaxel 
 
The dose of docetaxel will be reduced according to the following guidelines. 
 Thrombocytopenia 
 


11 January 2022 
Protocol: 2016-0982 
 
 
 
41 
 
 
• If grade 4 thrombocytopenia occurs, the dose of docetaxel will be reduced by 1 dose level for 
subsequent cycles. If grade 4 thrombocytopenia persists despite two dose reductions, docetaxel 
treatment will be discontinued. 
 
 
Neutropenia 
 
 
The dose of docetaxel will be reduced for the following neutropenic conditions as outlined 
in Table 8.2B: 
• Grade 4 neutropenia lasting ≥ 7 days 
 
• Grade 3 or 4 febrile neutropenia 
 
 
 
Table 8.2B: Docetaxel Dose Modifications for Neutropenia 
 
 
Dose Description 
Docetaxel Dose (mg/m2) 
starting dose 
75 mg/m2 (dose level 0) 
1st dose reduction due to neutropenia 
(patients not receiving prophylactic growth 
factor support) 
75 mg/m2 (dose level 0) 
add growth factor support 
1st dose reduction due to neutropenia 
(patients receiving prophylactic growth factor 
support) 
75% of starting dose (dose 
level -1) continue growth 
factor support 
2nd dose reduction due to neutropenia 
50% of starting dose (dose 
level -2) continue growth 
factor support 
 
 
If grade 4 neutropenia or grade 3-4 febrile neutropenia persists despite dose reduction to 
50 mg/m2 (dose level -2) with growth factor support, docetaxel treatment will be discontinued. 


11 January 2022 
Protocol: 2016-0982 
 
 
 
42 
 
 
 
Stomatitis 
 
• If grade 3 or 4 stomatitis occurs, the dose of docetaxel will be reduced by one dose level 
for subsequent cycles. If grade 3 or 4 stomatitis persists despite two dose reductions, 
docetaxel treatment will be discontinued. 
 
 
Peripheral Neuropathy 
 
• If grade 3, or clinically significant grade 2 (as judged by the investigator) neuropathy occurs, 
the dose of docetaxel will be reduced by one dose level. If grade 3, or clinically significant 
grade 2 (as judged by the investigator) neuropathy persists despite two dose reductions, 
docetaxel treatment will be discontinued. 
 
 
If grade 4 neuropathy occurs, docetaxel treatment will be discontinued. 
 
 
Hypersensitivity Reactions 
 
• There are no dose reductions for hypersensitivity reactions. Management of acute 
hypersensitivity reaction should follow the Institutional guidelines. Re-treatment with 
docetaxel will be allowed at the investigator’s discretion. 
 
• If grade 4 hypersensitivity reactions occur, docetaxel treatment will be discontinued. 
 
 
 
Fluid Retention 
 
• There are no dose reductions for fluid retention. 
 
 
Patients developing new onset edema, progression of existing edema, or another sign of 
fluid retention (e.g. 2 pound weight gain) are to be treated with oral diuretics. Regimens found 
to be effective in the management of fluid retention due to Taxotere are listed below. 
 
 


11 January 2022 
Protocol: 2016-0982 
 
 
 
43 
 
Triamterene/hydrochlorothiazide one capsule (37.5 mg / 25 mg) po qd up to tid. 
 
• Furosemide 40 mg po daily if edema progresses despite 
Triamterene/hydrochlorothiazide therapy. Potassium supplementation should be given as 
needed. 
 
• If after a two-week trial, furosemide 40 mg po qd is ineffective, the patient may be treated 
with furosemide 20 mg po daily plus metolazone 2.5 mg po daily with potassium 
supplementation as needed. 
 
 
Further therapy should be customized depending upon the clinical situation. The clinical 
tolerance of the patient, the overall tumor response and the medical judgment of the 
investigator will determine if it is in the patient’s best interest to continue or discontinue 
treatment. 
 
 
Liver Enzyme Elevation 
 
If liver enzyme elevations are considered to be related to docetaxel the algorithm in Table 
8.2C below should be followed: 
 
 
Table 8.2C: Docetaxel Dose Modification for Liver Enzyme Elevation: 
 
Total 
Bilirubin 
Alkaline 
Phosphatase 
SGOT      
or  
SGPT 
Action 
> ULN 
OR 
> 5 x ULN 
OR 
> 5 x ULN 
Delay treatment ≤3 
weeks until 
recovery. If 
recovered*, reduce 
docetaxel dose by 
25%. If not 
recovered in ≤3 
weeks, discontinue 
docetaxel. 


11 January 2022 
Protocol: 2016-0982 
 
 
 
44 
 
≤ ULN 
AND 
≤ 5 x ULN 
AND 
1.6 – 5 
x 
ULN 
Reduce 
docetaxel dose 
by 25% 
*Bilirubin ≤ULN and alkaline phosphatase ≤5 x ULN and SGOT or SGPT ≤5 x ULN 
Note: a maximum of two dose reductions per patient are allowed. If liver toxicities persist despite 
two dose reductions, docetaxel treatment will be discontinued. 
 
 
Other Non-Hematologic Toxicities 
 
If grade 3 or 4 clinically significant (as judged by the treating physician) non-hematologic 
toxicities occur (other than those listed above), docetaxel treatment will be withheld until 
the toxicity has resolved to ≤ grade 1 and then reinstituted (if medically appropriate) at the 
next lower dose level. If a grade 3 or 4 clinically significant toxicity recurs despite two dose 
reductions, docetaxel treatment will be discontinued. 
 
 
If treatment is delayed for > 3 weeks due to a grade 3 or 4 toxicity, docetaxel treatment will be 
discontinued. 
 
Dose Modifications for Cisplatin 
 
The dose of cisplatin will be reduced according to the following guidelines. 
 
Thrombocytopenia 
 
If grade 4 thrombocytopenia occurs, the dose of cisplatin will be reduced by 1 dose level for 
subsequent cycles. If grade 4 thrombocytopenia persists despite two dose reductions, cisplatin 
treatment will be discontinued. 
 
Neutropenia 
 
The dose of cisplatin will be reduced for the following neutropenic conditions as outlined in 
Table 8.2D below: 
• Grade 4 neutropenia lasting ≥ 7 days 
 
• Grade 3 or 4 febrile neutropenia 
 


11 January 2022 
Protocol: 2016-0982 
 
 
 
45 
 
 
Table 8.2D: Cisplatin Dose Modifications for Neutropenia 
 
Dose Description 
Cisplatin Dose (mg/m2) 
starting dose 
75 mg/m2 (dose level 0) 
1st dose reduction due to neutropenia 
(patients not receiving prophylactic growth 
factor support) 
75 mg/m2 (dose level 0) 
add growth factor support 
1st dose reduction due to neutropenia 
(patients receiving prophylactic growth factor 
support) 
75% of starting dose (dose 
level -1) continue growth 
factor support 
2nd dose reduction due to neutropenia 
50% of starting dose (dose 
level -2) continue growth 
factor support 
 
 
 
If grade 4 neutropenia or grade 3-4 febrile neutropenia persists despite dose reduction to 50 
mg/m2 (dose level -2) with growth factor support, cisplatin treatment will be discontinued. 
 
Other Non-Hematologic Toxicities 
 
If any grade 3 or 4 toxicity occurs that is consistent with the cisplatin side effect profile (e.g., 
renal toxicity manifested by BUN and serum creatinine elevation, tinnitus and audiologic 
impairment in the high frequency range [4000 to 8000 Hz], nausea and vomiting, 
hyperuricemia, moderate anemia, and irreversible peripheral neuropathy), the dose of cisplatin 
will be reduced by one dose level. If toxicities persist despite two dose reductions, cisplatin 
treatment will be discontinued. 
 
 
Dose Modifications for Pemetrexed 
 
Patients will be monitored closely for toxicity and the dose of pemetrexed may be adjusted as 
indicated in Table below. Pemetrexed dose reductions are permanent; once the dose is 


11 January 2022 
Protocol: 2016-0982 
 
 
 
46 
 
reduced, it may not be re-escalated in subsequent cycles. 
The dose of pemetrexed will be reduced for the following neutropenic conditions as outlined 
in Table 8.2E below: 
• Grade 4 neutropenia lasting ≥ 7 days 
 
• Grade 3 or 4 febrile neutropenia 
 
 
 
Table 8.2E: Pemetrexed Dose Modifications for Neutropenia 
 
Dose Description 
Pemetrexed Dose (mg/m2) 
starting dose 
500 mg/m2 (dose level 0) 
1st dose reduction due to neutropenia 
(patients not receiving prophylactic growth factor 
support) 
500 mg/m2 (dose level 0) 
add growth factor support 
1st dose reduction due to neutropenia 
(patients receiving prophylactic growth factor 
support) 
75% of starting dose (dose 
level -1) continue growth 
factor support 
2nd dose reduction due to neutropenia 
50% of starting dose (dose 
level -2) continue growth 
factor support 
  
Thrombocytopenia 
 
If grade 4 thrombocytopenia occurs, the dose of pemetrexed will be reduced by 1 dose level 
for subsequent cycles. If grade 4 thrombocytopenia persists despite two dose reductions, 
pemetrexed treatment will be discontinued. 
 
Renal toxicity 
Discontinue pemetrexed if creatinine clearance < 45 mL/min. 
 
Other Non-Hematologic Toxicities 
 
If any grade 3 or 4 toxicity occurs that is consistent with the pemetrexed side effect profile 
(e.g., fatigue, skin rash and/or desquamation and/or pruritus, increased ALT and AST, nausea 


11 January 2022 
Protocol: 2016-0982 
 
 
 
47 
 
and vomiting, anorexia, stomatitis, diarrhea, moderate anemia, pharyngitis, edema, 
neuropathy, hypersensitivity reaction, conjunctivitis, constipation) the dose of pemetrexed will 
be reduced by one dose level. If toxicities persist despite two dose reductions, pemetrexed 
treatment will be discontinued. 
 
 
Dose Modifications for Carboplatin 
 
For the following hematologic toxicities the investigator must modify the carboplatin dose as 
detailed below: 
 
Neutrophil Count Decreased Grade 4 (< 500/mm3 or < 0.5 x 109/L): Reduce one dose 
level and consider prophylactic GCSF in subsequent cycles 
Platelet Count Decreased Grade 3 (25,000 to < 50,000/mm3; 25.0 to < 50.0 x 109/L): Reduce 
one dose Level 
Platelet Count Decreased Grade 4 (< 25,000/mm3; < 25.0 x 109/L): Reduce one dose level 
Hemoglobin decreased Grade 2 (< 10.0 to 8.0 g/dL; < 6.2 to 4.9 mmol/L; < 100 - 80 g/L): 
Reduce one dose level 
Hemoglobin decreased Grade 3 (< 8.0 g/dL; < 4.9 mmol/L, < 80 g/L): Reduce one dose 
level 
Hemoglobin decreased Grade 4 (Life-threatening consequences): Hold drug  
 
For the following non-hematologic toxicities the investigator must modify the carboplatin dose 
as detailed below: 
Febrile Neutropenia Grade ≥ 3 Reduce one dose level 
Diarrhea Grade ≥ 3 No change  
Allergic reactiona Grade ≥ 3 Discontinue  
Neuropathy Grade 2 No change 
Neuropathy Grade ≥ 3 Discontinue  
Calculated creatinine clearance < 50 mL/min Discontinue if creatinine clearance < 20 mL/min 
Other Grade ≥ 3 toxicity (except for fatigue and transient arthralgia and myalgia). 
8.2.2 Re-treatment Criteria for Platinum-based Chemotherapy 
 
Prior to receiving any dose of docetaxel or pemetrexed and cisplatin, patients must have an 
 
ANC ≥1.5 X 109/Land a platelet count ≥100 X 109/L; calculated creatinine clearance must be 
≥45 mL/min or according to institutional standard practices for treatment with pemetrexed and 
cisplatin. If the ANC is < 1.5 X 109/L and platelet count is < 100 X 109/L, the treatment should be 
delayed for ≤ 3 weeks. If the patient is unable to be treated after a 3-week delay, the patient will 
be discontinued from chemotherapy. Patients who have temporarily discontinued chemotherapy 
will be allowed to continue on nivolumab, at the discretion of the treating physician. 


11 January 2022 
Protocol: 2016-0982 
 
 
 
48 
 
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11 January 2022 
Protocol: 2016-0982 
 
 
 
49 
 
bronchospasm, diarrhea, colitis, neurologic adverse event, hypersensitivity reactions, 
and infusion reactions 
 
• 
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic 
adverse event, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation 
 
• 
Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except those noted below 
 
• 
Grade 3 drug-related thrombocytopenia > 7 days or associated with 
bleeding requires discontinuation 
 
• 
Any drug-related liver function test (LFT) abnormality that meets the 
following criteria require discontinuation: 
 
• 
AST or ALT > 8 x ULN 
 
• 
Total bilirubin > 5 x ULN 
 
• 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
 
• 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
 
• 
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. 
 
• 
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 
 
• 
Any dosing interruption lasting > 6 weeks with the following exceptions: 
 
Dosing interruptions to allow for prolonged steroid tapers to manage drug- 
related adverse events are allowed. Prior to re-initiating treatment in a subject 
with a dosing interruption lasting > 6 weeks, the Principal Investigator must be 
consulted. Tumor assessments should continue as per protocol even if dosing is 
interrupted 


11 January 2022 
Protocol: 2016-0982 
 
 
 
50 
 
 
• 
Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be 
allowed if approved by the Investigator. Prior to re-initiating treatment in a 
subject with a dosing interruption lasting > 6 weeks, the Investigator must be 
consulted. Tumor assessments should continue as per protocol even if dosing is 
interrupted 
 
• 
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 or ipilimumab dosing 
 
If a patient discontinues treatment early, every attempt should be made to keep the patient in 
the study and perform the required End of Treatment assessments and Long-Term Follow-up 
Information. 
 
NOTE: If a subject meets criteria for discontinuation and investigator is unable to determine 
whether the event is related to nivolumab, ipilimumab or chemotherapy (if chemotherapy is part 
of the treatment regimen), the subject should discontinue nivolumab, ipilimumab and 
chemotherapy (if chemotherapy is part of the treatment regimen), and be taken off the treatment 
phase of the study. Continuation of ipilimumab after discontinuation of nivolumab is not allowed 
on study. The assessment for discontinuation of nivolumab and ipilimumab should be made 
separately from the assessment made for discontinuation of chemotherapy doublet. If criteria for 
discontinuation for nivolumab and ipilimumab are met before the nivolumab and ipilimumab 
plus platinum doublet chemotherapy cycles have been completed, platinum doublet 
chemotherapy may continue to the discretion of the treating physician. 
 
If the investigator is unable to determine whether an adverse event is due to nivolumab or 
ipilimumab or platinum doublet chemotherapy, then all drugs must be discontinued.  
 
A subject who is discontinued from the chemotherapy treatment due to toxicities related to 
chemotherapy only, may remain on the study and receive nivolumab therapy only at the 
discretion of the treating physician. 
 
If any adverse event meeting the dose delay criteria for chemotherapy is felt to be related to only 
one particular agent in the platinum doublet chemotherapy regimen, then that 
chemotherapy agent alone may be omitted for that cycle while the other agents are given. Dosing 
of nivolumab and both chemotherapy agents should be delayed if criteria for nivolumab or “both 
platinum-doublet chemotherapy agents” are met. 
 
Concomitant Medication(s) During Platinum-Based Chemotherapy 


11 January 2022 
Protocol: 2016-0982 
 
 
 
51 
 
 
Anticancer therapy with agents other than cisplatin/pemetrexed or cisplatin/docetaxel and I-
O agents is not allowed. Medications intended solely for supportive care (ie, anti-emetics, 
analgesics, megestrol acetate for anorexia) are allowed. NSAIDs with long half-lives, eg, 
>10 hours, should be discontinued at least 5 days before, the day of and 2 days following 
pemetrexed dosing. Patients who take NSAIDs concomitantly with pemetrexed should be 
monitored closely for toxicity, especially myelosuppression, renal and gastrointestinal 
toxicity. 
 
 
 
 


11 January 2022 
Protocol: 2016-0982 
 
 
 
52 
 
    9 STUDY ASSESSMENTS AND PROCEDURES 
 
 
Baseline evaluation: 
 
Investigations 
Timing 
History and Physical 
Exam including: 
• Treatment history 
• Vital signs 
• Medical history 
• ECOG PS 
• Smoking history 
• TNM stage 
• Height and weight 
Within 14 days    
prior to treatment 
initiation 
Current Smoking Status 
and Tobacco Use 
• Assessment of patient’s current 
smoking status and tobacco use 
Within 14 days 
prior to 
randomization 
Symptoms & Toxicities 
• Evaluation and documentation of 
symptoms and toxicities using the NCI 
CTCAE v4.0 
Within 14 days 
prior to treatment 
initiation 
Concomitant Medications 
• Documentation of concomitant medications Within 14 days 
prior to treatment 
initiation 
Hematology and 
Coagulation 
• 
CBC with hemoglobin, platelets, and 
W BC with differential 
• 
Prothrombin time (PT) / 
Partial thromboplastin time 
(PTT) 
Within 14 days 
prior to treatment 
initiation 
Biochemistry 
• Albumin 
• Glucose 
• Alkaline 
• LDH 
phosphatase 
• Potassium 
• Total bilirubin, 
• SGOT (AST) 
direct, indirect 
• SGPT (ALT) 
• BUN 
• Sodium 
• Creatinine 
• Magnesium 
• Total protein 
• Uric acid 
• Free T4, TSH 
Within 14 days 
prior to treatment 
initiation 
Pregnancy Test 
• 
Urine or serum (for women of 
childbearing potential only) 
Within 48 hours prior 
to treatment initiation 


11 January 2022 
Protocol: 2016-0982 
 
 
 
53 
 
Radiology 
• 
CT chest 
Within 30 days 
prior to treatment 
initiation 
Radiology 
• 
PET-CT 
Within 60 days 
prior to treatment 
initiation 
Radiology 
• 
MRI brain or CT brain (only for 
patients with stage II or III on pre-
operative staging) 
Within 60 days 
prior to treatment 
initiation 
Mediastinal staging 
• 
CT chest / PET-CT, 
mediastinoscopy, and/or 
endobronchial ultrasound 
Within 60 days 
prior to treatment 
initiation 
Pulmonary tests 
• 
Complete pulmonary function test2 
• 
6-Minute Walk Test3 
Prior to treatment 
initiation 
Tumor Tissue Collection 
for Biomarkers 
• 
Archival tissue or new biopsy of 
primary tumor for biomarker 
analysis (optional) 
• 
Tissue obtained for mediastinal 
staging (optional) 
Prior to treatment 
initiation 
Blood-based  biomarkers 
• 
Blood sample 
Prior to treatment 
initiation 
Stool-based Microbiome 
• 
Stool sample 
Prior to 
treatment 
initiation 
1 If information / studies have already been obtained but chemotherapy is delayed for any reason, repeated 
studies are not necessary prior to next cycle of chemotherapy.  
2Complete pulmonary function test may not be required if patient is no longer considered a surgical 
candidate post immunotherapy plus chemotherapy based on the treating physician’s discretion.  
3 This test is encouraged and not mandatory. Before the 6MWT: The patient should rest for at least 15 
minutes before beginning the 6MWT. Record: Blood pressure, Heart rate, Oxygen saturation (SpO2), 
Respiratory rate At the End of the 6MWT: Put a marker on the distance walked, Seat the patient or, if the 
patient prefers, allow to the patient to stand, Immediately record oxygen saturation (SpO2)%, heart rate and 
respiratory rate.   
 
 
 
 
 
 


11 January 2022 
Protocol: 2016-0982 
 
 
 
54 
 
Evaluation during neoadjuvant treatment (prior to each nivolumab 
single agent infusion- ARM A and B): 
 
 
Investigations 
Timing 
Physical Exam 
Including: 
• BSA 
• Vital signs 
Within 7 days prior to dose #2 
and #3 of nivolumab 
Hematology 
• 
CBC with hemoglobin, platelets, 
and WBC with differential 
Within 7 days prior to dose #2 
and #3 of nivolumab 
Biochemistry1 
• Albumin 
• 
Alkaline 
phosphatase 
• Total 
bilirubin, 
direct, 
indirect 
• BUN 
• Creatinine 
• Total protein 
• Free T4, TSH 
• Glucose 
• LDH 
• Potassium 
• SGOT (AST) 
• SGPT (ALT) 
• Sodium 
• Magnesium 
• Uric acid 
Within 7 days prior to dose #2 
and #3 of nivolumab 
Radiology 1 
• 
CT chest 
• 
PET-CT 
At least 14 days after the last dose 
of immunotherapy 
Symptoms & 
Toxicities 
• 
Evaluation and documentation of 
symptoms and toxicities using the 
NCI CTCAE v4.0 
On an ongoing basis throughout 
the study until the final study 
visit 


11 January 2022 
Protocol: 2016-0982 
 
 
 
55 
 
Concomitant 
Medications 
• 
Documentation of 
concomitant medications 
On an ongoing basis throughout 
the study until the final study 
visit 
Blood-based 
biomarkers1 
• Blood sample 
Within 7 days prior to dose #2 
and #3 of nivolumab and at least 
14 days after the last dose of 
immunotherapy 
Pulmonary  tests 
• 
Complete pulmonary function test2 
 
At least 14 days after the last dose 
of immunotherapy 
Stool-based 
Microbiome 
• 
Stool sample 
At least 14 days after the last 
dose of immunotherapy 
1 If information / studies have already been obtained but chemotherapy is delayed for any reason, repeated studies are not 
necessary prior to next cycle of chemotherapy. 
2Complete pulmonary function test may not be required if patient is no longer considered a surgical candidate post 
immunotherapy based on the treating physician’s discretion.  
 
 
 
Evaluation during neoadjuvant treatment (prior to each I-O agent/s plus platinum-based 
chemotherapy infusion- ARM C and ARM D): 
Investigations 
Timing 
Physical Exam 
Including: 
• BSA 
• Vital signs 
Within 7 days prior to 
cycles 2- 3, and at least 14 
days after the last cycle of 
chemotherapy and 
immunotherapy 
Hematology 
• 
CBC with hemoglobin, platelets, 
and WBC with differential 
Within 7 days prior to cycles 2-
3, and at least 14 days after the 
last cycle of chemotherapy and 
immunotherapy 


11 January 2022 
Protocol: 2016-0982 
 
 
 
56 
 
Biochemistry1 
• Albumin 
• 
Alkaline 
phosphatas
e 
• Total 
bilirubin, 
direct, 
indirect 
• BUN 
• Creatinine 
• Total protein 
• Free T4, TSH 
• Glucose 
• LDH 
• Potassium 
• SGOT (AST) 
• SGPT (ALT) 
• Sodium 
• Magnesium 
• Uric acid 
Within 7 days prior to cycles 
2-3, and at least 14 days after 
the last cycle of 
chemotherapy and 
immunotherapy 
Radiology 1 
• 
CT chest 
• 
PET-CT 
At least 14 days after the 
last cycle of 
chemotherapy and 
immunotherapy 
Symptoms & 
Toxicities 
• 
Evaluation and documentation of 
symptoms and toxicities using the 
NCI CTCAE v4.0 
On an ongoing basis 
throughout the study until 
the final study visit 
Concomitant 
Medications 
• 
Documentation of 
concomitant medications 
On an ongoing basis 
throughout the study until 
the final study visit 
Blood-based 
biomarkers1 
• Blood sample 
Within 7 days prior to cycle 
#2 and #3 of chemotherapy 
and nivolumab and at least 14 
days after the last dose of 
immunotherapy 
Pulmonary tests 
• 
Complete pulmonary function test2 
• 
6-Minute Walk Test3 
At least 14 days after the 
last dose of chemotherapy 
and immunotherapy 


11 January 2022 
Protocol: 2016-0982 
 
 
 
57 
 
Stool-based 
Microbiome 
• 
Stool sample 
At least 14 days after the 
last dose of chemotherapy 
and immunotherapy 
1 If information / studies have already been obtained but chemotherapy is delayed for any reason, repeated 
studies are not necessary prior to next cycle of chemotherapy.  
2Complete pulmonary function test may not be required if patient is no longer considered a surgical 
candidate post immunotherapy plus chemotherapy based on the treating physician’s discretion.  
3 This test is encouraged and not mandatory. Before the 6MWT: The patient should rest for at least 15 
minutes before beginning the 6MWT. Record: Blood pressure, Heart rate, Oxygen saturation (SpO2), 
Respiratory rate At the End of the 6MWT: Put a marker on the distance walked, Seat the patient or, if the 
patient prefers, allow to the patient to stand, Immediately record oxygen saturation (SpO2)%, heart rate and 
respiratory rate.   
 
Assessments at surgery: 
 
Investigations 
Timing 
Surgical procedure 
• Title of operation 
• 
Status of resection margins 
(R0, R1, R2) 
Through chart review 
• 
pTNM 
• 
Major pathologic response 
• 
Percentage of viable tumor cells 
• 
Nodal stations dissected / 
sampled and nodal status 
(positive vs. negative) at 
each station 
• 
Evaluation of extra-capsular 
nodal spread 
 
 
 
 
 
 
 


11 January 2022 
Protocol: 2016-0982 
 
 
 
58 
 
End of treatment assessments: 
 
Investigations 
Timing 
Physical 
Exam 
• Vital Signs 
Approximately within 8 weeks after 
surgery 
Blood-based 
biomarkers 
• Blood sample 
Approximately within 8 weeks after 
surgery 
Symptoms & 
Toxicities 
• 
Evaluation and documentation of 
symptoms and toxicities using 
the NCI CTCAE v4.0 
• 
Retrospective evaluation of any 
Approximately within 8 weeks after 
surgery 
 
 
Long-term follow-up 
 
After the End of Treatment evaluation, information on additional oncologic treatment 
(including post-operative systemic therapy and radiation therapy), time to disease 
progression/recurrence, sites of recurrence, development of second primary tumors, 
additional therapy for recurrence, long-term survival, and other relevant clinical data will 
be obtained. Patients (or their family members or designees) may be contacted by 
telephone or in writing or by electronic mail or during clinic visits after treatment 
discontinuation for collection of long-term follow-up data. Long-term follow-up clinical 
information may also be obtained through chart reviews. 
 
Long-term follow up will be conducted as long as needed to obtain relevant 
information for accurate interpretation of the study. No pre-specified time frame is 
defined. 
 
 
9.1 Description of Study Assessments 
 
 
9.1.1 Performance status 
 
The performance status of all patients will be graded according to the ECOG PS scale. 


11 January 2022 
Protocol: 2016-0982 
 
 
 
59 
 
9.1.2 Clinical laboratory tests 
 
Clinical laboratory tests will be performed to assess eligibility for enrolment and will 
be repeated according to Tables included in this section. 
 
Laboratory tests can be repeated more frequently, if clinically indicated. 
 
 
9.1.3 Symptoms and toxicity assessment 
 
The symptoms and adverse events of all patients will be graded at scheduled intervals according 
to the NCI CTCAE, v4.0. Patients will be monitored continuously throughout the study for the 
occurrence of adverse events. Planned medical interventions (e.g., planned surgical resection) 
will not be considered an adverse event. For the purpose of this study, adverse events that in the 
opinion of the treating investigator are related to planned surgical procedure (e.g., usual pain, 
usual bleeding, intra- or post-operative electrolyte imbalances and other clinically insignificant 
laboratory abnormalities) will not be captured and/or reported. Unexpected surgical 
complications will be retrospectively reviewed at the end of treatment assessments. 
 
 
9.1.4 Radiology assessments 
 
CT chest, PET-CT, and CT brain / MRI brain will be obtained according to Tables included 
in this section. CT chest examinations maybe obtained with dual energy modality. 
 
Response and progression will be evaluated in the study using the international criteria 
proposed by the RECIST committee,30 and preferably by the same investigator or 
collaborator. 
 
Patients enrolled to this study may also be offered optional participation in a separate IRB- 
approved protocol evaluating additional imaging modalities for NSCLC. An independent 
informed consent process will be followed for accrual to such protocol. 
 
9.1.5 Mediastinal staging 
 
Mediastinal staging should be accomplished by obtaining at least a CT chest or PET-CT. It is 
recommended that patients with suspicious mediastinal lymph node involvement by PET-CT 
and/or CT chest undergo a mediastinoscopy or endobronchial ultrasound with biopsies for more 
detailed mediastinal staging. It is also strongly recommended that patients with clinical N1 
disease and/or central tumors undergo mediastinoscopy or endobronchial ultrasound with 


11 January 2022 
Protocol: 2016-0982 
 
 
 
60 
 
biopsies. Patients with clinical N0 disease and a peripheral lesion may not warrant 
mediastinoscopy or endobronchial ultrasound with biopsies. 
 
 
9.1.6 Tumor tissue samples 
 
Archival tissue samples will be collected for histopathological examination and biomarkers, 
when available (at least 20 unstained slides and/or a tissue block are preferred). A new 
baseline tumor tissue sample from the primary tumor may be collected for histopathological 
examination and biomarkers. Samples will be obtained by an outpatient image-guided biopsy 
procedure (preferably core biopsy) or bronchoscopy. These specimens should be fixed in 10% 
formalin, preferably immediately and not more than 1 (one) hour after excision. Fixed biopsy 
samples will be processed for paraffin-embedding according to the Institutional Standard 
Operating Procedures. The paraffin blocks and slides should be labeled with the protocol 
number and the patient’s unique study identification number and stored at room temperature. 
A portion of the specimen obtained (or a second biopsy) will also be embedded in optimal 
cutting temperature compound and/or RNA later and/or culture media immediately after 
received and not more than 1 (one) hour after excision, frozen, and processed and/or stored at 
-80 oC for future biomarker analysis. All samples stored at -80 oC should be placed in 
appropriate containers, labeled with the protocol number and the patient’s unique study 
identification number. 
 
Tissue obtained during mediastinal staging may also be collected for biomarker evaluation. 
 
Tumor tissue will also be obtained at surgical resection. The recommended procedure for 
obtaining the tissue specimens is as follows: a portion of the resected tumor tissue will be 
fixed in 10% formalin immediately after received and not more than 1 (one) hour after 
excision. Fixed samples will be processed for paraffin-embedding according to the 
Institutional Standard Operating Procedures. The paraffin blocks and slides should be labeled 
with the protocol number and the patient’s unique study identification number and stored at 
room temperature. Another portion of the tumor specimen (preferably at least one sample ≥ 2 
mm3 or 100 mg) will be embedded in optimal cutting temperature compound and/or RNA 
later and/or culture media immediately after received and not more than 1 (one) hour after 
excision, frozen and processed and/or stored at -80 oC for biomarker analysis. The freshly 
collected tumor tissues with or without adjacent lung tissue samples placed in culture media 
immediately after received will be processed for single cell suspension for single cell genomics 
(37). Each cell will be bar-coded using 10x genomics technology (or other equivalent 
technologies) and libraries (RNA, DNA, or epigenomics) for sequencing. The sequenced data 
will be analyzed and we plan to associate sequencing data with clinical parameters. The 


11 January 2022 
Protocol: 2016-0982 
 
 
 
61 
 
remaining specimens resected during surgery will be used for routine histopathological 
diagnosis and will also be stored for future biomarker studies. Normal lung tissue uninvolved 
by tumor and/or normal lymph node tissue uninvolved by tumor may also be collected and 
processed / stored as above, for biomarker evaluation. 
 
The surgical specimens will be evaluated for pathologic staging (pTNM) according to the 
AJCC 7th edition, pathologic complete response, quantification of percentage of viable tumor 
cells, status of resection margins, number of lymph nodes removed at each level, number of 
lymph nodes positive for cancer at each level, presence of extra-capsular nodal spread. To 
determine the pathologic response, specimens will be grossed and processed by the thoracic 
pathologist. The entire specimen measurement and the size of visible residual tumor will be 
documented. At least 1 block/1 cm of tumor will be submitted (average of 5-10 
blocks/patient). All slides prepared from blocks taken from each specimen will be reviewed by 
the thoracic pathologist, as well as slides from each dissected lymph node. 
 
Sample sharing: In some cases samples may be sent to or received from outside 
collaborators such as Broad Institute for next-generation sequencing and/or analysis.  All 
samples will be sent under a specific contract or Material Transfer Agreement (MTA).  We 
will protect participant’s privacy by coding samples and keeping the master list of identifiers 
accessible to only key project staff.  Data will be kept on secure computers and samples will 
be kept in freezers in locked laboratories and buildings.  Additionally in some other cases, 
samples may be provided from outside collaborators or institutions for discovery and 
research purposes. In such cases, the samples should be obtained under IRB-approved 
protocols at these outside collaborators and institutions to allow them for participation in this 
protocol and under a specific grant/ contract or Material Transfer Agreement (MTA) with 
MD Anderson Cancer Center. 
 
Internal/External Sequencing may be done here at MD Anderson, in one of the Core labs 
such as Cancer Genomics Lab, but in some cases samples may be sent to outside 
collaborators for sequencing and/or analysis such as Broad Institute.  Sequencing performed 
by Broad or any other external collaborator will be conducted under specific contract or 
Material Transfer Agreement (MTA).     
 
Data Sharing:  Researchers can do more powerful studies when they share with each other 
the information they get from studying human samples.  NGS data may be placed in a local 
M.D. Anderson Institutional Data Repository, commonly referred to as BigData; where both 
deposition of and access to data require governance and approval.   In some cases, grant 
requirements may require deposition of large-scale data into the public Genotypes and 
Phenotypes database (dbGaP) an access controlled database overseen by the National Center 
for Biotechnology Information (NCBI).  In other cases peer reviewed Journals may require 


11 January 2022 
Protocol: 2016-0982 
 
 
 
62 
 
data to be shared through a resource such as dbGaP.  Data submitted to those repositories 
will only be shared in a de-identified fashion and without associated clinical data or 
identifiers. This data will be used only for research purposes, and the data elements collected 
and analyzed   will only be those that are necessary to conduct this research. 
 
Database access additional protections: The precedent to publically broadcast sequence data 
has been set by large consortial projects, such as The Cancer Genome Atlas (TCGA) and the 
Encyclopedia of DNA Elements (ENCODE), in order to maximize data utility.   However, 
we know there is the potential for privacy risks associated with the release of sequence data 
to databases and while the risk may be small it could grow in the future as technology 
advances.  To minimize this potential, we will implement good faith efforts to ensure patient 
confidentiality and reduce patient exposure.   The database of Genotypes and Phenotypes 
and others like it are extremely access restricted.  Only authorized researchers may deposit 
or access the data and either or both efforts require MD Anderson institutional approval.  
Sequence data will only be broadcast through secure transmission processes.  All samples 
will be de-identified with access to the linking table available only to the MD Anderson PI 
and his/her designees.  Only non-identifiable data will be deposited to dbGaP i.e., no linking 
table or access to a linking table will be available.  Research records will be kept separate 
from medical records and patients will not have access to any of the research data. 
 
Protected health information (PHI) may be collected from medical records that are related to 
health and/or disease history including test results, medical procedures, and images (such as 
X-rays) in addition demographic and environmental factors may be requested. Researchers 
will use this information to better understand how genes affect health and response to 
treatment.   All samples will be de-identified with access to the linking table available only 
to the MD Anderson PI and his/her designees.   
 
 
9.1.7 Blood-based biomarkers 
 
Blood will be collected (60 mL), at scheduled intervals according to Tables 9-1 to 9-5 for 
plasma and blood cells separation and storage. Samples from the main campus will be 
forwarded to the core laboratory to be processed. Samples from the Regional Care Centers 
(Katy, Sugarland, Bay Area, and Woodlands) will be collected and placed in ice-bags for 
delivery to the core laboratory preferably by 3 PM on the day it is collected. 
 
 
9.1.8 Stool-based biomarkers 
 
Patients will provide their stool samples as detailed in the tables above.  Stool collection will 


11 January 2022 
Protocol: 2016-0982 
 
 
 
63 
 
be performed with commercially available collection kits from DNA Genotek company. 
These kits will be provided to patients at no cost. 
 
 
9.1.9 CT imaging-based biomarkers 
 
The imaging data will be saved to retrospectively reconstruct and post-process the images for 
further investigating advanced quantitative algorithms with the goal to improve detection and 
characterization of disease along with potential biomarkers to assess response to immune 
checkpoint blockade. 
 
 
9.1.10 Long-term follow-up 
 
After the End of Treatment evaluation, information on additional oncologic treatment 
(including post-operative systemic therapy and radiation therapy), time to disease 
progression/recurrence, sites of recurrence, development of second primary tumors, additional 
therapy for recurrence, long-term survival, and other relevant clinical data will be obtained. 
Patients (or their family members or designees) may be contacted by telephone or in writing or 
by electronic mail or during clinic visits after treatment discontinuation for collection of long-
term follow-up data. Long-term follow-up clinical information may also be obtained through 
chart reviews. 
 
 
9.1.11 Assessments for premature discontinuation from study 
 
If a patient discontinues treatment early, every attempt should be made to keep the patient in 
the study and perform the required End of Treatment assessments and to obtain Long-Term 
Follow-up Information. 
 
10 TISSUE AND BLOOD SAMPLE REPOSITORY 
 
As part of the study, a tissue and blood sample repository will be created. The objective of this 
tissue sample repository will be to provide material for the correlative studies proposed to 
evaluate the endpoints proposed (including primary, secondary, exploratory endpoints and 
additional assessments previously described in this protocol), and for future evaluations of 
other relevant biomarkers that may be associated with clinical outcomes. A written informed 
consent will be obtained from patients enrolled in this study so that these samples may be 
analyzed in the future for biomarkers not described in this protocol. 
 


11 January 2022 
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11 January 2022 
Protocol: 2016-0982 
 
 
 
65 
 
11 ADVERSE EVENT COLLECTION AND REPORTING 
 
All Serious Adverse Events (SAEs) that occur upon the subject’s first protocol specific 
intervention on this study through 100 days of discontinuation of dosing must be reported to 
BMS Worldwide Safety. 
 
 
In accordance with local regulations, BMS will notify investigators of all reported SAEs that are 
suspected (related to the investigational product) and unexpected (i.e., not previously described 
in the IB). In the European Union (EU), an event meeting these criteria is termed a Suspected, 
Unexpected Serious Adverse Reaction (SUSAR). Investigator notification of these events will be 
in the form of an expedited safety report (ESR). 
 
 
Other important findings which may be reported by BMS as an ESR include: increased 
frequency of a clinically significant expected SAE, an SAE considered associated with study 
procedures that could modify the conduct of the study, lack of efficacy that poses significant 
hazard to study subjects, clinically significant safety finding from a nonclinical (eg, animal) 
study, important safety recommendations from a study data monitoring committee, or sponsor 
decision to end or temporarily halt a clinical study for safety reasons. 
 
 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with the 
IB. Where required by local regulations or when there is a central IRB/IEC for the study, the 
sponsor will submit the ESR to the appropriate IRB/IEC. The investigator and IRB/IEC will 
determine if the informed consent requires revision. The investigator should also comply with 
the IRB/IEC procedures for reporting any other safety information. 
 
 
In addition, suspected serious adverse reactions shall be reported by BMS to the relevant 
competent health authorities in all concerned countries according to local regulations (either as 
expedited and/or in aggregate reports). 
 
11.1 Definitions 
 
11.1.1 Adverse events 
 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered an investigational 
(medicinal) product and that does not necessarily have a causal relationship with this treatment. 


11 January 2022 
Protocol: 2016-0982 
 
 
 
66 
 
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. 
 
For the purpose of this study, adverse events that in the opinion of the treating investigator are 
related to planned surgical procedure (e.g., usual pain, usual bleeding, intra- or post-operative 
electrolyte imbalances and other clinically insignificant laboratory abnormalities) will not be 
captured and/or reported. 
 
Attribution or the causal relationship to study drug is determined by a physician and should be 
used to assess all adverse events (AE). The casual relationship can be one of the following: 
 
 
Related: There is a reasonable causal relationship between study drug administration and the 
AE.  The term "reasonable causal relationship" means there is evidence to suggest causal 
relationship. There are three attributions listed for related to investigational agent/intervention: 
 
 
• 
Possible- The AE may be related to the intervention 
 
• 
Probable-The AE is likely related to the intervention 
 
• 
Definite- The AE is clearly related to the intervention 
 
 
Not related (unrelated): There is not a reasonable causal relationship between study drug 
administration and the AE. There are two attributions listed for unrelated to investigational 
agent or intervention: 
 
 
• 
Unrelated-The AE is clearly NOT related to the intervention 
 
• 
Unlikely-The AE is doubtfully related to the intervention 
 
Adverse events that will be captured in this study consist 
of: 
 
• 
adverse events grades 3, 4, and 5 regardless of relationship or attribution 
• 
adverse events grades 1 and 2 that are possibly, probably or definitely related to 
treatment 


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Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not 
be questioned regarding the specific occurrence of one or more AEs.) 
 
 
11.1.2 Serious adverse events 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 
 
• 
Death 
 
• 
A life-threatening adverse drug experience – any adverse experience that places 
the patient, in the view of the initial reporter, at immediate risk of death from the 
adverse experience as it occurred. It does not include an adverse experience that, 
had it occurred in a more severe form, might have caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
 
• 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• 
A congenital anomaly/birth defect. 
 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
 
 
Potential drug induced liver injury (DILI) is also considered an important medical event. 
 
 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE. 


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Although pregnancy, overdose, and cancer are not always serious by 
regulatory definition, these events must be handled as SAEs. 
 
 
Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
 
 
NOTE: 
 
The following hospitalizations are not considered SAEs: 
 
 
 
• 
a visit to the emergency room or other hospital department < 72 hours, that does not 
result in admission (unless considered an important medical or life-threatening event) 
 
 
• 
elective surgery, planned prior to signing consent 
 
 
• 
admissions as per protocol for a planned medical/surgical procedure 
 
 
 
• 
routine health assessment requiring admission for baseline/trending of 
health status (eg, routine colonoscopy) 
 
 
• 
Medical/surgical admission other than to remedy ill health and planned prior 
to entry into the study. Appropriate documentation is required in these cases 
 
 
• 
Admission encountered for another life circumstance that carries no bearing 
on health status and requires no medical/surgical intervention (eg, lack of 
housing, economic inadequacy, caregiver respite, family circumstances, 
administrative reason). 


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11.2 Serious Adverse Event and Pregnancy Reporting 
 
11.2.1 Serious Adverse Event Reporting 
 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“The University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy 
for Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and Devices”. 
Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported to 
the IND Office, regardless of attribution (within 5 working days of knowledge of the event). 
 
 
SAEs, whether related or not related to study drug, must be reported to BMS within 24 
hours. SAEs must be recorded on BMS approved form. 
 
SAE Email Address: Worldwide.Safety@BMS.com 
 
 
SAE Facsimile Number: 609-818-3804 
 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports should include the same investigator term(s) initially reported.) 
 
 
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 the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report. 
 
 
All SAEs should be followed to resolution or stabilization. 
 
 
The principal investigator will ensure that all SAEs in the clinical database are reported to 
BMS and any applicable health authority during the conduct of the study. This reconciliation 
will occur at least quarterly and be initiated by the principal investigator. The principal 
investigator will request a reconciliation report from: aepbusinessprocess@bms.com. 
 
 
During reconciliation, any events found to not be reported previously to BMS must be sent 


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to Worldwide.Safety@BMS.com. 
 
 
SAEs will be reported on the BMS approved form for prompt reporting (full form): 
 
“Internal SAE Report Form for Prompt Reporting” Institutional Review Board. 
 
SAEs will be submitted to both the Office of Protocol Research, Unit 1437 at The University of 
Texas MD Anderson Cancer Center and also sent to: 
 
 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
 
 
All SAEs should simultaneously be faxed or e-mailed to: 
BMS at: Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb 
Company Fax Number: 
609- 818-3804 
Email: Worldwide.safety@bms.com 
 
 
An SAE report should be completed for any event where doubt exists regarding its 
seriousness. 
 
 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a 
study procedure), the relationship should be specified in the narrative section of the SAE 
Report Form. 
 
 
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new 


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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. All SAEs should be followed to 
resolution or stabilization. 
 
 
• 
All life-threatening or fatal events, that are unexpected, and related to the study 
drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in the IND Office. 
• 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized 
for safety reporting to the IND Office and MDACC IRB. 
• 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 100 days after the last dose of drug, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical 
recovery is complete and laboratory tests have returned to baseline, progression of 
the event has stabilized, or there has been acceptable resolution of the event. 
• 
Additionally, any serious adverse events that occur after the 100 day time period that 
are related to the study treatment must be reported to the IND Office. This may include 
the development of a secondary malignancy. 
 
 
Reporting to FDA: 
 
 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
 
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, 
the protocol guidelines, the sponsor’s guidelines, and Institutional Review Board 
policy. 
 
 
11.2.2 Pregnancy and Reporting 
 
 
If, following initiation of the investigational product, it is subsequently discovered that a 
study subject is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 6 half-lives after product administration, the 


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investigational product will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for subject safety). 
The investigator must immediately notify Worldwide Safety @BMS of this event via the 
Pregnancy Surveillance Form in accordance with SAE reporting procedures within 24 hours. 
 
 
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 
 
 
11.2.3 Potential Drug Induced Liver Injury 
 
 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs. Potential drug induced liver injury is 
defined as: 
 
 
1) ALT or AST elevation > 3 times upper limit of normal 
(ULN) AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase) 
AND 
 
3) No other immediately apparent possible causes of AST/ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing 
chronic or acute liver disease, or the administration of other drug(s) known to be 
hepatotoxic. 
 
 
11.2.4 Non-serious adverse events 
 
 
Non-serious Adverse Events are to be provided to BMS in aggregate via interim or final study 


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reports as specified in the agreement or, if a regulatory requirement [e.g. IND US trial] as part 
of an annual reporting requirement. 
 
 
A non-serious adverse event is an AE not classified as serious. 
 
 
Non-serious adverse events will be captured as defined in section 11.1.1 from initiation of 
the study drug until the end of treatment assessment (as defined by the schedule in section 
9), or to resolution or stabilization, whichever is longer. 
 
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for non-serious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as appropriate. 
 
 
 
11.3 Laboratory test abnormalities 
 
 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. Test results that constitute SAEs should be documented and reported 
as such. 
 
 
Laboratory abnormalities are usually not recorded as adverse events; however, signs and/or 
symptoms that are associated with laboratory findings requiring study withdrawal, dose 
modification, or medical intervention (e.g., anemia requiring transfusions or hyperglycemia 
requiring treatment) or other abnormal assessments (e.g., ECG, radiographs, vital signs) must 
be recorded as adverse events (or serious adverse events) if they meet the definition of an 
adverse event (or serious adverse event). 
 
 
The following laboratory abnormalities should be documented and reported appropriately: 
 
• 
any laboratory test result that is clinically significant or meets the definition of an SAE 
 
 
• 
any laboratory abnormality that required the subject to have study drug discontinued or 
interrupted 


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• 
any laboratory abnormality that required the subject to receive specific corrective 
therapy. 
 
 
11.4 Overdose 
 
 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must 
be reported as an SAE. 
 
 
11.5 Other Safety Considerations 
 
 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a non-serious or serious 
AE, as appropriate, and reported accordingly. 
 
 
 
 
 


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12 
RECORDING AND COLLECTION OF DATA 
 
 
12.1 Case Report Forms 
 
 
 
Clinical data capture called DMI (Data Management Initiative) will be the electronic 
database used for this study’s electronic case report forms. 
 
 
Use of concomitant medications is routinely captured in the patient’s electronic medical record 
and the information is readily available if it needs to be obtained for analysis of study results. As 
such, concomitant medications will not be captured in the Protocol’s database. 
 
 
 
13.  Sample and Data Sharing 
 
Samples and data collected during this study will be shared with internal and external 
collaborators for the purposes of meetings study related objectives. Data/Samples are being 
shared with institutional and external and for tissue/data analyses described in this protocol, 
including the International Association for The Study of Lung Cancer (IASLC); the University 
of Pittsburg and the Yale School of Medicine/Yale Cancer Center.  
 
 


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14 STATISTICAL CONSIDERATIONS 
 
In this multi single arm phase II study, eligible patients will be accrued to the nivolumab alone 
arm (Arm A), the nivolumab plus ipilimumab arm (Arm B), the nivolumab plus platinum-
based chemotherapy arm (Arm C) or nivolumab plus ipilimumab plus platinum-based 
chemotherapy (Arm D). The primary efficacy endpoint of the study is the major pathologic 
response in resected tumor tissues following neoadjuvant therapy, as compared to the MPR 
induced by neoadjuvant chemotherapy in historical controls. Patients that do not undergo 
surgery will be considered as treatment failure for the major pathologic response analysis. At 
the end of the trial, if the primary efficacy endpoints demonstrate significant findings, further 
evaluation of the immune- based neoadjuvant therapy in NSCLC will be warranted. 
 
Time-to-event endpoints will be computed using the Kaplan-Meier method. 
 
Multivariate analysis will be used to explore the role of biomarkers in predicting pathologic 
response to treatment, in an exploratory way. 
 
By performing WES in blood germline genetic alterations may be detected. As a 
consequence, patients will be contacted and informed and a genetic consult will be placed and 
or recommended for possible retesting. 
 
 
Sample size calculation is based on the assumptions described below. 
 
 
Primary endpoint of major pathologic response: 
 
• 
The study is a multi -arm phase II trial with modular design and this primary endpoint 
will be compared to the pre-specified major pathologic response target based on the 
historical data. 
 
• 
The historic major pathologic response rate to neoadjuvant chemotherapy alone is 
19% (as described by Pataer et al.) (20). However, some patients that receive 
neoadjuvant chemotherapy may not receive surgery for one reason or another, and 
these cases will be considered treatment failure. Assuming the 19% major pathologic 
response rate is calculated from 80% of patients who receive surgery, a conservative 
estimate of the major pathologic response is 15%. Preliminary results from a small 
scale phase 2 study evaluating the safety and feasibility of neoadjuvant nivolumab 
for early stage NSCLC patients indicate that nivolumab is safe and neither delays 
surgery nor induces surgical complications when given preoperatively (19). Indeed, 
neoadjuvant nivolumab induces major pathologic response in 45% (9/20) of 


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patients (19), which is markedly increased relative to the one noted following 
neoadjuvant chemotherapy (19%) (20). Our goal is to determine if nivolumab alone 
or nivolumab plus ipilimumab, or nivolumab plus platinum-based chemotherapy, or 
nivolumab plus ipilimumab plus platinum-based chemotherapy can produce a 
major pathologic response which is better than 15% (i.e., immunotherapy would be 
at least as effective as chemotherapy, the major pathologic response rate under the 
null hypothesis) with a target a major pathologic response rate of 40% (i.e., the 
target major pathologic response rate). 
 
• 
Simon’s minimax two-stage design (38) will be applied to test the major pathologic 
response rate for each one of the treatment arms. We assume the 15% major 
pathologic response rate under the null hypothesis versus the 40% major pathologic 
response rate under the alternative hypothesis. For each treatment arm, 15 patients 
will be enrolled in the first stage. If only two or less of the 15 patients have major 
pathologic response, enrollment to that treatment arm will be terminated and the 
treatment is considered inefficacious. Otherwise, with at least three major pathologic 
responses, additional 6 patients will be enrolled to reach a total of 21 patients. At the 
end of trial, if we observe 6 or more patients have major pathologic response, the 
treatment is considered efficacious and inefficacious otherwise. The trial will have 
90% power when the major pathologic response rate is 40%. When the major 
pathologic response rate is 15%, the probability of early termination is 0.60 with an 
average sample size of 17.4 and one-sided 10% type I error rate. With 21 patients 
and assuming the major pathologic response rate is at 0.40, we can estimate the major 
pathologic response rate with a standard error of 0.107. 
 
• 
We will also apply the Bayesian framework to calculate the posterior probability of 
major pathologic response rate. The 95% credible interval of the major pathologic 
response rate will be constructed. In addition, we will calculate the probability that 
the major pathologic response rate is at least 15% under the beta-binomial model. 
Assume that the prior distribution of the major pathologic response rate is Beta (0.15, 
0.85). With 6 responses in 21 patients, we will be 92.9% confident to conclude that 
the major pathologic response rate for the treatment is at least 15%. 
 
 
From the above calculations, the study will need up to 21 evaluable patients in each arm. 
Assuming a non-evaluable rate of 5% (e.g., patients drop out, lost to follow-up, or rescind the 
consent due to non-treatment related reasons before endpoints can be evaluated), we will 
need to enroll up to a total of 88 patients (total 22 patients per arm with up to 21 evaluable 
patients in each arm). With an estimated accrual rate of 2-3 patients a month, the accrual 
period is approximately 35 months. 


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Analysis of Secondary Objectives/Endpoints: 
 
Analysis for the secondary objectives and/or secondary endpoints will be descriptive and 
exploratory in nature.  Descriptive statistics will be provided to summarize the data 
distribution. Association analysis by Pearson or Spearman correlation coefficient will be 
calculated for continuous data and chi-square or Fisher's exact test for categorical data. The 
goals for these analyses are for hypothesis generating. The results will need to be confirmed 
by future studies. 
 
 
 
 


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15  STUDYMONITORING AND EARLY STOPPING RULES 
 
 
The study will be monitored by the MD Anderson Data Safety and Monitoring 
Board. 
 
 
To ensure the safety of the proposed treatment in the neoadjuvant setting, precautions have 
been taken into consideration and implemented: 
 
 
• 
A careful review of the literature has demonstrated that the use of neoadjuvant 
chemotherapy does not increase surgical morbidity or mortality (12). Because single 
agent nivolumab has been found to have a more favorable adverse event profile than 
single agent chemotherapy (17, 18) it is expected that neoadjuvant immunotherapy will 
be feasible and safe. 
• 
A Bayesian method to monitor the toxicity in the perioperative phase will be used. 
Unacceptable toxicity is defined as: severe pneumonitis precluding performance of 
planned surgical resection, death during neoadjuvant treatment or within 30 days after 
surgery; severe post op acute respiratory distress syndrome (ARDS) not attributable to 
aspiration requiring prolonged ventilator support; development of broncho-pleural fistula 
not attributable to surgical technique; wound healing delays that require management 
with a major surgical procedure; wound infections that require intravenous antibiotic use 
for more than 21 days; re-operation for bleeding or infection deemed secondary other 
factors than surgical technique; empyema; stroke or myocardial infarction within 30 days 
after surgery; any treatment-related adverse events leading to a delay in surgery resulting in > 
8 week interval between the last dose of nivolumab and surgery, any surgical complication 
that is considered major by the treating physician and possibly, probably or definitely 
related the immunotherapy medications. The incidence of surgical complications for 
thoracoscopy/thoracotomy for non-small cell lung cancers is approximately 16-31% 
(39). We consider that a neoadjuvant therapy with one of the regimens is not feasible if it 
results in unacceptable toxicities in at least 30% of the patients with 70% or higher 
probability. 
 
With a prior probability of toxicity as Beta (0.5,0.5), the toxicity stopping boundaries 
are defined as seeing unacceptable toxicity in >= 3 of 6-7, 4 of 8-10, 5 of 11-13, 6 of                
14-16, 7 of 17-19, or 8 of 22 patients. When the true toxicity rates are 0.1, 0.3, and 0.5, 
the probabilities of early stopping are 0.03, 0.54, and 0.96 with the corresponding 
average sample sizes of 21.5, 14.8, and 7.9, respectively. In case one arm needs to be 
closed due to excessive toxicity, accrual to the remaining arm will continue in a non-


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randomized way. The calculation was performed using the Shiny Application: 
Bayesian Toxicity Monitoring version 2.1 (http://ibl.mdanderson.org/BTM/) 
 
In case one arm needs to be discontinued at completion of stage I due to lack of 
efficacy, according to the Simon’s two stage design described above, accrual to the 
other arms will continue. 
 
 
The Investigator is responsible for completing the efficacy/safety summary report and 
submitting it to the IND office Medical Monitor for review and approval.  These should 
be submitted as follows: 
 
 
For Safety Monitoring: 
 
After the first 6 evaluable patients per arm, reach 30 days post-surgery, after the first 8, and 
every 3 consecutive evaluable patients per arm, thereafter. On every report submission, the 
toxicity information from previous reported patients will need to be updated. 
 
 
For Efficacy Monitoring: 
 
After the first 15 evaluable patients per arm, reach 30 days after surgery, and after all 
evaluable subjects per arm, complete 30 days post-surgery. 
 
 
A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder under 
“sponsor correspondence”. 
 
 
 


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    16 APPENDICES 
 
 
Appendix 1 Sample of Drug Ordering and Pharmacy Reference Material 
 
 
Initial Orders 
 
 
• 
Following submission and approval of the required regulatory documents, a 
supply of nivolumab and ipilimumab may be ordered from by completing a Drug 
Request Form provided by BMS for this specific trial. 
 
• 
The initial order should be limited to the amount needed for two doses. Allow 5 business days 
for shipment of drug from BMS receipt of the Drug Request Form. Drug is protocol specific, 
but not patient specific. All drug products will be shipped by courier in a temperature-
controlled container. It is possible that sites may have more than one nivolumab clinical 
study ongoing at the same time. It is imperative that only drug product designated for 
this protocol number be used for this study. 
 
• 
Pharmacy supplies not provided by BMS: Empty IV bags/containers, approved diluents, 
In- line filters and infusion tubing 
 
Re-Supply 
 
• 
Drug re-supply request form should be submitted electronically at least 7 business 
days before the expected delivery date. Deliveries will be made Tuesday through 
Friday. 
 
• 
When assessing need for resupply, institutions should keep in mind the number of vials 
used per treatment dose, and that shipments may take 14 business days from receipt of 
request. Drug is not patient-specific. Be sure to check with your pharmacy regarding 
existing investigational stock to assure optimal use of drug on hand. 
 
Drug Excursions 
 
• 
Drug  excursions should be reported immediately to BMS on the form provided with the 
study-specific drug order form 
 
 


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Please refer to the most recent version of the nivolumab and ipilimumab Investigator 
Brochure for additional information to be included as per institutional or regulatory 
standards. 
 
 
 
 
Nivolumab (BMS-936558) Pharmacy Reference Material 
 
 
 
As this is provided for guidance only, please see investigator brochure for 
additional information regarding preparation and administration 
 
 
Nivolumab has a concentration of 10mg/mL and is provided in a 10mL vial. Ten or five 
vials are provided in a carton. 
 
 
Storage Conditions & Handling: 
 
• 
Store at 2-8°C (36-46°F), protect from light, freezing, and shaking. 
 
• 
If any temperature excursions are encountered during storage, please report these to 
BMS for assessment via the Temperature Excursion Response Form. 
• 
As with all injectable drugs, care should be taken when handling and preparing nivolumab. 
 
Whenever possible, nivolumab should be prepared in a laminar flow hood or safety 
cabinet using standard precautions for the safe handling of intravenous agents applying 
aseptic technique. 
 
• 
Partially used vials should be disposed at the site following procedures for 
the disposal of anticancer drugs. 
 
After final drug reconciliation, unused nivolumab vials should be disposed at the site 
following procedures for the disposal of anticancer drugs. For further information, please 
either discuss with your BMS CSR&O protocol manager or refer to your site IP Destruction 
policies and procedures 
 
 


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Please refer to the appropriate section of the current Investigator Brochure 
or Addendum. Due to parameters surrounding the use time of nivolumab and ipilimumab, the 
time of preparation should be noted in the Pharmacy Source documents [accountability logs] or 
in study files as required for investigator sponsored research [FDA and GCP] 
Use Time/Stability: 
 
 
 
 
 
 
 
The administration of BMS-936558-01 injection prepared for dosing nivolumab infusion 
must be completed within 24 hours of preparation. If not used immediately, the infusion 
solution may be stored up to 20 hours in a refrigerator at under refrigeration conditions (2°-
°-8°C (, 36°-46°F) and used within 24 hours, and a maximum of 4 hours of the total 24 
hours can be at room temperature (20°-25°C, 68°-77°F) and under room light. The 
maximum 4-hour period under room temperature and room light conditions for undiluted 
and diluted solutions of BMS-936558- 01 injection in the IV bag includes the product 
administration period. 
 
 
Preparation and Administration: 
 
 
1. 
Visually inspect the drug product solution for particulate matter and discoloration prior to 
administration. Discard if solution is cloudy, if there is pronounced discoloration 
(solution may have a pale-yellow color), or if there is foreign particulate matter other than 
a few translucent-to-white, amorphous particles. Note: Mix by gently inverting several 
times.  Do not shake. 
2. 
Aseptically withdraw the required volume of nivolumab solution into a syringe, and 
dispense into an IV bag. If multiple vials are needed for a subject, it is important to use 
a separate sterile syringe and needle for each vial to prevent problems such as dulling of 
needle tip, stopper coring, repeated friction of plunger against syringe barrel wall. Do 
not enter into each vial more than once.  Do not administer study drug as an IV push or 
bolus injection 
3. 
Add the appropriate volume of 0.9% Sodium Chloride Injection solution or 5% 
Dextrose Injection solution. It is acceptable to add nivolumab solution from the 
vials into an appropriate pre-filled bag of diluent. 
4. 
Note: Nivolumab infusion concentration must be at or above the minimum 
allowable concentration of 0.35 mg/mL [IBV13 Addendum Section 3.2.2] 
5. 
Note: It is not recommended that so-called “channel” or tube systems are used 
to transport prepared infusions of nivolumab. 


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6. 
Attach the IV bag containing the nivolumab solution to the infusion set and filter. 
 
7. 
At the end of the infusion period, flush the line with a sufficient quantity of 
approved diluents. 
 
 
Ipilimumab Pharmacy Reference Material 
 
Ipilimumab vials (40 mL) are shipped in quantities of four. 
 
Ipilimumab (BMS-734016) Injection (5 mg/ml) must be stored refrigerated (2-8°C, 36-46°F) 
with protection from light and from freezing. Ipilimumab may be stored in IV infusion bags 
(PVC, non- PVC/non-DEHP) or glass infusion containers for up to 24 hours at room 
temperature (20-25°C, 68-77°F) or refrigerated (2-8°C, 36-46°F). This would include any time 
in transit and the total time for infusion. Drug must be completely delivered within 24 hours of 
preparation. 
 
 
Storage Conditions & Handling: 
 
Ipilimumab injection may be stored undiluted, 200 mg/vial (5 mg/mL), or following dilution 
to concentrations between 1 mg/mL and 4 mg/mL in 0.9% Sodium Chloride Injection 
(USP), or 5% Dextrose Injection (USP) in PVC, non-PVC/ or glass containers for up to 24 
hours in the refrigerator (2°C to 8°C) or at room temperature/room light. For longer storage, 
ipilimumab should be kept refrigerated (2 C to 8 C) with protection from light. 
Ipilimumab injection must not be frozen. 
 
Partially used vials or empty vials of Ipilimumab Injection should be discarded at the 
site according to appropriate drug disposal procedures. 
 
 
Preparation and Administration 
 
As this is provided for guidance only, please see investigator brochure for additional 
information regarding preparation and administration. 
 
 
1. As ipilimumab is stored long term at refrigerated temperatures (2-8ºC) and 
protected from light, allow the appropriate number of vials of ipilimumab to 
stand at room temperature for approximately five minutes. 


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2. Ensure that the ipilimumab solution is clear colorless, essentially free from 
particulate matter on visual inspection. If multiple vials are needed for a subject, it 
is important to use a separate sterile syringe and needle for each vial to prevent 
problems such as dulling of needle tip, stopper coring, repeated friction of plunger 
against syringe barrel wall, etc. 
3. Aseptically transfer the required volume of ipilimumab solution into a syringe. 
[Note: A sufficient excess of ipilimumab is incorporated into each vial to account 
for withdrawal losses]. 
4. Do not draw into each vial more than once. Discard partially used vials or empty vials. 
 
5. Ipilimumab solution should be added to an appropriate size infusion container 
to accommodate the calculated final volume. 
Total dose should be calculated using the most recent subject weight; if weight on 
dosing day differs by 10% from prior weight used to calculate dosing, the dose should 
be recalculated and study drug adjusted accordingly. 
Mix by GENTLY inverting several times. DO NOT shake. 
 
Ipilimumab injection may be diluted in 0.9% Sodium Chloride Injection, USP 
or 5% Dextrose Injection, USP. 
 
6. Visually inspect the final solution. If the initial diluted solution or final solution for 
infusion is not clear or contents appear to contain precipitate, the solution should be 
discarded. 
7. Immediately after the infusion is complete, flush with an adequate amount of 0.9% 
Sodium Chloride injection (USP) or 5% Dextrose injection (USP) to completely flush 
the residual fluid (dead space) in your administration set (approximately 30-50mL); 
this will ensure that all active drug is delivered to the study participant 
8. Safely discard any unused portion of the infusion solution. Do not store for reuse. 
 
 
Ipilimumab should be administered under the supervision of a physician experienced in the 
use of intravenous (IV) agents. Ipilimumab is administered as an IV infusion only 
 
 
 
It is possible that sites may have more than one ipilimumab clinical study ongoing 
at the same time. It is imperative that only product designated for this protocol 
be used for 
 
 


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   Appendix 2 Management Algorithms 
 
 
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 immuno- 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 immuno-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 immuno-oncology agent or regimen being 
used. 
 
 
 
 
 
 
 
 


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