Conditions: Non Small Cell Lung Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 46
Healthy volunteers: no

Brief summary:
Phase II, single-arm, open-label multicenter study that assesses feasibility, safety and efficacy of combined neoadjuvant chemotherapy and immunotherapy with Nivolumab 360 mg IV Q3W + Paclitaxel 200mg/m2 + Carboplatin AUC 6 IV Q3W in resectable stage IIIA N2-NSCLC adult patients followed by adjuvant treatment for 1 year with Nivolumab 240 mg IV Q2W for 4 months and Nivolumab 480mg Q4W for 8 months.

Detailed description:
Phase II, single-arm, open-label multicenter study that assesses feasibility, safety and efficacy of combined neoadjuvant chemotherapy and immunotherapy with Nivolumab 360 mg IV Q3W + Paclitaxel 200mg/m2 + Carboplatin AUC 6 IV Q3W in resectable stage IIIA N2-NSCLC adult patients followed by adjuvant treatment for 1 year with Nivolumab 240 mg IV Q2W for 4 months and Nivolumab 480mg Q4W for 8 months.

Three cycles of neoadjuvant chemotherapy in combination with nivolumab will be administered.

After completion of neoadjuvant therapy (3 cycles) and before surgery, a tumor assessment will be done. Patients have to leave the study if there is evidence of progression. Patients with in-stable disease or partial response may be considered for surgery.

The report imaging response vs pathological response rate will be evaluated.

Patients eligible for the trial are those with a histological diagnosis or cytologically proven operable and resectable non-small-cell lung cancer. The total number of patients to be included will be 46 from 23 participating sites in Spain.

Accrual period of 1.5 years or until the inclusion of the last patient necessary to achieve the sample set in the protocol of 46 patients. After that all patients will be treated for 1 year with adjuvant immunotherapy and they will be followed during 3 years after adjuvant treatment.

Arms:
arm 1: Nivolumab 360 mg IV Q3W + Paclitaxel 200mg/m2 + Carboplatin AUC 6 IV Q3W in resectable stage IIIA N2-NSCLC adult patients followed by adjuvant treatment for 1 year with Nivolumab 240 mg IV Q2W for 4 months and Nivolumab 480mg Q4W for 8 months

Interventions: intervention 1: Nivolumab 360 mg intervention 2: Paclitaxel 200mg/m2 intervention 3: Carboplatin AUC 6
Intervention descriptions: intervention 1: Nivolumab 360 mg IV Q3W + Followed by adjuvant treatment for 1 year with Nivolumab 240 mg IV Q2W for 4 months and Nivolumab 480mg Q4W for 8 months intervention 2: Paclitaxel 200mg/m2 IV Q3W intervention 3: Carboplatin AUC 6 IV Q3W

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
Official Title: “Neo-adjuvant chemo/immunotherapy for the treatment of 
resectable stage IIIA non small cell lung cancer (NSCLC): a phase II multicenter 
exploratory study” NADIM 
 
 
 
       NCT Number: NCT03081689 
 
 
 
Document Dates: Summary of Protocol Amendment Version 7.0:  
08 June 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           2 
 
 
NEO -ADJUVANT CHEMO/IMMUNOTHERAPY FOR THE TREATMENT OF 
RESECTABLE STAGE IIIA NON SMALL CELL LUNG CANCER (NSCLC): A PHASE 
II MULTICENTER EXPLORATORY STUDY 
 
NADIM: Neo-Adjuvant Immunotherapy 
 
 
 
 
Study Sponsor: Fundación GECP 
 
EudraCT Number: 2016-003732-20 
Sponsor code: GECP 16/03 
 
 
Version 7.0 
08 June 2022  
 
 
              
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
 
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Contacts 
 
 
Trial Chair  
 
 
Dr. Mariano 
Provencio, MD, 
PhD 
Fundación GECP 
President 
Oncology Service 
Hospital Univ. Puerta de Hierro, 
Majadahonda, Madrid,  
 
 
Email: gecp@gecp.org 
 
Seguridad y 
Regulación (Safety 
and Regulatory 
Affairs) 
Coordinating office 
of the Fundación 
GECP  
Meridiana 358, 6ª planta 
08027 Barcelona 
Tel. 93 430 20 06 
Fax. 93 419 17 68 
Email: 
 
 
Coordinating office 
of the Fundación 
GECP 
Monitoring team 
 
Monitor/CRA 
 
 
 
 
 
 
 
 
 
 
Lead CRA 
 
 
 
 
 
 
Project Manager: 
 
 
 
 
Meridiana 358, 6ª planta 
08027 Barcelona 
Tel. 93 430 20 06 
 
 
 
 
 
 
 
 
Meridiana 358, 6ª planta 
08027 Barcelona 
Tel. 93 430 20 06 
 
 
 
Meridiana 358, 6ª planta 
08027 BarcelonaTel. 93 430 20 06 
 
 
 
 
 
 
 


  
 
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Protocol Signature Page 
 
NEO -ADJUVANT CHEMO/IMMUNOTHERAPY FOR THE TREATMENT OF 
RESECTABLE STAGE IIIA NON SMALL CELL LUNG CANCER (NSCLC): A PHASE 
II MULTICENTER EXPLORATORY STUDY 
 
NADIM: Neo-Adjuvant Immunotherapy 
 
Sponsor code: GECP 16/03 
 
Approved by: 
 
Signature 
 
 
 
_____________________________ 
Dr. Mariano Provencio 
Trial Chair 
 
Signature 
 
 
 
 
______________________________ 
 
 
 
Signature 
 
 
 
_____________________________ 
Dr. Mariano Provencio 
Fundación GECP  President 
 
 
 
 
 
 


  
 
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Principal Investigator Protocol Signature Page 
 
 
Study Title: “Neo-adjuvant chemo/immunotherapy for the treatment of resectable stage IIIA non small 
cell lung cancer (NSCLC): a phase II multicenter exploratory study” NADIM 
 
Sponsor protocol code: GECP 16/03 
 
EudraCT Number: 2016-003732-20 
 
Protocol version: v 7.0_08 June 2022 
 
 
As principal investigator of this site, I hereby confirm that: 
 
I have read the protocol and agree that it contains all necessary details for conducting this trial. I will 
conduct the trial as outlined in the following protocol and in compliance with GCP, and will apply due 
diligence to avoid protocol deviations.  
 
I will provide copies of the protocol and all drug information relating to pre-clinical and prior clinical 
experience furnished to me by the Fundación GECP, to all physicians responsible to me who participate 
in this trial. I will discuss this material with them to assure that they are fully informed regarding the 
drug and the conduct of the trial.  
 
I agree to keep accurate records on all patient information including patient's informed consent 
statement, drug shipment and return forms, and all other information collected during the trial for a 
minimum period of 25 years according to the new Royal Decree 1090/2015 approved in Spain. 
 
 
Name of Principal Investigator:_______________________________________________ 
 
 
Institution’s name and place:_________________________________________________ 
 
 
 
_____________________________________________________ ______________ 
 
 
Signature                                                                                                                 Date 
 
 
 


  
 
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1. 
SUMMARY 
 
 
  
1.0. 
 StudyType: 
 
Clinical trial  
 
1.1. 
 Sponsor Identification: 
Fundación GECP 
Avda. Meridiana 358, 6ª planta 
08027 Barcelona 
 
1.2.  
Title: 
 
Neo-adjuvant chemo/immunotherapy for the treatment of resectable stage IIIA non small cell 
lung cancer (NSCLC): a phase II multicenter exploratory study”  
 
NADIM: Neo-Adjuvant Immunotherapy 
 
 
1.3. 
Sponsor Protocol Code:  
 
GECP 16/03 
 
1.4. 
Principal investigator:  
 
Dr. Mariano Provencio, MD, PhD 
 
1.5. 
Participating centers: 
 
25 hospitals in Spain 
  
 
1.6. 
Experimental drug: doses, type, route of administration 
 
- 
Neoadjuvant treatment: Nivolumab 360 mg IV Q3W + Paclitaxel 200mg/m2 + Carboplatin 
AUC 6 IV Q3W, 3 cycles 
- 
Surgery 
- 
Adjuvant treatment: Nivolumab 240 mg Q2W for 4 months and Nivolumab 480 mg Q4W for 
8 months (1 year) after surgical resection  
 
 


  
 
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1.7. 
Clinical trial type  
 
Phase II, single-arm, open-label study 
 
1.8. 
Primary and secondary objectives  
 
Primary objective: 
- 
Estimate progression-free survival (PFS) at 24 months from diagnosis. The PFS is defined as 
the time from diagnosis to relapse, progression or death, whichever occurred first. 
 
The tumor assessment schedule after surgery will be: 
- 
Every 3 months (Q3 month)  CT for 1 year 
 
During the follow up phase the tumor assessments will be done as follows: 
 
- 
Every 3 months (+/- 7 days) (Q3 month) CT for 1 year (from day 1 of adjuvant 
treatment) 
- 
Every 4 months (+/- 7 days) (Q4 month) CT during the second year 
- 
Every 6 months (+/- 7 days) (Q6 month) CT thereafterduring the third year 
- 
Every 6 months (+/- 28 days) (Q6 month) CT therafter 
RECIST criteria v 1.1 will be used for the tumor assessment. 
 
Secondary objectives: 
- 
Assess the toxicity profile of the combination, the down-staging rate, complete resection rate, 
time to progression and overall survival at 5 years (follow up visits after adjuvant treatment, 
every 3 months for 1 year, every 4 monts the second year and every 6 months the following 3 
years). Also, surgical outcome and operative and post-operative complications will be assessed. 
- 
Perform correlatives studies with the objectives of exploring the expression of other 
biomarkers, such as PD-L1, in tumor tissue: at screening and after surgery (resected tumor 
sample), free DNA and circulating tumor cells in liquid biopsy 
- 
To describe whether PD-L1 expression is a predictive biomarker for ORR 
- 
To describe Progression Free Survival (PFS) in PD-L1+ (>=1%) population 
- 
Report imaging response vs pathological response rate 
- 
To describe the tumoral microenvironment and to identify response biomarkers and resistance 
mechanisms to neoadjuvant chemo-inmune treatment and which of them are accessible by 
liquid biopsy: 
In Tumor tissue: 
o To characterize the immune microenvironment in pre- and post-treatment tumoral 
biopsies by Multiplexed immunofluorescence. 
o To analyze mRNA levels of immune-oncology and metabolism related genes.  


  
 
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o To characterize TCR locus clonality using next generation sequencing (NGS) on tissue. 
In Blood: 
o To characterize the different populations, proportions, metabolism and activation levels 
of T cells, B cells and NK cells from patients treated with chemo-immunotherapy and on 
healthy adults as a control.  
o To characterize TCR locus clonality using next generation sequencing (NGS) on PBMCs. 
o To analyze the levels of 160 cytokines secreted by the tumor microenvironment on 
patient plasma and healthy controls. 
o To analyse mutations in cfDNA from patients’ blood 
 
 
1.09. Design  
 
Phase II, single-arm, open-label multicenter study that assesses feasibility, safety and efficacy of 
combined neoadjuvant chemotherapy and immunotherapy with Nivolumab 360 mg IV Q3W + 
Paclitaxel 200mg/m2 + Carboplatin AUC 6 IV Q3W in resectable stage IIIA NSCLC adult patients 
followed by adjuvant treatment for 1 year with Nivolumab 240 mg IV Q2W for 4 months and 
Nivolumab 480mg Q4W for 8 months. 
 
 
Three cycles of neoadjuvant chemotherapy in combination with nivolumab will be 
administered.  
 
After completion of neoadjuvant therapy (3 cycles) and before surgery, a tumor assessment will 
be done. Patients have to leave the study if there is evidence of progression. Patients with 
instable disease or partial response may be considered for surgery. 
 
The report imaging response vs pathological response rate will be evaluated. 
 
 


  
 
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1.10. Disease or Disorder to be investigated 
 
Operable and resectable, non-small-cell lung cancer, stage IIIA 
 
1.11.  Primary and secondary endpoints  
 
The primary endpoint will be PFS at 24 months. The secondary endopoints will be overall 
survival at 5 years, response rate (RR), toxicity profile of the combination, the down-staging 
rate and complete resection rate. Also, surgical outcome and complications will be assessed. 
  
1.12 
Trial population and sample size 
 
Patients eligible for the trial are those with a histological diagnosis or cytologically proven 
operable and resectable non-small-cell lung cancer. The total number of patients to be included 
will be 46 from 25 participating sites in Spain. 
It is expected that approximately the 10% of the patients initially enrolled should be discarded 
because they do not meet the inclusion criteria; so that in order to reach the proposed sample 
size, if a patient initially enrolled in the study does not fulfil the inclusion criteria, they will be 
replaced by a new one subject that fulfil them, this replacement will ensure that the sample 


  
 
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size will be the one calculated initially. 
 
 
1.13. Study Duration  
 
Accrual period of 1.5 years or until the inclusion of the last patient necessary to achieve the 
sample set in the protocol of 46 patients. After that, all patients will be treated for 1 year with 
adjuvant immunotherapy and they will be followed during 5 years after adjuvant treatment. 
  
 
 
The information contained herein is confidential and belongs to the sponsor. This information is provided for the purposes of the 
trial and must not be disclosed without the prior written consent of the sponsor. 
The people to whom this information is provided for the trial purposes should be informed that it is confidential information and 
can not be disclosed. 


  
 
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2. 
INDEX 
1. 
SUMMARY ....................................................................................................................... 6 
2. 
INDEX ............................................................................................................................ 11 
3. 
GENERAL INFORMATION ................................................................................................ 14 
 
4.        RATIONALE AND OBJECTIVES…………………………………………………………………………………………13 
4.1 
BACKGROUND AND INTRODUCTION ...................................................................................................... 16 
4.2. 
WORKING HYPOTHESIS ............................................................................................................................... 16 
4.3. 
OBJECTIVES ..................................................................................................................................................... 22 
5. 
CLINICAL TRIAL TYPE AND DESIGN .................................................................................. 23 
5.1. 
CLINICAL TRIAL TYPE ................................................................................................................................. 23 
5.2.  
DESIGN OF THE STUDY ................................................................................................................................ 23 
6. 
PATIENT SELECTION CRITERIA ........................................................................................ 24 
6.1. 
INCLUSION CRITERIA ................................................................................................................................... 24 
6.2. 
EXCLUSION CRITERIA ................................................................................................................................. 27 
6.3 
PROPOSED NUMBER OF SUBJECTS AND SAMPLE SIZE ..................................................................... 28 
6.4.      WITHDRAWAL CRITERIA ............................................................................................................................ 28 
6.5 
RECRUITMENT PERIOD DURATION AND FOLLOW UP ...................................................................... 28 
7. 
TREATMENT DESCRIPTION ............................................................................................. 29 
7.1 
 CARBOPLATIN ................................................................................................................................................ 29 
7.2 
PACLITAXEL .................................................................................................................................................... 29 
7.3. 
NIVOLUMAB ..................................................................................................................................................... 29 
TREATMENT SCHEDULES ....................................................................................................................................... 31 
7.4. 
SPECIAL REQUIREMENTS FOR THE HANDLING OF THE STUDY DRUGS .................................... 32 
7.4.1.  
Dosage and Administration of Nivolumab .................................................................................................... 32 
7.4.2.        Administration of Carboplatin ...................................................................................................................... 32 
7.4.3.  
Administration of Paclitaxel.......................................................................................................................... 33 
7.5. 
 DOSE DELAY/REDUCTION CRITERIA ..................................................................................................... 34 


  
 
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7.5.1. 
NIVOLUMAB ................................................................................................................................................. 39 
7.5.2. 
PACLITAXEL AND CARBOPLATIN ................................................................................................................... 40 
7.5.3.  
OTHER TOXICITIES ........................................................................................................................................ 41 
7.5.4. 
HYPERSENSIVITY REACTIONS ........................................................................................................................ 42 
7.6. 
TREATMENT DURATION .............................................................................................................................. 43 
7.7 
PERMITTED AND PROHIBITED CONCOMITANT TREATMENTS ..................................................... 44 
8. 
TRIAL PROGRESS AND PATIENT EVALUATION ................................................................. 44 
8.1  
TRIAL PROGRESS ........................................................................................................................................... 47 
8.2  
PATIENT EVALUATION  ............................................................................................................................... 47 
9. 
ADVERSE EVENTS ........................................................................................................... 52 
 
9.1. 
GENERAL INFORMATION ............................................................................................................................ 64 
9.6.3. ADVERSE EVENTS ASSOCIATED WITH NIVOLUMAB ......................................................................... 64 
9.6.3. ADVERSE EVENTS ASSOCIATED WITH PACLITAXEL ........................................................................ 64 
9.6.3. ADVERSE EVENTS ASSOCIATED WITH CARBOPLATIN ..................................................................... 64 
9.6.3. CAUSALITY CRITERIA .................................................................................................................................. 64 
9.6.3. COMUNICATION OF ADVERSE EVENTS .................................................................................................. 64 
Other Safety Considerations.......................................................................................................................................... 65 
10. 
 ETHICAL ASPECTS .......................................................................................................... 65 
10.1 
GENERAL CONSIDERATIONS ..................................................................................................................... 65 
10.2 
INFORMED CONSENT .................................................................................................................................... 66 
10.3 
CONFIDENTIALITY ........................................................................................................................................ 66 
10.4 
INSURANCE POLICY ...................................................................................................................................... 67 
11. 
PRACTICAL CONSIDERATIONS ......................................................................................... 67 
11.1 
RESPONSIBILITIES OF THE INVESTIGATOR ......................................................................................... 67 
11.2 
RESPONSIBILITY FOR THE PRODUCT ..................................................................................................... 67 
11.3 
RECORDS AND REPORTS ............................................................................................................................. 68 
11.4 
PROTOCOL ADHERENCE ............................................................................................................................. 68 
11.5 
STUDY MONITORING .................................................................................................................................... 68 


  
 
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11.6 
PUBLICATION POLICY ................................................................................................................................. 69 
12. 
STATISTICAL ANALYSES .................................................................................................. 69 
13. 
REFERENCES ................................................................................................................... 71 
APPENDIX A PERFORMANCE STATUS EVALUATION SCALES ...................................................... 74 
APPENDIX B COMMON TOXICITY CRITERIA (CTC-NCIC) ............................................................. 75 
APPENDIX C  SAE FORM AND PREGNANCY FORM .................................................................... 76 
APPENDIX D CARBOPLATIN DOSE CALCULATION ...................................................................... 81 
APPENDIX E: SYSTEM OF CLASSIFICATION FOR NON-MICROCYTIC LUNG CANCER (NSCLC) AND 
DEFINITION OF LYMPH-NODES MAPS 7TH EDITION ................................................................... 82 
 
 
 
 
 
ANNEX I       INVESTIGATOR BROCHURE 
Attached 
ANNEX II       HELSINKI DECLARATION 
Attached 
 
 
 


  
 
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3. 
GENERAL INFORMATION 
 
 
A. 
Trial Identification 
 
  
Sponsor code: GECP 16/03 
  
 
  
Eudract: 2016-003732-20 
 
Protocol title: Neo-adjuvant chemo/immunotherapy for the treatment of resectable stage IIIA 
non small cell lung cancer (NSCLC): a phase II multicenter exploratory study.  
 
B. 
Type of clinical trial: Open-label, multicenter, Phase II single-arm clinical trial.  
 
C. 
Trial products description 
 
 
 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.1 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. Nivolumab is expressed in Chinese hamster ovary (CHO) cells and is produced using 
standard mammalian cell cultivation and chromatographic purification technologies. The 
clinical study product is a sterile solution for parenteral administration. 
 
D. 
Sponsor details  
 
Fundación GECP 
  
Avda.Meridiana 358, 6ª planta 
  
08027 Barcelona  
 
 
 
E. 
Technical director responsible for sample production/control 
 
Not applicable since the product is commercially available  
 
 
 


  
 
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F. 
Monitor identification 
 
 
 
 
Fundación GECP CRA 
Meridiana 358, 6ª planta 
08027 Barcelona 
+34 93 430 20 06 
 
 
 
Fundación GECP Lead CRA 
Meridiana 358, 6ª Planta 
08027 Barcelona 
+34 93 430 20 06 
 
 
 
G. 
Trial investigators and participant study centers 
This trial will be carried out in 25 participant study sites in Spain. 
      
H. 
Proposed trial duration 
 
7.5 years (1.5 years recruiting patients, 1 year of adjuvant treatment of the last patient included 
and 5 years of follow up) 
 


  
 
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4. 
RATIONALE AND OBJECTIVES 
 
 
4.1 
BACKGROUND AND INTRODUCTION 
Lung cancer is the primary cause of cancer mortality in western countries. Approximately 80% of lung 
cancers are non-small-cell lung cancer (NSCLC).  
In Spain occur about 18,800 new cases per year1 and has been responsible for 19,513 deaths in 2006, 
twice the mortality of colon cancer (the most common tumor in absolute terms in Spain) 2 and NSCLC 
accounts for 85% of newly diagnosed cases. Most patients are diagnosed with unresectable disease 
and around 40% advanced3 disease. The cure is unlikely in patients with NSCLC and locally advanced 
stage who are not surgical candidates, with a 3-year survival rate of 27% in those patients receiving 
chemotherapy and concomitant radiotherapy4. On the contrary, in localized stages (stage I, II, IIIA) with 
surgical resection and cytostatic therapy, a survival of 5 years of 51% 5 is achieved and those with an 
absolute benefit in survival at 5 years of 5.4%, especially in patients with good performance status (PS) 
6. 
 
At diagnosis, at least 40% of patients are diagnosed at an advanced stage and a third locally advanced 
disease (stage III). We understand as locally advanced disease when the tumor exceeds the lung 
structures, but without clinical evidence of distant spread, and are a very heterogeneous group of 
patients with a controversial treatment based on a combination of surgery, chemotherapy and 
radiotherapy. 
In the past, radiation therapy was considered standard therapy for patients with stage IIIA and IIIB, but 
presented poor survival with poor local control and early development of distant disease. Patients with 
inoperable stage III treated with chest radiation therapy alone, had a median survival of 11.9 months, 
survival at 2 years of 10-20% and 3 years 5-10% 7. 
Currently, there is no consensus on the best standard treatment and it has been demonstrated that 
the experience of the therapeutic team plays an important role in the decisions to take. 
 
Only 25-30% of the NSCLC are candidates for curative-intent surgery. The rest are advanced local 
tumors or widespread metastases. Survival at 5 years depends, among other factors, on the size of the 
tumor and lymph node involvement. But even without mediastinal involvement, less than half of the 
patients survive more than 5 years and the majority dies of disseminated metastases. 
  
Patients with stage IIIA disease with clinically evident N2 nodal spread have an overall 5-year survival 
rate of only 10%-15%, although this falls to 2%-5% in those with bulky mediastinal N2 involvement. The 
surgical management of stage IIIA NSCLC remains highly controversial and most patients with stage IIIB 
disease are generally considered inoperable. The aims of therapy in stage III NSCLC are to increase 
both locoregional and systemic control of the disease. As a matter of fact, it is reported that at least 
80% of patients treated with local modalities alone will have micrometastases and will relapse.  These 


  
 
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aims could in some way be in conflict and may require different combined modality therapy 
sequencing strategies. Success in achieving them is measured in time of progression, survival and cure 
rate. Strategies that have been investigated include induction chemotherapy, concomitant 
chemoradiotherapy, intensified radiotherapy and adjuvant treatment. Since distant metastases remain 
the major site of failure, it is likely that more effective cytotoxic or other anti-tumor agents will be 
required further to improve current levels of response and survival8. Meta-analysis has suggested that 
cisplatin-based induction chemotherapy prior to surgery reduces risk of death by 13 % and increased 
absolute 5 year survival rates by 5%9. Neoadjuvant therapy has theoretical advantages: in vivo 
assessment of response to chemotherapy helps identify patients who will potentially benefit from 
adjuvant chemotherapy, early treatment of micrometastatic disease, reduction in drug resistance by 
early exposure to treatment and downstaging with improved resectability. Potential disadvantages 
include: delay in local therapy secondary to toxicity, risk progression in chemoresistant patients and 
pre-operative complications. 
Several newly available chemotherapeutic agents are both highly active against NSCLC and potent 
radiosensitizers. 
The results of stage IIIA with induction treatment of clinical practice outside the clinical trial show a 
median survival of 22 months and a 3-year survival rate of 34%10. An EORTC study11  with  carboplatin 
and paclitaxel used as induction regimen in patients with biopsy-proven stage N2 non-small cell lung 
cancer of the 52 eligible patients, 33 patients responded, one CR and 32 PR, for an overall response 
rate of 64% (95% CI, 48%- 76%). In addition, there were 10 patients with no changes (10%) and 9 with 
progressive disease (17%). The median duration of survival was 20.5 months (95% CI, 16.1-31.2 
months) with an estimated 1-year survival rate of 68.5% (95% CI, 55.2-81.7). Furthermore, phase II 
neoadjuvant studies of docetaxel alone, in combination with cisplatin or carboplatin, or in combination 
with platinum and gemcitabine have produced promising results, with more recently reported RRs 
ranging from 44 to 82% and rates of complete resection raging from 67 to 79%12 
 
Prognostic factors after neoadjuvant therapy 
 
Complete surgical resection13, 14, tumor downstaging and pathologic complete response are predictors 
of long term survival following neoadjuvant therapy.  
Pathologic complete response after induction chemotherapy generally ranges from 0% to 9.5%others 
higher complete response: one Martini15with 16.7% and one Kumar with 15%16 are rare.  
Andre analyzed a cohort of 702 patients with resected N2 disease and identified four negative factors: 
preoperative clinical N2 status, involvement of multiple lymph node levels, pathological T3 or T4 
disease, and absence of preoperative chemotherapy17 . Choi et al18, reviewed cases of pathologic 
proven N2 disease, complete resection rate was 83,2% and overall 5-year was 23,3%. Five-year 
recurrence –free survival was 19,6%. Among 19 clinicopathological prognostic factors, incomplete 
resection and non-downstaging after neoadjuvant therapy were unfavorable prognostic factors in 
univariate analyses. Clinical N2 status, multiple N2 nodes, and cell type of adenocarcinoma showed 


  
 
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poor prognosis but were not statistically significant. Postoperative chemotherapy showed good 
prognosis but was not statistically significant. Multivariate analysis showed that significant favorable 
prognostic factors were complete resection and adjuvant chemotherapy19. Experience of Memorial 
Sloan-Kettering Cancer Center confirms survival is significantly influenced by patient age, the median 
survival for complete resection 27.8 months compared with 11.4 months for incomplete resection, 
pathologic stage with 3-year survival for N0/N1 was 43.3% and 25.5% for N2 patients20. 
An emerging hallmark of cancer is immunoevasion—the cancer cell’s ability to avoid destruction by the 
immune system. The three general categories of immunoevasive mechanisms include: (A) an 
insufficient number of T cells generated within the lymphoid compartment; (B) an insufficient number 
of T cells extravasating into the tumor; and (C) inhibition of T cells in the tumor microenvironment. The 
tumor microenvironment, in turn, offers three main immunoevasive tools: (1) surface membrane 
proteins that function as immune checkpoints, including PD-1, CTLA-4, lymphocyte-activation gene 3 
(LAG-3) protein, T-cell immunoglobulin and mucin domain–containing protein 3 (TIM-3), B- and T-
lymphocyte attenuator (BTLA), and the adenosine A2a receptor (A2aR); (2) the relationship between 
selected soluble factors and metabolic alterations, such as IL-10, transforming growth factor beta, 
adenosine, indoleamine 2,3-dioxygenase (IDO), and arginase; and (3) inhibitory cells, including cancer-
associated fibroblasts (CAFs), regulatory T cells, myeloid-derived suppressor cells (MDSCs), and tumor-
associated macrophages.  
   
The immune response and the use of strategies to upregulate surface proteins, including programmed 
death 1 (PD-1), is a new approach for the treatment of tumors. PD-L1 overexpression has been 
observed in 40% - 50% of all NSCLC tumours, on the set of all stages and histologies21. Targeted 
therapy to PD-1 receptor and to PD-L1 ligands is intended to inhibit their intervention and is an 
attractive therapeutic option in the locally advanced NSCLC stage, which can reactivate the host 
immune responses and allow good long term control of the tumor22.  
In lung cancer, inhibition of the Check Point PD-1 pathway with antibodies directed against PD-1 or 
against its ligand, PD-L1, has showed preliminary and encouraged results that suggest a "class effect" 
and validate this pathway as a therapeutic target in NSCLC.  
Results from cohorts of heavily pretreated NSCLC patients in phase I studies showed objective 
responses dose dependent, ranging from 10% to 32%23. 
Inhibition of the Checkpoint PD-1 pathway with antibodies against PD-1 or PD-L1 produces long lasting 
tumor response and stable disease as well, for more than 6 months.  
Exploratory analysis of PD-L1 tumor expression and treatment response have confirmed the 
prevalence of > 40% of PD-L1 expression in NSCLC. Some studies suggest an association between 
treatment response and PD-L1 tumor expression before treatment.  
However, PD-L1 expression role as a biomarker for response has not yet been validated. 
Immunotherapy with antibodies anti-PD-1 and anti-PD-L1 in many different tumors types has been, in 
general, well tolerated.  Frequent adverse events related to the drug are limited episodes of grade 1 or 
2 fatigue, diarrhea, rash, pruritus, nausea and decreased appetite.  


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           19 
 
In clinical trials, grade 3 or 4 adverse events related to the treatment occur in < 15% of patients. 
Inmune related adverse events treatment related are infrequent (<2%) and include pneumonitis, 
vitiligo, colitis, hepatitis, thyroiditis and hypophysitis24  
Numerous ongoing trials are evaluating the combination of chemotherapy and checkpoint blockade in 
solid tumors, including melanoma, NSCLC, and SCLC. In untreated metastatic melanoma, a phase III 
study showed that ipilimumab (at 10 mg/kg) plus dacarbazine improved OS compared with 
dacarbazine alone (11.2 vs 9.1 months, respectively), but this was at the expense of higher toxicity and 
there was no ipilimumab-alone comparator arm  A phase II study showed that phased but not 
simultaneous ipilimumab plus platinum doublet chemotherapy (carboplatin/paclitaxel) improved 
immune-related PFS in patients with stage IIIB or IV NSCLC and extensive-stage SCLC, when compared 
with chemotherapy alone25, 26. The choice of chemotherapy and dosing schedule are thus critical to 
optimizing outcomes of checkpoint blockade and chemotherapy combinations. With this in mind, a 
phase I four-cohort study evaluated first-line nivolumab at 10 mg/kg (N10) vs 5 mg/kg (N5) in 
combination with gemcitabine/cisplatin (N10) in advanced squamous-cell NSCLC, pemetrexed/cisplatin 
(N10) in advanced nonsquamous NSCLC, and paclitaxel/carboplatin (N5 vs N10) in combined cohorts of 
squamous and nonsquamous NSCLC27 .The toxicity profile was additive, representing effects of both 
nivolumab and chemotherapy. The ORR, PFS, and 1-year OS outcomes were acceptable. In particular, 
the 1-year OS rate was 85% for the N5 paclitaxel/carboplatin group and 87% for the N10 
pemetrexed/cisplatin group, which may reflect a positive signal. 
A phase Ib study enrolled untreated patients with locally advanced or metastatic NSCLC to three 
treatment arms of atezolizumab plus chemotherapy, including carboplatin/pemetrexed, 
carboplatin/paclitaxel, and carboplatin/nab-paclitaxel28. Atezolizumab at 15 mg/kg every 3 weeks was 
administered with standard chemotherapy for 4 to 6 cycles followed by atezolizumab maintenance or 
atezolizumab/pemetrexed maintenance in the carboplatin/pemetrexed arm. A preliminary analysis on 
41 patients showed that the ORR was 64% (95% CI, 46.9–77.9) by RECIST, with the 
carboplatin/pemetrexed arm having the highest response rate at 75% (95% CI, 45–93). The four 
complete responses occurred in the carboplatin/nab-paclitaxel arm. The toxicity profile was as 
expected for chemotherapy, and no pneumonitis was observed. There was one grade 5 adverse event 
in a patient in the carboplatin/nab-paclitaxel arm who developed candidemia after prolonged 
neutropenia. Overall, the combination therapy response rates exceeded the 30% traditionally 
expected with platinum doublet chemotherapy; more mature data are forthcoming. 
In this study, prospective tissue and blood samples will be obtained from all patients to increase our 
knowledge of the predictive value of molecular variables. Determining mutational profiles is crucial in 
NSCLC. The relationship between known promoters or other mutations and PD-L1 status and clinical 
outcomes will be studied29. 
 
Other markers, such as IFN-γ, TNF-α (tumor necrosis factor), and IL-2, IL-6, IL-10, IL-8 and IL-12 may 
have a correlation with clinical outcomes and response to treatment. In addition to these correlation 
studies that are planned prospectively, it will be preserved in tissue banks. 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           20 
 
 
Rationale for Nivolumab 360 mg Flat Dose 
 
Nivolumab monotherapy has been extensively studied in NSCLC patient population in studies 
CA209003, CA209063, CA209017, and CA209057 with body weight normalized dosing (mg/kg). 
Nivolumab pharmacokinetics (PK) and exposures of subjects in these studies have been characterized 
by population pharmacokinetic (PPK) analysis of data collected from these studies, together with PK 
data from several Phase 1, 2, and 3 clinical studies of nivolumab monotherapy in solid tumors. 
Nivolumab PK was determined to be linear, with dose proportional exposures over a dose range of 0.1 
to 10 mg/kg. Nivolumab clearance and volume of distribution was found to increase with increasing 
body weight, but the increase was less than proportional, indicating that mg/kg dose represents an 
over-adjustment for the effect of body weight on nivolumab PK. 
 
Flat dosing offers several advantages over body weight normalized dosing, including reduced potential 
for dosing errors and shortened dosage preparation time. A flat dose of 360 mg every 3 weeks is 
expected to produce the equivalent average exposure to 3 mg/kg every 2 weeks at the median body 
weight of ~80 kg in nivolumab-treated subjects. 
A PPK model predicted overall nivolumab exposures across subjects with a wide range of body weight 
(35-160 kg) for a 360 mg every 3 weeks flat dose to be similar to that from 3 mg/kg every 2 weeks. 
Although the flat dose is expected to lead to higher exposure in lighter patients, relative to the 
exposure in heavier patients given the relationship between nivolumab PK and body weight, the 
predicted median and 95th percentile of exposures from these regimens are maintained well below 
those in 10 mg/kg every 2 weeks, which was established as a safe and well-tolerable dose. 
 
In addition, data from the Japanese Phase 1 study ONO-4538-01 did not demonstrate 
doselimitingtoxicity at nivolumab up to 20 mg/kg every 2 weeks in Japanese subjects and showed 
similarity in PK properties between Global and Japanese population. Therefore, the proposed 360 mg 
flat dose is expected to be safe and tolerable in an Asian population. 
Nivolumab 5 or 10 mg every 3 weeks plus platinum-based chemotherapy was evaluated in CA209012 
and deemed to be tolerable. In addition, nivolumab 360 mg every 3 weeks plus platinum-based 
chemotherapy is further being evaluated in the global randomized Phase 3 trial (CA209227). 
 
Rationale for Nivolumab 240 mg Q2W and 480 mg Q4W as adjuvant treatment 
 
The every 4-week schedule (Q4W) will be more convenient for subjects.  
Based on pharmacokinetic modeling, the 480 mg Q4W (after steady state is reached with 3 mg/kg or 
240 mg every 2 weeks for 4 months) will provide steady-state average concentrations similar to 3 
mg/kg or 240 mg Q2W, which has been shown to provide longer survival in NSCLC patients.  
However, 480 mg Q4W is expected to result in higher (approximately 20%) steady-state maximum 
concentration (peaks), and lower (approximately 10%) steady-state trough concentrations compared 
to steady state of 3 mg/kg Q2W. Nivolumab was adequately tolerated up to 10 mg/kg, the highest 
dose level tested, and no maximum tolerated dose was identified. In addition, the exposure-response 
relationship for safety is flat. Thus, a slight increase in the steady-state maximum concentration is not 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           21 
 
expected to increase the safety risk of nivolumab. However, a marginal decrease in steady-state trough 
concentration is not expected to reduce the efficacy as high trough concentrations and > 90% intra-
tumoral receptor occupancy are still maintained at 480 mg Q4W dose. Nivolumab 480 mg Q4W is 
expected to have similar efficacy and safety profile to 3 mg/kg Q2W. 
 
Rationale for the correlative’s studies regarding tumoral microenvironment and response biomarkers 
 
Immunotherapy is the routine treatment for advanced non-small cell lung cancer (NSCLC), a cancer 
with a high incidence and mortality rate. The next step is the locally advanced stage, in this field the 
Fundación GECP has sponsored the study NADIM, which is testing the benefit of using immunotherapy 
together with chemotherapy as a neoadjuvant treatment in patients with stage IIIA NSCLC. Currently, 
the preliminary data for this new setting is encouraging, showing a rate of complete pathological 
responses never seen before for in these patients. 
 
However, due to its novelty, there are currently no good biomarkers available to identify which 
patients will benefit most from this type of treatment.  
Combining patients’ clinical data and their tumor microenvironment molecular information, this 
study will identify new predictive biomarkers of response to chemo-immunotherapy. For this 
purpose, biopsies of tumor tissue before and after treatment will be analyzed, as well as liquid 
biopsies from 5 time points (before and after neoadjuvant treatment, 6 and 12 months of 
adjuvant treatment, and after a relapse). 
Different lymphocyte populations (NK, T and B cells), their activation levels and the TCR 
repertoire will be studied. On the other hand, levels of gene expression related to inflammatory 
signature and immune evasion in the tumor, as well as the levels of different modulating factors 
such as cytokines and metabolic changes will be analysed. In addition, cfDNA will be collected 
from blood samples to analyse tumor mutations through ddPCR at diferent timepoints. 
The knowledge derived from this study could improve the selection of patients, reducing 
unnecessary patient treatment and reducing costs for the NHS. It can also identify relevant new 
pathways and resistance mechanisms for the development of new personalized therapies to 
rescue non-responders. 
 
 
4.2.     WORKING HYPOTHESIS 
 
Chemotherapy stimulates an immune response against tumors, which may facilitate immunotherapy´s 
anticancer activity. Evidence of synergy between chemotherapy and immunotherapy was shown in 
several studies. The feasibility of combining both targeted agents and immunotherapy is also being 
studied in the CheckMate 012 trial and more recently in CheckMate 227 phase III study. 
This approach can be used in N2, the combination of chemotherapy based on platine doublets + 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           22 
 
immunotherapy with anti PD1 (nivolumab) could be feasible achieving good responses and tumor 
donwstaging; in addition, the possibility to study in vivo the presence of tumor biomarkers and analyze 
the expression of different immune markers and TILs/ frequency and functional activity of Tregs within 
the tissue.   
4.3. 
OBJECTIVES 
 
Primary objective:  
 
- 
To assess the efficacy of the combination of chemotherapy with immnutherapy in NSCLC, PFS 
at 24 months from diagnosis.  
 
 
Secondary objectives:  
 
- 
Assess the toxicity profile of the combination, the down-staging rate, complete resection rate, 
time to progression and overall survival at 5 years (follow up visits after adjuvant treatment, 
every 3 months for 1 year, every 4 monts the second year and every 6 months the following 5 
years). Also, surgical outcome and surgical complications will be assessed. 
- 
Perform correlatives studies with the objectives of exploring the expression of other 
biomarkers, such as PD-L1, in tumor tissue: at screening and after surgery (resected tumor 
sample), free DNA and circulating tumor cells in liquid biopsy 
- 
To describe whether PD-L1 expression is a predictive biomarker for ORR 
- 
To describe Progression Free Survival (PFS) in PD-L1+ (>=1%) population 
- 
Report imaging response vs pathological response rate 
- 
To describe the tumoral microenvironment and to identify response biomarkers and resistance 
mechanisms to neoadjuvant chemo-inmune treatment and which of them are accessible by 
liquid biopsy: 
In Tumor tissue: 
o To characterize the immune microenvironment in pre- and post-treatment tumoral 
biopsies by Multiplexed immunofluorescence. 
o To analyze mRNA levels of immune-oncology and metabolism related genes.  
o To characterize TCR locus clonality using next generation sequencing (NGS) on tissue. 
In Blood: 
o To characterize the different populations, proportions, metabolism and activation levels 
of T cells, B cells and NK cells from patients treated with chemo-immunotherapy and on 
healthy adults as a control.  
o To characterize TCR locus clonality using next generation sequencing (NGS) on PBMCs. 
o To analyze the levels of 160 cytokines secreted by the tumor microenvironment on 
patient plasma and healthy controls. 
o To analyse mutations in cfDNA from patients’ blood 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           23 
 
 
 
5. 
CLINICAL TRIAL TYPE AND DESIGN 
5.1. 
CLINICAL TRIAL TYPE 
 
Open-label, multicenter, phase II, single-arm clinical trial 
5.2.  
DESIGN OF THE STUDY 
 
Prospective, phase II, single-arm, open-label, and multicenter study that assesses feasibility, safety and 
potential efficacy of combined neo-adjuvant chemotherapy and immunotherapy with Nivolumab 360 
mg IV + Paclitaxel 200mg/m2 + Carboplatin AUC 6 IV Q3W as neoadjuvant treatment followed by 
Nivolumab 240 mg IV Q2W for 4 months and Nivolumab 480 mg IV Q4W for 8 months as adjuvant 
treatment during 1 year in resectable stage IIIA NSCLC patients. 
 
 
 
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           24 
 
 
6. 
PATIENT SELECTION CRITERIA  
 
 
There will be NO EXCEPTIONS to eligibility requirements at the time of registration. Questions 
about eligibility criteria should be addressed prior to registration or randomization. 
 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are 
standards used to ensure that patients who enter this study are medically appropriate 
candidates for this therapy. For the safety of the patients, as well as to ensure that the results 
of this study can be useful for making treatment decisions regarding other patients with similar 
diseases, it is important that no exceptions be made to these criteria for admission to the 
study. 
 
Patients must fulfill all of the following criteria to be eligible for admission to the study. 
 
6.1. 
INCLUSION CRITERIA 
Target Population 
 
1. The subjects eligible for the study are those with histologically- or cytologically- documented 
NSCLC who present stage IIIA disease (according to version 8th of the International Association 
for the Study of Lung Cancer Staging Manual in Thoracic Oncology) and previously untreated. 
Locally advanced patients who present stage IIIA by the previous version can be included if are 
considered potencially resectable. In case of N2 disease suspicion, pathological assessment by 
EBUS, mediastinoscopy or thoracotomy has to be carried out for N2 confirmation. 
 
2. Tumor should be considered resectable before study entry by a multidisciplinary team.  
 
3. Performance Status of 0 or 1 if using ECOG/Zubrod. 
 
 
4. Screening laboratory values must meet the following criteria and should be obtained within 14 
days prior to registration/inclusion. 
i. WBC   
≥ 2000/μL 
ii. Neutrophils  ≥ 1500/μL 
iii. Platelets 
 ≥ 100 x103/μL 
iv. Hemoglobin  > 9.0 g/dL 
v. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using 
the Cockcroft-Gault formula below): 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           25 
 
a. Female CrCl = (140 - age in years) x weight in kg x 0.85 
1. 72 x serum creatinine in mg/dL 
 
b. Male CrCl = (140 - age in years) x weight in kg x 1.00  
a. 72 x serum creatinine in mg/dL 
vi. AST/ALT  
≤ 3 x ULN  
vii. Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have 
total bilirubin < 3.0 mg/dL)  
viii. INR/APTT within normal limits 
5. The patients need to have a forced expiratory volume (FEV1) ≥ 1.2 liters 
6. All patients are notified of the investigational nature of this study and signed a written 
informed consent in accordance with institutional and national guidelines, including the 
Declaration of Helsinki prior to any trial-related intervention 
 
Age and Reproductive Status 
 
7. Patients aged > 18 years 
 
8. Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. 
WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the 
time required for nivolumab to undergo five half-lives) after the last dose of investigational 
drug  
Women of childbearing potential 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 
9. Women must not be breastfeeding 
10. 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 (ie, who are 
postmenopausal or surgically sterile as well as azoospermic men do not require contraception) 
Women of childbearing potential are 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. In addition, women under the 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           26 
 
age of 62 must have a documented serum follicle stimulating hormone (FSH) level less than 
40mIU/mL.  
Women of childbearing potential receiving nivolumab will be instructed to adhere to contraception 
for a period of 23 weeks after the last dose of investigational product. 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. These durations have been calculated 
using the upper limit of the half-life for nivolumab (25 days) and are based on the protocol 
requirement that WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually 
active with WOCBP use contraception for 5 half-lives plus 90 days. 
 
Highly effective methods of contraception 
Male condoms with spermicide 
Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, 
injectables, implants and intrauterine devices (IUDs) such as Mirena by WOCBP subject or male 
subject’s WOCBP partner Female partners of male subjects participating in the study may use 
hormone based contraceptives as one of the acceptable methods of contraception since they will 
not be receiving study drug 
Nonhormonal IUDs, such as ParaGard 
Tubal ligation  
Vasectomy 
Complete Abstinence* 
 
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but female subjects must continue to have 
pregnancy tests. Acceptable alternate methods of highly effective contraception must be discussed 
in the event that the subject chooses to forego complete abstinence. 
 
Less effective methods of contraception 
Diaphragm with spermicide 
Cervical cap with spermicide 
Vaginal sponge 
Male Condom without spermicide  
Progestin only pills by WOCBP subject or male subject’s WOCBP partner  
Female Condom 
A male and female condom must not be used together 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           27 
 
6.2. 
EXCLUSION CRITERIA 
 
1. All patients carrying activating mutations in the TK domain of EGFR or any variety of alterations 
in the ALK gene.  
 
2. Patients with active, known or suspected autoimmune disease. Subjects with vitiligo, type I 
diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring 
hormone replacement or unexpected conditions of recurrence in the absence of an external 
trigger are allowed to be included. 
 
3. Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment. 
Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone 
equivalent, are permitted in the absence of active autoimmune disease. 
 
4. Patients with a history of interstitial lung disease cannot be included if they have sympthomatic 
ILD (Grade 3-4) and/or poor lung function. In case of doubt please contact trial team. 
 
5. Patients  with other active malignancy requiring concurrent intervention and/or concurrent 
treatment with other investigational drugs or anti-cancer therapy 
 
6. Patients with previous malignancies (except non-melanoma skin cancers, and the following in 
situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) are 
excluded unless a complete remission was achieved at least 2 years prior to study entry AND no 
additional therapy is required during the study period. 
 
7. Any medical, mental or psychological condition which in the opinion of the investigator would 
not permit the patient to complete the study or understand the patient information  
 
8. Patients who have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 
antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune 
checkpoint pathways 
 
9. Patients with positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus 
ribonucleic acid (HCV antibody) indicating acute or chronic infection 
10. Patients with known history of testing positive for human immunodeficiency virus (HIV) or 
known acquired immunodeficiency syndrome (AIDS) 
11. Patients with history of allergy to study drug components excipients 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           28 
 
6.3 PROPOSED NUMBER OF SUBJECTS AND SAMPLE SIZE 
 
The sample size is 46 patients recruited from 25 hospitals in Spain. 
 
6.4. WITHDRAWAL CRITERIA  
 
Patients may be withdrawn from the protocol under the following circumstances: 
 
a) Intercurrent illnesses or other reasons that, in the opinion of the investigator, would 
significantly affect the patient´s safety or render trial results for this patient unacceptable and 
those that require interruption of treatment.  
 
b) Unacceptable toxicity (defined in Section 7.5). 
 
c) Patient’s request to withdraw from the study. 
 
d) Protocol non-compliance or study termination by Sponsor  
 
Specific reasons for trial discontinuation include (further collection of data is not allowed):  
 
o Withdrawal of consent  
o Patient lost to follow-up  
o  Death  
 
 
All possible measures will be undertaken to maintain the investigation program and to continue the 
follow-up even if the treatment was prematurely concluded and/or if the patient did not attend the 
follow-up visits at the participating institution.  
 
6.5 
RECRUITMENT PERIOD DURATION AND FOLLOW UP 
 
Recruitment period: 1.5 years. Follow up: 5 years 
 
 
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           29 
 
 
7. 
TREATMENT DESCRIPTION 
 
 
7.1 
 CARBOPLATIN 
 
Structure: 
The cis-diamino (cyclobutan-1, 1 dicarboxilate) platin. 
 
 
Stability: 
24 hours at ambient temperature in 5% glucose, glucosaline or physiologic saline. 
It is recommended not to dilute with chlorinated solutions since this could affect 
the cisplatin. 
 
Route of administration: Intravenous infusion. 
 
7.2 
PACLITAXEL 
 
 Structure: 
A diterpene whose composition is: 5β, 20-epoxi-1, 2α, 4,7β, 10β, 13α-
hexahidroxytax-11-en 9 one 4,10-diacetato 2-benzoate 13-ester with (2R,3S)- N-
benzoyl-3-phenylisoserine. 
 
 
Stability: 
Concentrations of 0.3-1.2 mg/ml in 5% dextrose or normal saline have 
demonstrated chemical and physical stability for more that 27 hours at ambient 
temperature (25ºC approximately). The intact vial must be stored between 15º 
and 25ºC.  
 
 
 
 
 
Route of administration: Intravenous infusion. 
 
7.3. 
NIVOLUMAB 
 
Structure: 
Nivolumab is a soluble protein consisting of 4 polypeptide chains, which include 
2 identical heavy chains and 2 identical light chains. 
 
 
Route of administration: Intravenous infusion. 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Storage Conditions & Handling: 
 
• Store at +2°C - +8°C (36-46°F), protect from light, freezing, and shaking. If stored in a glass front 
refrigerator, vials should be stored in the carton. 
• If any temperature excursions are encountered during storage, please report these to - Fundación 
GECP 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. 
Recommended safety measures for preparation and handling of nivolumab include laboratory 
coats and gloves. 
• Partially used vials should be disposed at the site following procedures for the disposal of 
anticancer drugs.  
 
For additional details on prepared drug storage and use time of nivolumab under room 
temperature/light and refrigeration, please refer to the BMS-936558 (nivolumab) data sheet section 
for “Recommended Storage and Use Conditions” 
 
 
Product Description: 
Product 
Description 
and Dosage 
Form 
Potency 
Primary 
Packaging 
(Volume)
/ Label 
Type 
Secondary 
Packaging 
(Qty) /Label 
Type 
Appearance 
Storage 
Conditions 
(per label) 
Nivolumab 
(BMS-
936558-01)* 
Injection 
drug product 
is a sterile, 
non-
pyrogenic, 
single-use, 
isotonic 
aqueous 
solution 
formulated 
at 10 mg/mL   
100 
mg/Vial 
(10 
mg/mL). 
Carton of 5 
or 10 vials 
10-cc Type 1 
flint glass vials 
stoppered 
with butyl 
stoppers and 
sealed with 
aluminum 
seals. 
Clear to 
opalescent, 
colorless to pale 
yellow liquid.  
May contain 
particles 
BMS-936558-01 
Injection must be 
stored at 2 to 8 
degrees C (36 to 
46 degrees F) and 
protected from 
light and  freezing  


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           31 
 
 
 
Guidelines for Nivolumab administration 
 
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 for up to 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 should be inclusive of the includes the product administration period. 
 
After final drug reconciliation, unused nivolumab vials should be disposed at the site following 
procedures for the disposal of anticancer drugs.  
TREATMENT SCHEDULES 
 
1. 
Neodjuvant Chemotherapy scheme:        
 
Administration of 3 cycles at 21-day intervals (+/-3 days) prior to surgery 
Nivolumab 360 mg IV Q3W over 30 minutes 
Paclitaxel: 200mg/m2 infusion over 3 hours  
Carboplatin: AUC6 at the end of the Paclitaxel infusion 
 
2. 
Surgery 
 
Within the 3rd-4th week from day 21 of cycle 3 of neoadjuvant treatment (day 42-49 after 
first day of cycle 3) 
3. 
Nivolumab as adjuvant therapy  
Within the 3rd to 8th week from surgery and for 1 year in patients that had response by 
surgical pathology evaluation 
Nivolumab 240 mg IV Q2W(+/-3days) over 30 minutes for 4 months followed by 
nivolumab 480 mg Q4W(+/-3 days) over 60 minutes for 8 months 
 
Radiotherapy is not allowed at any time.  
 
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           32 
 
7.4. 
SPECIAL REQUIREMENTS FOR THE HANDLING OF THE STUDY DRUGS 
 
7.4.1.  Dosage and Administration of Nivolumab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Dose Modifications 
 
  
 
      7.4.2.     Administration of Carboplatin 
 
Carboplatin must be administered by intravenous infusion, according to the standards of each 
center.  
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           33 
 
      7.4.3.  
Administration of Paclitaxel 
 
Guidelines for Paclitaxel administration  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           34 
 
7.5. 
 DOSE DELAY/REDUCTION CRITERIA 
 
 
7.5.1. NIVOLUMAB  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           35 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Management Algorithms 
 
 
 
 
 
  
 
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           36 
 
Discontinuation Criteria 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
• 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           37 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
Treatment of Nivolumab Related Infusion Reactions 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           38 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           39 
 
7.5.2. PACLITAXEL AND CARBOPLATIN 
Dose modification based on Hematological toxicity criteria 
 
 
Decrease Paclitaxel, Carboplatin one dose level in case of: 
 
- 
 
 
 
 
 
 
 
 
 
 
 
Suspension of treatment until hematological recovery:  
 
 
 
 
  
 
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           40 
 
 
 
 
Dose modification based on non-hematological toxicity criteria 
 
The toxicity effects are graded using the new toxicity criteria (CTC) of the NCI (National Cancer 
Institute) (Appendix B). If for a given symptom the NCI system does not describe a grade, the 
toxicity will be described as: 
 
1= slight; 2= moderate; 3= severe; 4= life threatening; 5=fatal  
 
 
 
 
 
 
 
  
 
 
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           41 
 
 
 
 
 
  
 
 
 
 
 
  
 TOXICITIES 
 
 
 
 
 
 
 
 


  
 
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Guidelines for the re-initiation of treatment following hypersensitivity reactions 
 
 
 
 
 
  
 


  
 
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7.6. 
TREATMENT DURATION  
 
Patients will receive 3 cycles every 21 days (+/-3 days) of Paclitaxel, Carboplatin and Nivolumab prior to 
surgery. Adjuvant therapy with Nivolumab will be given for 1 year.  


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           44 
 
7.7 
PROHIBITED AND PERMITTED CONCOMITANT TREATMENTS 
 
 
 
 
 
 
  
 
Permitted Concomitant Therapy 
 
 
8. TRIAL PROGRESS AND PATIENT EVALUATION 
 
 
The investigation team of each center will be responsible for all treatment administration and 
evaluations throughout the study. 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           45 
 
 
 
8.1 
TRIAL PROGRESS 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           46 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           47 
 
 
8.2  
PATIENT EVALUATION  
 
8.2.1.     Pre treatment and Neoadjuvant treatment patient evaluation 
 
A complete history, physical  examination, complete blood cell count with differential serum 
biochemistry, spirometry, bronchoscopy, computed tomography (CT) scan of chest and upper 
abdomen and PET-CT and an electrocardiogram are obtained at baseline.  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           48 
 
 
 
 
Patients are monitored every 3 weeks with complete blood cell counts and recording of toxic 
events according the CTCAE v. 4.0. 
 
 
 
 
 
 
  
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
  
 
 
8.2.2.     Surgery 
 
 
  
 
  
 
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           49 
 
  
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           50 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.3.     Adjuvant treatment patient evaluation 
 
 
 
. 
 A complete history, physical examination, complete blood cell count with differential serum 
biochemistry has to be done during adjuvant treatment  
 
 
 
 
  
 
Adverse events have to be followed for 1 year and until 100 days from the last dose of 
Nivolumab. 
 
 
 
 
 
8.2.4     Follow up 
 
A complete history, physical examination, complete blood cell count with differential and 
serum biochemistry has to be done.  
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           51 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
8.2.5 Analysis of CT-SCANs performed on patients during the study 
 
 
Analysis the CT SCANs images for the NADIM included and valid patients will be analysed over 
time for patient outcome prediction. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           52 
 
 
 
 
 
. 
 
9. 
ADVERSE EVENTS  
 
 
9.1. 
GENERAL INFORMATION  
 
Adverse events (AE): 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. 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. 
The medical occurrence is considered as an AE when it occurs from the day of enrolment in the 
study until 100 days after the final dose of IMP, regardless of whether it is considered related to 
the trial treatment.  
The relationship of the adverse event with the administered trial treatment is determined by a 
physician and should be used to assess all adverse events (AE). The casual relationship can be 
one of the following: 
- Related: There is a reasonable causal relationship between study drug administration 
and the AE. 
- Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.  
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.) 
The severity and causality will be classified according to the NCI CTCAE v.4. The CTCAE is 
available for downloading on the internet, see Appendix B.  
The adverse event severity grade provides a qualitative assessment of the extent or intensity of 
an adverse event, as determined by the investigator or as reported by the patients.  The 
severity grade does not reflect the clinical seriousness of the event, only the degree or extent 


  
 
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of the affliction or occurrence (e.g. severe nausea, mild seizure), and does not reflect the 
relationship to study drug. 
Severity grade for other adverse events not covered in the toxicity grading scale: 
 
 
1 = Grade 1 
Mild 
2 = Grade 2 
Moderate 
3 = Grade 3 
Severe 
4 = Grade 4 
Life-threatening 
5 = Grade 5 
Fatal 
 
 
Serious Adverse Event (SAE): Defined as any untoward medical occurrence that at any dose:  
• results in death (fatal due to any cause) 
• is life-threatening (defined as an event in which the subject was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if 
it were more severe) 
• requires inpatient hospitalization or causes prolongation of existing hospitalization  
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect  
• is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention [eg, 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above.) Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.)  
• 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.  
• Although pregnancy, overdose (defined as accidental or intentional dose of a product that is 
considered both excessive and medically important), and cancer are not always serious by 
regulatory definition, these events must be handled as SAEs. 
• Second malignancies are always considered SAEs, no matter when they are diagnosed. 
These events should be reported on the Serious Adverse Event Forms. 
 


  
 
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Other definitions 
Non-serious adverse event: All adverse events not classifiable as severe.  
Unexpected adverse event: An event not described in nature in terms of gravity or 
incidence and not included in the basic product information (data sheet)  
Expected adverse event: An event described in the basic product information (data 
sheet). 
Adverse event associated with the use of the drug: Adverse event with a reasonable 
possibility of being related to the drug (adverse reaction).  
 
 
9.2 
ADVERSE EVENTS ASSOCIATED WITH NIVOLUMAB 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Target Adverse Events 
 
 
 
 
 
  
 
 
 
 
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           56 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.2.1. Pulmonary Adverse Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.2.2. Gastrointestinal Adverse Events 
 
 
 
 
 
  


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           57 
 
 
9.2.3. Hepatic Adverse Events 
 
 
 
 
 
 
9.2.4. Endocrinopathies 
 
 
 
 
 
 
 
 
 
. 
 
9.2.5. Skin Adverse Events 
 
 
 
 
  
 
9.2.6. Renal Adverse Events 
 
 
 
 
  
 
9.2.7. Neurologic Adverse Events 
 
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           58 
 
 
 
 
 
 
9.2.8. Lipase/Amylase Elevations 
 
 
 
 
 
 
 
 
 
 
9.2.9. Uveitis and Visual Complaints 
 
 
 
 
  
 
9.2.10. Infusion Reactions 
 
 
 
 
 
 
 
9.2.11. Overdose, Warnings, and Precautions 
 
 
 
. 
 
 
 


  
 
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9.2.12. Precautions for Women of Childbearing Potential 
 
The nonclinical findings of increased late-stage pregnancy loss and early infant deaths/euthanasia in 
nivolumab-exposed pregnant monkeys suggest a potential risk to human pregnancy if there is 
continued treatment with nivolumab during pregnancy. Given the potential risk suggested by 
preliminary data from nonclinical and clinical data, dosing during pregnancy will continue to be 
prohibited. In addition, women of childbearing potential (WOCBP) receiving nivolumab will be 
instructed to adhere to contraception 
 
 
 
 
9.3. ADVERSE EVENTS ASSOCIATED WITH PACLITAXEL 
 
The Paclitaxel data sheet provides detailed information on adverse events observed during Phase 
I/Phase II trials with Paclitaxel  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           60 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           61 
 
 
9.4. 
ADVERSE EVENTS ASSOCIATED WITH CARBOPLATIN 
 
  
 
 
  
 
1. Hematological toxicity 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
2. Gastrointestinal toxicity        
 
 
 
 
 
3. Neurotoxicity 
 
 
  
 
 
 
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           62 
 
 
  
 
4. Nephrotoxicity 
 
 
  
 
5. Hepatotoxicity  
 
 
 
 
 
 
6. Allergy 
 
 
 
 
 
 
7. Others 
 
 
 
  
  
         
9.5. 
 CAUSALITY CRITERIA 
 
The investigator will use the following definitions to evaluate the possible relationship between the 
adverse event and the medications of the study: 
 
- 
Not related: Any event, illness or effect of other medications not related with the medication of 
the study (e.g. if transitory, or not having temporal relationship with the study drug, or 
presence of a definitive alternative etiology). 
  


  
 
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- 
Related: A temporal relationship with the administration of the study drug of the study, which 
reappears on re-instatement and in which there does not appear to be an alternative etiology.  
 
 
9.6. 
 COMMUNICATION OF ADVERSE EVENTS 
 
An AE classified as SEVERE must conform to the legal requirements. When a severe AE occurs, based 
on the classification described above, the investigator must not only record it in the appropriate page 
in the CRF but must notify it IMMEDIATELY to the health authorities and to the Ethical Committee; as 
must all adverse events that are severe, unexpected and possibly related to the study treatment.    
 
Similarly, severe AE possibly related to the treatments in the study must be communicated by the 
study sponsor to the respective owners of the authorization of commercialization of the drugs used in 
the trial.  
 
9.6.1. Reporting SAE and targeted adverse events 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs that occur within 100 days of discontinuation of dosing must be 
reported.  
All SAEs that occur during the screening period must be reported. If applicable, SAEs that relate to any 
protocol-specified procedure (eg, a follow-up skin biopsy) must be reported.  The investigator should 
report any SAE that occurs after these time periods that is believed to be related to study drug or 
protocol-specified procedure.  
 
 
 
 
 
 
 
 
 
 
 
.  
 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           64 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
Fundación GECP (SLCG/GECP) Pharmacovigilance office will record the SAE and prepare a summary 
report of all SAEs received. Listings of SAEs will be prepared as required. 
Any SUSAR occurred during the trial will be notified under Spanish clinical regulation to the Health 
Authorities via Eudravigilance within the timelines specified in GCP. Also, the principal investigators 
must be informed. 
 
9.6.2. Nonserious Adverse Event Collection and Reporting 
The collection of nonserious AE information should begin at initiation of study drug. All nonserious 
adverse events (not only those deemed to be treatment-related) should be collected continuously 
during the treatment period and for a minimum of 100 days following the last dose of study treatment.  
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they become 
serious. Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study drug and for those present at the end of study treatment as appropriate.  
9.6.3. 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. 
 
 
 
 
 
 
 
  


  
 
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9.6.4. Pregnancy 
If, following the 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, 
 
  
 
 
  
 
 
 
 
 
 
 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Fundación GECP (SLCG/GECP) Pharmacovigilance office via Pregnancy Form.  
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. 
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 nonserious or serious AE, as appropriate, and reported 
accordingly. 
 
10. 
 ETHICAL ASPECTS 
 
10.1 
GENERAL CONSIDERATIONS 
 
The study will be conducted according to the requirements of the Helsinki Declaration as 
amended in Tokyo, Venice, Hong Kong and South Africa and will follow the Rules of Good 
Clinical Practice of the European Community as well as complying with current Spanish 
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Protocol approval by the Ethics Committee for Clinical Investigation (ECCI)  
 
Before starting the study, this protocol together with the informed consents (oral and written 
before witnesses) and the patient information documentation will be submitted for approval by 
the ECCI responsible. This notification of approval by the ECCI will be submitted to the clinical 
monitor together with the names and responsibilities of the Committee members. 
 
If the protocol needs to be amendmed, this amendment will be submitted for approval to the 
Ethic Committees and Health Authorities (if applicable). 
 
10.2 
INFORMED CONSENT 
 
 
Before recruitment and entry into the study, a complete explanation will be given to each 
patient eligible for participation in this study. The formula for informed consent will be 
submitted to the Ethical Committee responsible for assessment and approval. 
 
Once this essential information has been provided to the patient and the investigator has 
ensured that the individual candidate has understood the implications of participating in the 
study, the consent will be requested for participation in the study. In case that the subject is 
not able to give informed consent (for example, minors, mentally deficient, or physically 
incapacitated such as those who are comatose) this informed consent of the patient may be 
given by a legal guardian. Nevertheless, the consent of the patient must be obtained as well 
when he/she is capable of understanding the nature, importance and level of risk associated 
with the clinical trial. It is preferable that the person who gives the consent signs the form. If 
this is not possible, the verbally testified consent with the signature of the witness will be 
sufficient. In whichever of these two cases, the informed consent form will carry an additional 
note to the effect that it was obtained with informed consent.  
 
10.3 
CONFIDENTIALITY AND DATA PROTECTION 
 
The data obtained from this study will be assessed and used exclusively to obtain scientific 
conclusions. The identity of the patient is confidential and will be known only to the 
investigator and his/her collaborators, the auditors, monitors and inspectors of the relevant 
authorities. 
The samples and data collected will be coded to protect patient confidentiality. Each patient 
will have a unique identifier assigned by the EDC (Electronic Data Capture) system. Sites are 


  
 
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responsible to keep a patient log locally in order to be able to link the unique identifier to the 
record of the patient.  
 
Biological material will be assigned the same unique identifier. No identifiable / personal data 
will be stored in the trial database or the tissue repositories in the central labs. 
Biological material will be transferred outside the treating institution for central screening and 
review. Results of the assays will be coded only by the patient identifier. 
 
Regulatory authorities and pertinent Ethics Committees (IRB/ERB) may have access to patient 
data on-site.  
 
In Spain, to ensure the patient confidenciality of the data applies the Organic Law of protection 
of data 15/1999.  
 
10.4 
INSURANCE POLICY 
 
Spanish legislation demands cover with a civil responsibility policy for subjects participating in a 
clinical trial. The sponsor of the study provides this in accordance with the current legal 
requirements. 
 
 
11. 
PRACTICAL CONSIDERATIONS  
11.1 
RESPONSIBILITIES OF THE INVESTIGATOR 
 
- 
Provide guarantee of sufficient time for the completion of the study, with a competent 
team and appropriate equipment for the conduct of the study and to give assurance that 
no other study is being conducted that may divert patients away from the present study.    
 
- 
To efficiently record and maintain up-to-date data notes and other documents of the 
study.  
 
11.2 
RESPONSIBILITY FOR THE PRODUCT 
 
The investigation teams in the study centers will be responsible for all treatment administration 
and evaluation throughout the period of the study. 
 
 
 


  
 
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Report on product inventory 
 
The investigator, or the responsible person designated, must ensure that the drug is not used 
incorrectly by maintaining inventories of prescription of the medication in the study.  
 
11.3 
RECORDS AND REPORTS  
 
The investigator takes responsibility for the recording of drug prescription, data acquisition 
records and documentation (Note: documentation includes: patient’s clinical history, hospital 
communications, office notes, patient’s notes and all original documents that contain 
information for the completion of the data acquisition forms).  
 
The investigator, for a minimum period of 25 years after the conclusion or interruption of the 
study, must keep the investigator file where it will be filed a copy of the patient’s identity code. 
The investigator must ensure that the initials and ID number of the patient corresponds to the 
patient’s real identity. 
 
11.4 
PROTOCOL ADHERENCE 
 
Except in situations of emergency in which the person responsible for the protection, security 
and well being of the subject of the study elects an alternative treatment, the study will 
conclude as and how described in the approved protocol.  
All deviations from the protocol must be documented and justified by the principal investigator 
of the center. 
 
11.5 
STUDY MONITORING 
 
The clinical monitor is obliged to rigorously follow the study. For this, the clinical monitor will 
regularly visit the study centers and the investigators as well as maintain necessary written and 
telephone communications.  
 
The clinical monitor will assess the data collected in the acquisition forms and compare them 
with the original data of the clinical history and other original documents in conjunction with 
the study investigator.  
 
The contact person will be: 
 


  
 
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NADIM (GECP 16/03)_v 7.0_08 June 2022                                                                                                                                           69 
 
 
 
Fundación GECP CRA 
Meridiana 358, 6ª planta 
08027 Barcelona 
Tel. 93 430 20 06 
 
 
 
 
 
Fundación GECP Lead CRA 
Meridiana 358, 6ª planta 
08027 Barcelona 
Tel. 93 430 20 06 
Fax. 93 419 17 68 
 
 
11.6 
PUBLICATION POLICY 
 
 
 
 
 
 
 
 
 
 
12. 
STATISTICAL ANALYSES 
 
 
Intention to treat population will be described using clinical and biological characteristics of all the 
patients included in the clinical trial.  
For this analysis, descriptive methods will be used and expressing the results as means, medians, 
standard deviations and distribution descriptions for continuous variables while the results for 
discrete variables will be expressed as percentages and frequency distributions. The estimates will 
be accompanied by confidence intervals (95%). These statistics will be repeated using the patient 
values according to the protocol.  
Progression-Free survival (PFS) is defined as the time from diagnosis until objective tumor 


  
 
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progression or death. Censoring dates are defined in patients with no documented progression 
before data cutoff or dropout. In these patients, the censoring date is defined as the last date on 
with progression status was adequately assessed. The PFS curve will be estimated using Kaplan-
Meier method, obtaining an estimate for PFS at 24 months (and its associated CI95%) and for 
median PFS time.  
Overall Survival (OS) is defined as the time from diagnosis until death from any cause. Censoring 
dates are defined in patients with no death before date cutoff or dropout. The OS curve will be 
estimated using Kaplan-Meier method. 
 
Safety and the tolerability of the therapy will be described by tabulation of the CTCAE Version 4 
grade. The safety cohort will encompass all patients who have received at least 1 dose of IMP 
treatment.  
 
 
 
 
 
 
 
 
 
 
Calculation of sample size 
 
The sample size estimation was completed using a one sample test based on exponential 
distribution. A sample size of 46 patients provided at least 80% power to detect an 
inprovement of 15% for PFS at 24 months 
 
 
with on-sided type I error of 5%. 
 
 This follow-up time 
 
 allows us to achieve secondary objectives established in the protocol 
 
 
. 
It is expected that approximately the 10% of the patients initially enrolled should be discarded 
because they do not meet the inclusion criteria; so that in order to reach the proposed sample 
size, if a patient initially enrolled in the study does not fulfil the inclusion criteria, it will be 
replaced by a new subject that fulfil them, this replacement will ensure that the sample size is 
the one calculated initially. 


  
 
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23. Vafai D, Israel V, Zaretsky S, Natale RB.  Phase III trial of combination carboplatin and taxol in non-
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24. Klastersky J, Sculier JP, Lacroix H, Dabouis G, Bureau G, Libert P, Richez M, Ravez P, Vandermoten 
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patients with advanced non-small-cell lung cancer:EORTC Protocol 07861. J. Clin. Oncol. 1990 Sep; 
8(9): 1556-1562. 
 
25. Bonomi P, Finkelstein D, Ruckdeschel J, et al. Combination Chemotherapy versus single agents 
followed by combination in stage IV non-small-cell lung cancer: astudy of the ECOG. J. Clin. Oncol. 
1989; 7: 1602.  
 
26. Greco FA y Hainsworth JD. Paclitaxel (1-hour infusion) plus carboplatin in the treatment of 
advanced NSCLC. Semin Oncol 1997; 24: S12-17. 
 
27. DeVore RF, Jagasia M y Johnson D. Paclitaxel by either 1-hour or 24h infusion in combination with 
carboplatin in advanced NSCLC. Semin Oncol 1997;24: S27-29. 
 
28. Palackdharry CS, Durham SJ, Durzinsky DS, et al: Preliminary results of neoadjuvant paclitaxel and 
carboplatin in the treatment of early stage NSCLC. Semin Oncol 1997; 24:S12-34-S12-36. 
 
29. Stroun M et al. Neoplastic  characateristics  of the DNA found  in the plasma of cancer patients. 
Oncology  1989; 46:318-322. 
 
 
 
 
 
 
 
 
 
 
 


  
 
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APPENDIX A Performance status evaluation scales 
 
STATUS 
SCALES 
STATUS 
 
 
 
Normal, without disease 
 
Capacity to continue 
habitual activity. Slight signs 
and symptoms of disease 
 
Normal activity with 
difficulty 
 
 
Incapacity for normal 
activities or for active work 
 
Requires occasional help but 
is capable of attending to 
almost all necessities 
 
Requires considerable help 
and frequent medical 
attention 
 
 
Incapacitated. Requires 
attention and special help 
 
Severely incapacitated. 
Hospitalisation indicated but 
death not imminent  
 
Very ill. Hospitalisation 
necessary. Active assistance-
treatment necessary 
 
Moribund 
 
Death 
 
KARNOFSKY 
 
100 
 
 
 
 
90 
 
 
80 
 
 
 
70 
 
 
 
 
60 
 
 
 
50 
 
 
 
40 
 
 
 
30 
 
 
 
 
20 
 
10 
 
0 
 
ZUBROD-ECOG-WHO 
 
0 
 
 
 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
5 
 
 
 
Normal activity  
 
 
 
Symptomatic, but 
completely 
ambulatory  
 
 
 
 
Symptomatic, but in 
bed <50% of the day 
 
 
 
 
Although not prostrate, 
needs to stay in bed  
>50% of the day 
 
 
 
 
Incapacity to rise from 
bed  
 
 
 
 
 
 
 
 
Death 
 


  
 
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APPENDIX B Common Toxicity Criteria (CTC-NCIC) 
 
 
Version 4.03: June 14, 2010 is available from the internet at:  
 
 
 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf 
 
 
 


  
 
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 APPENDIX C SAE FORM AND PREGNANCY FORM 
 
 
 
 


  
 
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APPENDIX D Carboplatin dose calculation 
 
 
 
To calculate the creatinine clearance (CrCl) of serum creatinine: 
 
CrCl= (140 - age) x weight in kg x 0.85 (females) or 1.0 (males) 
72 x serum creatinine in mg/100 ml 
 
umol/l x 0.0113 = mg/100 ml 
 
CALCULATION OF CARBOPLATIN DOSE ACCORDING TO THE FORMULAR OF CALVERT: 
 
USING: THE CALCULATED CREATININE CLEARANCE (see above) TO CALCULATE GLOMERULAR 
FILTRATION RATE (GFR) 
  
(6)*(GFR + 25) = CARBOPLATIN DOSE (in mg) PER CYCLE 
(6)*(____ +25) = _____________ mg of carboplatin 
 
This is the TOTAL DOSE of carboplatin in mg (NOT in mg/m2) 
 
*The carboplatin dose must be calculated before each cycle  
 
**Use current weight 
 
 


  
 
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APPENDIX E: System of classification for non-microcytic lung cancer (NSCLC) and definition of lymph-
nodes maps, 8th Edition     
 
 
       


  
 
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PROPOSED STAGE GROUPINGS FOR 8TH EDITION TNM FOR LUNG CANCER (CHANGES TO THE 7TH EDITION ARE 
HIGHLIGHTED IN BOLD AND UNDERLINED)