Clinical trial NCT04282109
Conditions: Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma
Keywords: Head and neck cancer Squamous cell carcinoma Nivolumab
Sponsor: Grupo Español de Tratamiento de Tumores de Cabeza y Cuello
Start date: 2020-06-03; Completion date: 2024-03-21
Enrollment: 141 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma is palliative and usually platinum based, and the patients often present with poor physical condition. Consequently, many of them are not able to withstand a platinum-based chemotherapy. The addition of taxanes to the armamentarium of drugs improve the outcome in this group of patients. An alternative and better tolerated regimen for these patients is paclitaxel in combination with cetuximab, included the in guidelines of the Spanish Society of Medical Oncology.

Recently, new treatments such as immune-checkpoint inhibitors have shown promising activity and good tolerability in patients with recurrent or metastatic head and neck squamous cell carcinoma and has been included in the recently published guidelines from the Society for Immunotherapy of Cancer. Nivolumab (anti-PD1) has been approved for patients progressing on or after platinum-based therapy, as it clearly impacts on overall survival.

This randomized phase II study will evaluate the efficacy of nivolumab plus paclitaxel for first-line treatment of recurrent or metastatic HNSCC in the platinum ineligible and platinum refractory settings. Control arm will be paclitaxel in combination with cetuximab, treatment included in the guidelines of the Spanish Society of Medical Oncology.

Detailed description:

Arms: arm 1: NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) arm 2: ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab)
Interventions: intervention 1: Nivolumab + Paclitaxel intervention 2: Cetuximab + Paclitaxel
Intervention descriptions: intervention 1: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped.

Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered.

Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months. intervention 2: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion.

After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
NIVOTAX Clinical Study Protocol 
 
 
 
Phase II multicenter randomized trial to assess the 
efficacy and safety of first line nivolumab in combination 
with paclitaxel in subjects with R/M HNSCC unable for 
cisplatin-based chemotherapy (NIVOTAX) 
 
NCT: NCT04282109 
 
 
 
 
 
 
 
 Version 5.0 – 19 October 2022 


 
 
 
 
 
 
 
 
COORDINATING INVESTIGATOR:  
Dr. Ricard Mesia 
 
 
 
 
 
 
 
Dra. Lara Iglesias 
PROTOCOL CODE: TTCC-2019-01 / CA209-7HE / TCC277007 
EudraCT No.: 2019-002922-60 
SPONSOR: Grupo Español de Tratamiento de Tumores de Cabeza y 
Cuello (TTCC) 
Previous protocol versions / amendments (number and date): 
 
- 1.0 dated on November, 18th 2019 
 
- 2.0 dated on March, 3rd 2020 
- 3.0 dated on July, 10th 2020 
- 4.0 dated on November, 4th 2021 
Current version (number and date):     
 
- 5.0 dated on October, 19th 2022 
CONFIDENTIAL: The information and data included in this protocol contain commercial 
secrets and privileged or confidential information that is the property of the Sponsor. No 
one is authorized to make this information public without written permission from the 
sponsor. These limitations apply to all information considered privileged or confidential that 
is facilitated to you in the future. This material may be divulged and used by the team and 
collaborators as needed to conduct the clinical trial. 
Phase II multicenter randomized trial to assess the 
efficacy and safety of first line nivolumab in combination 
with paclitaxel in subjects with R/M HNSCC unable for 
cisplatin-based chemotherapy (NIVOTAX) 
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Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
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1. 
PROTOCOL SUMMARY 
1.1. 
Sponsor 
Grupo Español de Tratamiento de Tumores de Cabeza y Cuello (TTCC) 
 
 
1.2. 
Study Title  
Phase II multicenter randomized trial to assess the efficacy and safety of first line 
nivolumab in combination with paclitaxel in subjects with R/M HNSCC unable for cisplatin-
based chemotherapy (NIVOTAX) 
 
1.3. 
Protocol code 
TTCC-2019-01 / CA209-7HE  
 
1.4. 
Ethics Committee 
CEIC Hospital Universitari Germans Trias I Pujol 
 
1.5. 
Company responsible of the monitoring 
APICES 
Av. Antonio López, 16 - 1A  
28320 Pinto (MADRID), SPAIN 
Phone: +34 918166804 
e-mail: ana.moreno@apices.es 
 
1.6. 
Investigational product 
Nivolumab. 
Nivolumab as monotherapy is indicated for the treatment of recurrent or metastatic 
squamous cell cancer of the head and neck in adults progressing on or after platinum-
based therapy. Nivolumab is indicated also in different types of cancer as melanoma, non-
small cell lung cancer, renal cell carcinoma, Hodgking lymphoma, urothelial carcinoma and 
gastro-oesophageal junction cancer. 
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb), which 
binds to the programmed death-1 (PD-1) receptor and blocks its interaction with PD-L1 
and PD-L2. The PD-1 receptor is a negative regulator of T-cell activity that has been 
shown to be involved in the control of T-cell immune responses [1]. Engagement of PD-1 
with the ligands PD-L1 and PD-L2, which are expressed in antigen presenting cells and 
may be expressed by tumours or other cells in the tumour microenvironment, results in 
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Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
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inhibition of T-cell proliferation and cytokine secretion. Nivolumab potentiates T-cell 
responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 
and PD-L2 ligands. 
 
1.7. 
Phase  
Phase II 
 
1.8. 
Trial objectives 
Primary objective: 
Primary objective of this study is to assess the efficacy of nivolumab plus paclitaxel, in 
terms of two years overall survival (OS), for first-line treatment of recurrent or metastatic 
HNSCC in the platinum ineligible and platinum refractory settings. 
OS is defined as the time between the date of randomization and the date of death. For 
subjects without documentation of death, OS will be censored on the last date the subject 
was known to be alive. 
Secondary objectives: 
Secondary objectives of this study are: 
- 
To evaluate the efficacy of Nivolumab with paclitaxel in patients with recurrent or 
metastatic HNSCC in the platinum ineligible and platinum refractory settings by:  
o Progression free survival (PFS) 
o Overall response rate (ORR) using Response Evaluation Criteria In Solid 
Tumors (RECIST 1.1) [2] as determined by investigator criteria 
o Disease control rate (DCR)  
o Duration of response (DoR) 
o Rate of progressive disease at 6 months  
o Five years Overall Survival (5y-OS) 
- 
To evaluate the efficacy of study treatment in patients ≥ 70 years and according to 
G8 result. 
- 
To evaluate efficacy (ORR, PFS, OS) based on: PDL1 expression measured by 
Combined Positive Score  (CPS), Presence of Human Papilomavirus (HPV) in 
Oropharynx Carcinoma (OPC), cisplatin refractory, cisplatin ineligibility and 
Karnofsky Performance Status Scale. 
- 
To evaluate safety profile of Nivolumab with paclitaxel by:  
o Percentage of patients with AEs 
o Percentage of patients with Grade 3 and Grade 4 AEs 
o Percentage of patients with SAEs 
o Percentage of patients who discontinued due to AEs 
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Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
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o Percentage of patients with each AE by grade 
 
1.9. 
Study design 
This is a randomized, open-label, controlled, multicenter, phase II trial to assess the 
efficacy of nivolumab plus paclitaxel for first-line treatment of recurrent or metastatic 
HNSCC in the platinum ineligible and platinum refractory settings. 
Approximately 141 subjects will be randomized to the two treatment arms in a 2:1 ratio (94 
in experimental arm and 47 in control arm) and stratified by the following factors: 
1. Karnofsky performance status (70% vs 80-100%) 
2. CPS ≥1 vs < 1 (DAKO PD-L1 IHC 22C3) (see annex 12). PD-L1 determination 
(CPS, before patient inclusion) will be performed by a central lab (Pathological 
Anatomy Service, Hospital 12 de Octubre, Madrid, Spain) 
3. Oropharyngeal cancer: oropharyngeal cancer HPV+ (p16 IHC & HPV DNA) vs 
oropharyngeal cancer HPV–(p16 IHC/ HPV DNA) / non-oropharyngeal cancer). For 
subjects with oropharyngeal cancer, sites defined in annex 8.  
HPV status of tumor tissue has to be locally determined at screening by any of the 
following methods: p16 IHC, in situ hybridization, or polymerase chain reaction based 
assay. If HPV status by p16 IHC is positive result confirmation by PCR is mandatory. 
HPV p16 status (OPC), PD-L1 status (CPS) and Karnofsky performance status will be 
needed prior to randomization. Subjects will undergo screening evaluations to determine 
eligibility prior to randomization.  
 
Once enrolled in the study, patients will be randomized in a 2:1 ratio to receive: 
- 
Arm 1 (experimental): NIVOTAX (Combination of nivolumab + paclitaxel, follow by 
maintenance with nivolumab).  
Combination treatment: Nivolumab 240 mg will be administered via IV infusion 
every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. 
After 12 weeks from the start of the combined treatment paclitaxel will be stopped.  
Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks 
after the last administration of nivolumab 240 mg. Once nivolumab is administered 
at 480 mg, paclitaxel can no longer be administered. 
Nivolumab will be continued alone until disease progression, unacceptable toxicity 
or withdrawal of consent up to a maximum of 24 months. 
- 
Arm 2 (standard): ERBITAX (Combination of cetuximab + paclitaxel follow by 
maintenance with cetuximab).  
Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) 
administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) 
administered via IV infusion. 
After 12 weeks from the start of the combined  treatment  paclitaxel will be 
stopped and weekly cetuximab will be continued alone until disease progression, 
unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.  
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Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
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ERBITAX has been chosen as a control group since it is the standard treatment in 
Spain for these patients and to have a contemporary reference with a profile of 
patients equal to that of the experimental arm. Guidelines for the Spanish Society 
of Medical Oncology (SEOM) includes for chemotherapy-naïve patients in 
recurrent and metastatic disease treatment this regimen. If patient cannot be 
treated with platinum (concomitant disease, previous treatment, etc.) or patients 
have PS 2, the combination ERBITAX (paclitaxel plus cetuximab) should be 
considered [3]. 
Study Scheme 
 
 
 
Study Treatment 
 
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Patient will start study treatment within 48 hours of randomization. 
Tumor progression and response endpoints will be assessed using RECIST 1.1 criteria. 
Since the combination of paclitaxel and nivolumab in HNSCC has not yet been studied, 
the sponsor will establish a study data monitoring committee for reviewing safety data of 
the combination. This committee will consist of the two coordinating investigators an at 
least 5 of the participating investigators who will review the available safety information.  
The study data monitoring committee will evaluate the safety profile of the combination 
once the first 10 patients included in the nivolumab arm have finished the combined 
treatment with paclitaxel. Additionally, the study data monitoring committee will review the 
available safety information every three months. It is not considered necessary to make 
more frequent reviews since both drugs are widely used in the participating oncology 
departments, there is sufficient experience in their use and the safety profile of both drugs 
is clearly defined. 
During the periodic reviews, the study data monitoring committee together with the 
sponsor will review the available safety data (adverse events, serious adverse events, 
dropouts) and make a recommendation on whether or not to continue recruiting patients in 
the study, depending on the safety data from patients included. In any case, if an 
unexpected event related to patient safety is detected, it will be notified to the participating 
investigators and will be evaluated by the sponsor and the study data monitoring 
committee, which could increase the frequency of safety reviews if deemed appropriate. 
 
1.10. 
Disease 
Recurrent or metastatic head and neck squamous cell carcinoma. 
 
1.11. 
Study outcome measures 
Primary outcome measure: 
Primary outcome measure of the study is two years overall survival. OS is defined as the 
time between the date of randomization and the date of death. For subjects without 
documentation of death, OS will be censored on the last date the subject was known to be 
alive. 
Secondary outcome measures: 
PFS is defined as the time from randomization to the date of first documented disease 
progression, as assessed by the investigator using RECIST 1.1 criteria, or death due to 
any cause, whichever occurs first. Subjects who died without a reported progression will 
be considered to have progressed on the date of their death. Subjects who did not 
progress or die will be censored on the date of their last evaluable tumor assessment. 
Subjects who did not have any on study tumor assessments and did not die will be 
censored on the date they were randomized. Subjects who started any subsequent anti-
cancer therapy without a prior reported progression will be censored at the last evaluable 
tumor assessment prior to/on initiation of the subsequent anti-cancer therapy. 
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Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
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ORR is defined as the number of subjects with a best overall response (BOR) of a 
complete response (CR) or partial response (PR) divided by the number of randomized 
subjects for each treatment group. The BOR is defined as the best response designation, 
as determined investigator assessment, recorded between the date of randomization and 
the date of progression, as assessed by investigator per RECIST 1.1 or the date of 
subsequent anticancer therapy, whichever occurs first. For subjects without evidence of 
RECIST 1.1 progression or subsequent anticancer therapy, all available response 
designations will contribute to the BOR assessment.  
 
Disease control rate (DCR) is defined as the number of subjects with a best overall 
response (BOR) of a complete response (CR), partial response (PR) or stable disease 
(SD) divided by the number of randomized subjects for each treatment group. 
 
Duration of Response (DoR) is defined as the time between the date of first confirmed 
response to the date of the first documented tumor progression (per RECIST 1.1), or 
death due to any cause, whichever occurs first. Subjects who neither progress nor die will 
be censored on the date of their last evaluable tumor assessment. Subjects who started 
any subsequent anti-cancer therapy without a prior reported progression will be censored 
at the last evaluable tumor assessment prior to or on initiation of the subsequent anti-
cancer therapy. DoR will be evaluated for responders (confirmed CR or PR) only. 
 
Rate of PD is defined as the number of subjects with PD at 6 months divided by the 
number of randomized subjects for each treatment group. 
Efficacy (ORR, PFS, OS) will be evaluated based on:  PDL1 expression measured by 
Combined Positive Score (CPS), Presence of Human Papilomavirus (HPV) in Oropharynx 
Carcinoma (OPC), cisplatin refractory, cisplatin ineligibility and Karnofsky-PS. 
All randomized subjects will be monitored by radiographic assessment at week 9 and 
every 12 weeks (± 7 days) thereafter.  RECIST 1.1 criteria will be used for the 
assessment.  
Subjects will be evaluated for safety if they have received any study drug. Toxicity 
assessments will be continuous during the treatment phase and the safety follow-up 
visits. Adverse events and laboratory values will be graded according to the NCI-CTCAE 
version 5.0. 
On-study weight, Karnofsky performance status, and vital signs should be assessed at 
each on-study visit prior to dosing. Vital signs should also be taken as per institutional 
standard of care prior to, during and after infusions. The start and stop time of the study 
therapy infusions should be documented. 
Physical examinations are to be performed as clinically indicated. If there are any new or 
worsening clinically significant changes since the last exam, report changes on the 
appropriate non-serious or serious adverse event form of the eCRF. 
Laboratory toxicities (eg, suspected drug induced liver enzyme evaluations) will be 
monitored during the follow-up phase via on site/local labs until all study drug related 
toxicities resolve, return to baseline, or are deemed irreversible. 
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Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
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APICES Project No.: TTCC277007 
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The safety analysis will be performed in all treated subjects. Descriptive statistics of 
safety will be presented using the NCI CTCAE version 5.0 by treatment arm. All AEs, 
drug-related AEs and SAEs will be tabulated using the worst grade per NCI CTCAE v 5.0 
criteria by system organ class and preferred term.  
Percentage of patients with AEs, percentage of patients with Grade 3 and Grade 4 AEs, 
percentage of patients with SAEs, percentage of patients who discontinued due to AEs 
and incidence of deaths will be provided.  
 
1.12. 
Study population and number of patients  
Patients with recurrent or metastatic head and neck squamous cell carcinoma unable for 
cisplatin-based chemotherapy will able to participate in the study. 
Patients will be distributed in the following way: 
- 
Group 1: Platinum resistant population (one third of the patients – 47 
patients): 
o Patients who have experienced disease progression or relapse during or 
within 6 months of receiving platinum-based therapy administered as 
neoadjuvant, adjuvant therapy or as concomitant chemotherapy with 
radiotherapy  and have received at least 200 mg/m2 of cisplatin. 
- 
Group 2: Platinum sensitive but unable for cisplatin-based therapy  
according to one of these criteria (one third of the patients – 47 patients): 
1. Karnofsky grade 70% or 
2. Impaired renal function, creatinine clearance >30 mL/min  and <80 mL/min 
GFR could be assessed by direct measurement (EDTA or creatinine 
clearance) if available or by calculation from serum or plasma creatinine, or 
3. Class III heart failure according to the New York Heart Association, or 
4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or  
5. History of allergic reactions to cisplatin, carboplatin, or other platinum-
containing compounds.  
If the patient meets more than one of the first three criteria, the patient cannot be 
included in the study. (Criteria 1, 2 and 3 cannot coincide in the same patient; 
criteria 4 and 5 can go alone or in combination with any other).  
- 
Group 3: Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for 
locally advanced disease (one third of the patients – 47 patients) (a patient who 
received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with 
cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the 
last cycle of cisplatin and the start of first line treatment for R/M disease is >6 
months.    
 
Once the planned recruitment in groups 1 or 3 is completed, sponsor will evaluate the 
number of patients recruited in each of the other groups as well as the remaining 
recruitment time to confirm whether the proportion of patients to be included in each group 
is maintained. 
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Protocol code: TTCC-2019-01 / CA209-7HE 
 
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Version 5.0 dated on 19/October/2022 
 
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Approximately 141 subjects will be randomized to the two treatment arms in a 2:1 ratio (94 
in experimental arm and 47 in control arm). 
Sample size has been calculated based on the primary objective of this clinical trial, to 
evaluate 2-year overall survival.  
Previous studies shown that the two year OS in patients with recurrent or 
metastatic head and neck squamous cell carcinoma was about 16%. To accept the treatment 
efficacy we will assume that the 2-year OS with nivolumab in combination with weekly paclitaxel will 
be at least 26%. A sample size of 94 evaluable patients achieves 80% power at a 0.05 significance 
level (alpha) to accept the efficacy of nivolumab in combination with weekly paclitaxel. An accrual 
time of 18 months and follow-up time of 24 months (treatment and follow-up time) have been 
considered in the sample size calculation. Sample size was calculated for the experimental arm. 94 
patients will be included in the experimental arm and 47 in the control arm. Total sample size is 141 
patients. Patients will be randomized in a 2:1 ratio.  
 
Sample size has been calculated with one-sample survival method. A control group has 
been included to have a contemporary reference with a profile of patients equal to that of 
the experimental arm. 
 
1.13. 
Selection criteria 
Patients diagnosed with HNSCC who are unable for first-line cisplatin-based 
chemotherapy and not previously treated for recurrent/metastatic disease will be include in 
the study. 
1.13.1. 
Inclusion criteria 
Each patient must meet all the following inclusion criteria to be enrolled in the study: 
1. Voluntary written consent must be given before performance of any study-related 
procedure not part of standard medical care.  
2. Histologically confirmed HNSCC (oral cavity, oropharynx, hypopharynx, larynx) not 
amenable to therapy with curative intent (surgery or radiation therapy with or 
without chemotherapy).  
3. Patients not previously treated for recurrent/metastatic disease. 
4. Radiographically measurable disease as defined by RECIST version 1.1. 
Previously irradiated lesions can only be considered as measurable disease if 
disease progression according to RECIST version 1.1. 
5. Patients unable for cisplatin-based chemotherapy, defined “unable” by: 
a. Karnofsky 70% or  
b. Karnofsky 80-100% and amenable to chemotherapy, but: 
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Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
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1) 
Impaired renal function, creatinine clearance >30 mL/min  
and <80 mL/min GFR could be assessed by direct measurement 
(EDTA or creatinine clearance) if available or by calculation from 
serum or plasma creatinine (see annex 5), or  
2) 
grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or  
3) 
Class III heart failure according to the New York Heart 
Association (annex 9), or 
4) 
History of allergic reactions to cisplatin, carboplatin, or other 
platinum-containing compounds or 
5) 
Prior dose of cisplatin ≥225 mg/m² for locally advanced 
disease (a patient who received prior RT + 3 cycles of cisplatin 100 
mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally 
advanced primary HN cancer can be included), or 
6) 
Disease progression or relapse during or within 6 months of 
receiving platinum-based therapy administered as neoadjuvant, 
adjuvant therapy or as concomitant chemotherapy with radiotherapy 
and have received at least 200 mg/m2 of cisplatin.  
6. Male or female patients aged ≥18 years. 
Patients aged ≥70 years old can only be included with a G8 (Geriatric 8) (see 
annex 10) health status screening score ≥ 14. 
a. Female patients: 
i. Are postmenopausal for at least 1 year before the Screening visit, or 
ii. Are surgically sterile, or 
iii. If they are of childbearing potential, agree to practice one highly 
effective method of contraception and one additional effective 
(barrier) method, at the same time (see annex 6), from the time of 
signing the informed consent through 180 days after the last dose 
of study drug, or 
iv. Agree to practice true abstinence, when this is in line with the 
preferred and usual lifestyle of the subject. (Periodic abstinence 
[eg, calendar, ovulation, symptothermal, postovulation methods] 
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Protocol code: TTCC-2019-01 / CA209-7HE 
 
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withdrawal, spermicides only, and lactational amenorrhea are not 
acceptable methods of contraception. Female and male condoms 
should not be used together). 
v. Women of childbearing potential (WOCBP) must have a negative 
serum or urine pregnancy test within 72 hours prior to the start of 
study drug. 
vi. Women must not be breastfeeding. 
b. Male patients, even if surgically sterilized (ie, status postvasectomy), who: 
i. Agree to practice effective barrier contraception during the entire 
study treatment period and through 6 months after the last dose of 
study drug, OR 
Agree to practice true abstinence, when this is in line with the preferred and 
usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods] withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. 
Female and male condoms should not be used together).Investigators shall 
counsel WOCBP and male subjects who are sexually active with WOCBP 
on the importance of pregnancy prevention and the implications of an 
unexpected pregnancy. 
7. Clinical laboratory values as specified below within 28 days before the first dose of 
study drug: 
a. Total bilirubin must be ≤2 × the upper limit of normal (ULN). 
b. Magnesium ≥ lower limit of normal. 
c. Calcium ≥ lower limit of normal. 
d. ALT and AST must be ≤3 × ULN unless liver metastases are present, in 
which case they must be ≤5x ULN. 
e. Hemoglobin must be ≥9 g/dL, absolute neutrophil count (ANC) must be 
≥1.500/µL, WBC must be ≥2.000/µL and platelet count must be 
≥100.000/µL. 
8. Subjects who have received radiation as primary therapy are eligible if radiation 
therapy treatment was completed > 4 weeks prior to inclusion. 
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9. Documentation of PD-L1 status by IHC performed by the central lab at 
randomization. A pre-treatment tumor tissue sample should be sent. 
A representative formalin-fixed paraffin-embedded (FFPE) tumor specimen (at 
least 5mm3 in which more than 60% of the sample is tumor) in paraffin block or 
unstained, freshly cut, serial sections (preferably at least 5) from an FFPE tumor 
specimen, are preferred.  A newly obtained biopsy (within 6 months prior to start of 
study treatment) is preferred but an archival sample is acceptable, if several tumor 
samples are available, testing should be performed on the most recently obtained 
tumor sample 
This specimen should be accompanied by the associated pathology report 
anonymized. Freshly cut, serial sections must have been cut no more than 14 days 
prior to analysis by central lab. Slides that have been cut more than 14 days prior 
to analysis by central lab should not be used and new slides should be made.  
PD-L1 expression determined by using Combined Positive Score (CPS) (see 
annex 12) before patient randomization (DAKO PD-L1 IHC 22C3) will be 
performed by a central lab (Anatomic Pathology Department, Hospital 12 de 
Octubre, Madrid, Spain). 
10. Documentation of HPV p16 status (OPC) is required for HNSCC tumor of the 
oropharynx. For subjects with oropharyngeal cancer, sites are defined in annex 8. 
HPV status of tumor tissue has to be locally determined at screening by any of the 
following methods: p16 IHC, in situ hybridization, or polymerase chain reaction 
based assay. If HPV status by p16 IHC is positive result confirmation by PCR is 
mandatory.  
1.13.2. 
Exclusion criteria 
Patients meeting any of the following exclusion criteria will not to be enrolled in the study: 
1. Male or female patients aged <18 years. Patients aged ≥70 years old should not be 
included with a G8 (Geriatric 8) health status screening score < 14. 
2. Karnofsky <70%. 
3. Patients that meets more than one of the following criteria: 
a. Karnofsky 70%,  
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b. Impaired renal function, creatinine clearance >30 mL/min  and <80 mL/min 
GFR could be assessed by direct measurement (EDTA or creatinine 
clearance) if available or by calculation from serum or plasma creatinine 
(see annex 5),  
c. Class III heart failure according to the New York Heart Association (annex 
9). 
4. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy 
except for alopecia, vitiligo, hear loss and the laboratory values defined in the 
inclusion criteria.  
  
5. Histologically confirmed squamous cell carcinoma of unknown primary, of the 
nasopharynx or non-squamous histologies (eg, mucosal melanoma). 
6. Active brain metastases or leptomeningeal metastases. 
7. Carcinomatous meningitis. 
8. 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. 
9. Diagnosis of immunodeficiency or any condition requiring systemic treatment with 
either corticosteroids (>10 mg daily prednisone equivalents) or other 
immunosuppressive medications within 14 days of treatment. 
10. History of pneumonitis requiring treatment with steroids; history of idiopathic 
pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia, or evidence 
of active pneumonitis on screening chest CT scan; history of radiation pneumonitis 
in the radiation field (fibrosis) is permitted. 
11. Patients with a history of interstitial lung disease cannot be included if they have 
symptomatic ILD (Grade 3-4) and/or poor lung function.  
12. Prior therapy with experimental antitumor vaccines; any T-cell co-stimulation 
agents or inhibitors of checkpoint pathways, such as anti-PD-1, anti-PD-L1, anti-
PD-L2, anti-CD137, or anti-CTLA-4 antibody; or other agents specifically targeting 
T cells are prohibited.  
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13. Any serious medical or psychiatric illness, including drug or alcohol abuse, that 
could, in the investigator’s opinion, potentially interfere with the completion of 
treatment according to this protocol. 
14. Life-threatening illness unrelated to cancer. 
15. Female patients who are lactating and breast-feeding or a positive serum 
pregnancy test during the screening period. 
16. Systemic anticancer treatment or radiotherapy less than 4 weeks or 5 half-lives, 
whichever is longer, before the first dose of study treatment or not recovered from 
acute toxic effects from prior chemotherapy and radiotherapy.  
17. Prior treatment with investigational agents ≤21 days (≤4 weeks for monoclonal 
antibodies with evidence of PD) or ≤5 their half-lives (whichever is shorter) before 
the first dose of study treatment. A minimum of 10 days should elapse from prior 
therapy to initiating protocol therapy. 
18. Major surgery within 14 days before the first dose of study drug and not recovered 
fully from any complications from surgery. 
19. Systemic infection requiring IV antibiotic therapy or other serious infection within 14 
days before the first dose of study drug. 
20. Known human immunodeficiency virus (HIV) positive (testing not required), or 
known acquired immunodeficiency syndrome (AIDS). 
21. Patients with positive test for hepatitis B virus or hepatitis C virus indicating 
presence of virus, eg, Hepatitis B surface antigen (HBsAg) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA negative).  
22. Active secondary malignancy that requires treatment. 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 
23. Any clinically significant co-morbidities, such as uncontrolled pulmonary disease, 
known impaired cardiac function or clinically significant cardiac disease (specified 
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below), active central nervous system disease, active infection, or any other 
condition that could compromise the patient’s participation in the study. 
Patients with any of the following cardiovascular conditions are excluded: 
a. Acute myocardial infarction within 6 months before starting study drug. 
b. Evidence of current uncontrolled cardiovascular conditions including cardiac 
arrhythmias, angina, pulmonary hypertension, or electrocardiographic 
evidence of acute ischemia or active conduction system abnormalities. 
c. Friderichia corrected QT interval (QTcF) >450 milliseconds (msec) (men) or 
>475 msec (women) on a 12-lead ECG during the screening period. 
d. Abnormalities on 12-lead ECG including, but not limited to, changes in 
rhythm and intervals that in the opinion of the investigator are considered to 
be clinically significant. 
24. Patients with history of hypersensitivity reactions to study drugs (nivolumab, 
cetuximab or paclitaxel) or any of their  excipients. 
25. Symptomatic peripheral neuropathy of Grade ≥ 2 based on the CTCAE v5.0 
26. Pulmonary embolism, deep vein thrombosis, or other significant thromboembolic 
event ≤ 8 weeks prior to starting the study treatment. 
27. History of severe skin disorder that in the opinion of the investigator may interfere 
with study conduct. 
 
1.14. 
Study calendar 
 
First patient inclusion: Jun 2020 
Last patient inclusion:  Nov 2021 
Subject participation duration: 5 years 
Study duration: 6.5 years 
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2. 
TABLE OF CONTENTS 
 
1. 
PROTOCOL SUMMARY ................................................................................................................................................................................ 2 
1.1. 
SPONSOR .......................................................................................................................................................................................................... 2 
1.2. 
STUDY TITLE ................................................................................................................................................................................................... 2 
1.3. 
PROTOCOL CODE............................................................................................................................................................................................. 2 
1.4. 
ETHICS COMMITTEE ....................................................................................................................................................................................... 2 
1.5. 
COMPANY RESPONSIBLE OF THE MONITORING ......................................................................................................................................... 2 
1.6. 
INVESTIGATIONAL PRODUCT ........................................................................................................................................................................ 2 
1.7. 
PHASE ............................................................................................................................................................................................................... 3 
1.8. 
TRIAL OBJECTIVES .......................................................................................................................................................................................... 3 
1.9. 
STUDY DESIGN ................................................................................................................................................................................................ 4 
1.10. 
DISEASE ............................................................................................................................................................................................................ 6 
1.11. 
STUDY OUTCOME MEASURES ....................................................................................................................................................................... 6 
1.12. 
STUDY POPULATION AND NUMBER OF PATIENTS ...................................................................................................................................... 8 
1.13. 
SELECTION CRITERIA...................................................................................................................................................................................... 9 
1.13.1. 
Inclusion criteria .................................................................................................................................................................................. 9 
1.13.2. 
Exclusion criteria ............................................................................................................................................................................... 12 
1.14. 
STUDY CALENDAR ........................................................................................................................................................................................ 15 
2. 
TABLE OF CONTENTS ................................................................................................................................................................................. 16 
3. 
ABBREVIATIONS ............................................................................................................................................................................................ 20 
4. 
CLINICAL TRIAL CHARACTERISTICS ............................................................................................................................................. 24 
4.1. 
CLINICAL TRIAL IDENTIFICATION ............................................................................................................................................................... 24 
4.2. 
PHASE ............................................................................................................................................................................................................. 24 
4.3. 
INVESTIGATIONAL PRODUCT ...................................................................................................................................................................... 24 
4.4. 
SPONSOR ........................................................................................................................................................................................................ 24 
4.5. 
ETHICS COMMITTEE ..................................................................................................................................................................................... 24 
4.6. 
COMPANY RESPONSIBLE OF THE MONITORING ...................................................................................................................................... 25 
4.7. 
STUDY CALENDAR ........................................................................................................................................................................................ 25 
5. 
STUDY RATIONALE AND OBJECTIVES ............................................................................................................................................ 26 
5.1. 
BACKGROUND INFORMATION .................................................................................................................................................................... 26 
5.1.1. 
HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC) .............................................................................................................. 26 
5.1.2. 
RECURRENT OR METASTATIC HNSCC TREATMENT ............................................................................................................................. 26 
5.1.2.1. 
PACLITAXEL ............................................................................................................................................................................................. 27 
5.1.2.2. 
CETUXIMAB.............................................................................................................................................................................................. 28 
5.1.2.3. 
IMMUNOTHERAPY IN HNSCC .............................................................................................................................................................. 29 
5.1.2.4. 
NIVOLUMAB ............................................................................................................................................................................................. 30 
5.2. 
STUDY RATIONALE ....................................................................................................................................................................................... 33 
5.3. 
STUDY OBJECTIVES ...................................................................................................................................................................................... 35 
6. 
STUDY DESIGN ................................................................................................................................................................................................. 36 
6.1. 
OVERALL DESIGN ......................................................................................................................................................................................... 36 
6.2. 
PRIMARY ENDPOINT ..................................................................................................................................................................................... 40 
6.3. 
SECONDARY ENDPOINTS ............................................................................................................................................................................. 40 
7. 
PATIENT SELECTION .................................................................................................................................................................................. 41 
7.1. 
INCLUSION CRITERIA .................................................................................................................................................................................... 42 
7.2. 
EXCLUSION CRITERIA................................................................................................................................................................................... 46 
7.3. 
RANDOMIZATION PROCEDURES ................................................................................................................................................................. 48 
7.4. 
BLINDING PROCEDURES .............................................................................................................................................................................. 49 
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8. 
WITHDRAWAL CRITERIA ........................................................................................................................................................................ 49 
8.1. 
REASONS FOR WITHDRAWAL .................................................................................................................................................................... 49 
8.2. 
DISCONTINUATION OF STUDY DRUG ......................................................................................................................................................... 49 
8.3. 
HANDLING OF WITHDRAWALS .................................................................................................................................................................. 50 
8.4. 
RESERVE AND REPLACEMENT SUBJECTS................................................................................................................................................. 50 
9. 
INVESTIGATIONAL PRODUCT .............................................................................................................................................................. 50 
9.1. 
INVESTIGATIONAL PRODUCT DESCRIPTION .............................................................................................................................................. 50 
9.1.1. 
Description ............................................................................................................................................................................................... 50 
9.1.2. 
Packaging ................................................................................................................................................................................................. 51 
9.1.3. 
Shipping, Storage and Disposal ........................................................................................................................................................... 52 
9.2. 
DOSAGE AND ADMINISTRATION ................................................................................................................................................................ 53 
9.3. 
TREATMENT DURATION .............................................................................................................................................................................. 55 
9.4. 
CRITERIA FOR DOSE ADJUSTMENTS ........................................................................................................................................................... 55 
9.4.1. 
NAUSEA AND/OR VOMITING ...................................................................................................................................................................... 57 
9.4.2. 
ANEMIA, THROMBOCYTOPENIA, AND/OR NEUTROPENIA ..................................................................................................................... 57 
9.4.3. 
NIVOLUMAB DOSE ADJUSTMENTS ............................................................................................................................................................. 57 
9.4.3.1. 
CRITERIA TO RESUME NIVOLUMAB TREATMENT ............................................................................................................................. 57 
9.4.3.2. 
IMMUNE-MEDIATED ADVERSE REACTIONS ...................................................................................................................................... 58 
9.4.3.3. 
OTHER IMMUNE-MEDIATED ADVERSE REACTIONS ........................................................................................................................ 58 
 
NIVOLUMAB CAN CAUSE OTHER CLINICALLY SIGNIFICANT AND POTENTIALLY FATAL IMMUNE-MEDIATED ADVERSE 
REACTIONS. IMMUNE-MEDIATED ADVERSE REACTIONS MAY OCCUR AFTER DISCONTINUATION OF NIVOLUMAB THERAPY. FOR 
ANY SUSPECTED IMMUNE-MEDIATED ADVERSE REACTIONS, EXCLUDE OTHER CAUSES. BASED ON THE SEVERITY OF THE 
ADVERSE REACTION, PERMANENTLY DISCONTINUE OR WITHHOLD NIVOLUMAB, ADMINISTER HIGH-DOSE CORTICOSTEROIDS, 
AND IF APPROPRIATE, INITIATE HORMONE-REPLACEMENT THERAPY. SEE THE LAST IB VERSION OF NIVOLUMAB FOR MORE 
INFORMATION RELATED TO OTHER IMMUNE-MEDIATED ADVERSE REACTIONS.  ............................................................................................. 58 
9.4.3.4. 
NIVOLUMAB INFUSION REACTIONS ..................................................................................................................................................... 58 
9.4.4. 
CETUXIMAB DOSE ADJUSTMENTS ............................................................................................................................................................. 59 
9.4.4.1. 
SKIN REACTION ........................................................................................................................................................................................ 59 
9.4.4.2. 
ALLERGIC REACTIONS ............................................................................................................................................................................ 60 
9.4.4.3. 
CETUXIMAB ADMINISTRATION AFTER HYPERSENSITIVITY REACTIONS......................................................................................... 60 
9.4.4.4. 
CETUXIMAB DOSE MODIFICATIONS OR DELAYED ADMINISTRATION FOR ANOTHER REASON ................................................... 60 
9.4.5. 
PACLITAXEL DOSE ADJUSTMENTS ............................................................................................................................................................. 61 
9.4.5.1. 
PREVIOUS REQUIREMENTS FOR PACLITAXEL ADMINISTRATION ..................................................................................................... 61 
9.4.5.2. 
PACLITAXEL DOSE REDUCTIONS ........................................................................................................................................................... 61 
9.4.5.3. 
PACLITAXEL INTERRUPTION .................................................................................................................................................................. 62 
9.5. 
ACCOUNTABILITY ........................................................................................................................................................................................ 62 
9.6. 
AUXILIARY MEDICINAL PRODUCTS.......................................................................................................................................................... 62 
9.7. 
CONCOMITANT MEDICATION ..................................................................................................................................................................... 63 
9.8. 
PROHIBITED DRUGS ...................................................................................................................................................................................... 63 
9.9. 
PRECAUTIONS................................................................................................................................................................................................ 64 
10. 
STUDY SCHEDULE ................................................................................................................................................................................... 65 
10.1. 
PRE-STUDY VISIT (SCREENING) .................................................................................................................................................................. 68 
10.2. 
PACLITAXEL COMBINATION TREATMENT VISITS (FIRST 12 WEEKS OF TREATMENT)........................................................................ 69 
10.3. 
MONOTHERAPY TREATMENT VISITS (CETUXIMAB OR NIVOLUMAB) .................................................................................................. 70 
10.4. 
END OF TREATMENT / WITHDRAWAL VISIT  ............................................................................................................................................ 70 
10.5. 
SAFETY FOLLOW-UP VISIT  .......................................................................................................................................................................... 71 
10.6. 
FOLLOW-UP VISITS ....................................................................................................................................................................................... 71 
11. 
ASSESSMENT OF SAFETY / ADVERSE EVENTS ...................................................................................................................... 72 
11.1. 
DEFINITIONS .................................................................................................................................................................................................. 72 
11.1.1. 
Adverse event (AE) ............................................................................................................................................................................ 72 
11.1.2. 
Serious adverse event (SAE) ............................................................................................................................................................ 72 
11.1.3. 
Additional considerations ................................................................................................................................................................. 73 
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11.2. 
CHARACTERISTICS OF AN ADVERSE EVENT ............................................................................................................................................. 73 
11.2.1. 
Causality assessment ......................................................................................................................................................................... 73 
11.2.2. 
Expectedness ....................................................................................................................................................................................... 73 
11.2.3. 
Severity ................................................................................................................................................................................................. 74 
11.3. 
REPORTING PROCEDURES ........................................................................................................................................................................... 74 
11.3.1. 
Reporting of adverse events (AEs) .................................................................................................................................................. 74 
11.3.2. 
Reporting of serious adverse events (SAEs) .................................................................................................................................. 74 
11.3.3. 
Reporting of serious adverse events (SAEs) to Health Authorities............................................................................................ 75 
11.3.4. 
Follow-up of AEs and SAEs ............................................................................................................................................................. 75 
11.3.5. 
AEs or SAEs that occur after the study ends ................................................................................................................................. 76 
11.3.6. 
Select adverse events ......................................................................................................................................................................... 76 
11.3.7. 
Special Situation Reports .................................................................................................................................................................. 77 
11.3.8. 
Pregnancy ........................................................................................................................................................................................... 77 
11.4. 
STUDY DATA MONITORING COMMITTEE .................................................................................................................................................. 78 
12. 
STATISTICAL CONSIDERATIONS ................................................................................................................................................... 78 
12.1. 
GENERAL CONSIDERATIONS ....................................................................................................................................................................... 78 
12.2. 
SAMPLE SIZE .................................................................................................................................................................................................. 78 
12.3. 
ANALYTICAL POPULATIONS ....................................................................................................................................................................... 78 
12.4. 
ANALYSIS OF PRIMARY OBJECTIVE .......................................................................................................................................................... 79 
12.5. 
ANALYSIS OF SECONDARY OBJECTIVES .................................................................................................................................................. 79 
12.5.1. 
Secondary Efficacy evaluations ....................................................................................................................................................... 79 
12.5.2. 
Secondary Safety evaluations .......................................................................................................................................................... 79 
13. 
DATA HANDLING AND QUALITY ASSURANCE ..................................................................................................................... 80 
13.1. 
MONITORING OF THE TRIAL ........................................................................................................................................................................ 80 
13.2. 
AUDITS ........................................................................................................................................................................................................... 80 
13.3. 
REPORTING OF SERIOUS BREACHES ........................................................................................................................................................... 80 
13.4. 
DATA MANAGEMENT .................................................................................................................................................................................. 80 
13.5. 
ELECTRONIC CASE REPORT FORMS (ECRFS) ......................................................................................................................................... 81 
13.6. 
WEB-BASED ECRF ....................................................................................................................................................................................... 81 
13.7. 
ENTERING OF DATA INTO THE ECRF ........................................................................................................................................................ 81 
13.8. 
THE QUERY PROCESS .................................................................................................................................................................................. 82 
13.9. 
SOURCE DOCUMENTS .................................................................................................................................................................................. 82 
13.10. 
USER ID .................................................................................................................................................................................................... 82 
13.11. 
AUDIT TRAIL ............................................................................................................................................................................................ 82 
13.12. 
INSPECTION OF RECORDS ....................................................................................................................................................................... 82 
13.13. 
TRIAL RECORD RETENTION .................................................................................................................................................................. 83 
14. 
ADMINISTRATIVE CONSIDERATIONS ........................................................................................................................................ 83 
14.1. 
LEGAL CONSIDERATIONS............................................................................................................................................................................ 83 
14.2. 
ETHICS COMMITTEE REVIEW ...................................................................................................................................................................... 83 
14.3. 
MODIFICATIONS OF THE PROTOCOL .......................................................................................................................................................... 83 
14.4. 
INFORMED CONSENT .................................................................................................................................................................................... 84 
14.5. 
CONFIDENTIALITY ........................................................................................................................................................................................ 84 
14.6. 
INSURANCE .................................................................................................................................................................................................... 85 
14.7. 
PUBLICATIONS .............................................................................................................................................................................................. 85 
15. 
SPONSOR’S SIGNATURE PAGE ......................................................................................................................................................... 86 
16. 
INVESTIGATOR’S SIGNATURE PAGE .......................................................................................................................................... 87 
17. 
REFERENCES ............................................................................................................................................................................................... 88 
ANNEX 1. DECLARATION OF HELSINKI..................................................................................................................................................... 92 
ANNEX 2. LIST OF SITES / PRINCIPAL INVESTIGATORS .................................................................................................................. 98 
ANNEX 3. INFORMED CONSENT FORM ...................................................................................................................................................... 99 
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ANNEX 4. NCI-CTC AE CRITERIA .................................................................................................................................................................. 100 
ANNEX 5 
COCKCROFT-GAULT EQUATION ...................................................................................................................................... 101 
ANNEX 6 
METHODS OF CONTRACEPTION CONSIDERED TO BE EFFECTIVE ........................................................... 102 
ANNEX 7 
ECOG AND KARNOFSKY PERFORMANCE STATUS ............................................................................................... 103 
ANNEX 8 
HEAD AND NECK SQUAMOUS CELL CARCINOMAS ............................................................................................. 104 
ANNEX 9 
NEW YORK HEART ASSOCIATION CLASSIFICATION OF CARDIAC DISEASE ...................................... 105 
ANNEX 10 
 G8 QUESTIONNAIRE ............................................................................................................................................................. 106 
ANNEX 11  
RECIST CRITERIA ................................................................................................................................................................... 107 
ANNEX 12  
COMBINED POSITIVE SCORE (CPS) ............................................................................................................................. 108 
ANNEX 13 MANAGEMENT ALGORITHMS FOR IMMUNE-MEDIATED ADVERSE REACTIONS ............................. 109 
 
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3. 
ABBREVIATIONS 
 
Abbreviation 
Full terminology 
AE 
Adverse event 
AEMPS 
Agencia Española de Medicamentos y Productos Sanitarios 
ALP 
alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APC 
Allophycocyanin 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATP 
adenosine triphosphate (ATP 
BMS 
Bristol-Myers Squibb 
BOR 
Best overall response 
BUN 
Blood urea nitrogen 
Ca 
Calcium 
CA 
Competent authority 
CBC 
Complete blood count 
CEIm 
Comité Ético de Investigación con medicamentos  
CNS 
Central nervous system 
CI 
Confidence interval  
Cl 
Chloride 
CPS 
combined positive score 
CR 
Complete response 
CRA 
Contract research associate 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-lymphocyte antigen 4 
CT 
Computed tomography 
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DC 
Dendritic cells 
DCR 
Disease control rate 
DILI 
Drug induced liver injury 
DoR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor  
EORTC 
European Organisation for the Research and Treatment of Cancer 
EOT 
End of treatment 
ESMO 
European Society of Medical Oncology 
EU 
European Union  
FDA 
Food and Drug Administration  
FFPE 
Formalin-Fixed Paraffin-Embedded 
FU 
Fluorouracil 
GCP 
Good clinical practice 
G-CSF 
granulocyte colony stimulating factor 
GFR 
Glomerular filtration rate  
GM-CSF 
granulocyte macrophage-colony stimulating factor 
GORTEC 
Groupe d’Oncologie Radiothérapie Tête Et Cou 
HBV 
Hepatitis B virus 
HCB 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
HMGB1 
High mobility group box 1 
HN 
Head and neck 
HNC 
Head and neck cancer 
HNSCC 
Head and neck squamous cell carcinoma  
HPV 
human papillomavirus 
HR 
Hazard Ratio 
HuMAb 
Human monoclonal antibody  
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IB 
Investigator brochure 
IC 
Tumor-Infiltrating Immune Cells 
ICD 
 Immunogenic cell death 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent ethic committee 
IFN 
Interferon 
Ig 
Immunoglobulin 
ILD 
Interstitial lung disease 
IMAE 
Immune-mediated AE 
Ir 
Immune-related 
IRR 
Infusion-related reactions 
ITT 
Intent-to-treat 
IV 
Intravenous 
K 
Potassium 
LDH 
Lactate dehydrogenase 
Mg 
Magnesium 
MoAb 
Monoclonal antibody 
MRI 
Magnetic resonance imaging 
Na 
Sodium 
NCI 
National Cancer Institute  
NK 
Natural Killer 
NSCLC 
Non-small cell lung cancer  
OPC 
oropharyngeal carcinoma 
OPSCC 
oropharyngeal squamous cell carcinoma 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progression disease 
PD-L1 
Programmed death-ligand 1 
PET 
Positron emission tomography 
PFS 
Progression free survival 
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PIL 
Patient Information Leaflet 
PR 
Partial response 
QC 
Quality control 
QTcF 
QT interval corrected using Fridericia’s formula 
RBC 
Red blood cells  
RCC 
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RT 
Radiotherapy 
SAE 
Serious adverse event 
SD 
Stable disease 
SEOM 
Sociedad Española de Oncología Médica  
SJS 
Stevens-Johnson syndrome 
SPC/SmPC 
Summary of Product Characteristics 
TEN 
Toxic epidermal necrolysis  
TMF 
Trial master file 
TPF 
Docetaxel, Carboplatin and Fluorouracil 
TSH 
Thyroid stimulating hormone 
TTCC 
Grupo Español de Tratamiento de Tumores de Cabeza y Cuello 
ULN 
Upper limit of normal  
WBC 
White blood cells 
WOCBP 
Women of childbearing potential 
WWPS 
Worldwide Patient Safety 
 
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4. 
CLINICAL TRIAL CHARACTERISTICS 
4.1. 
Clinical trial identification 
 
Code: TTCC-2019-01 / CA209-7HE 
 
Title: Phase II multicenter randomized trial to assess the efficacy and safety of first line 
nivolumab in combination with paclitaxel in subjects with R/M HNSCC unable for cisplatin-
based chemotherapy (NIVOTAX) 
 
4.2. 
Phase 
Phase II 
 
4.3. 
Investigational product 
Nivolumab. 
Nivolumab as monotherapy is indicated for the treatment of recurrent or metastatic 
squamous cell cancer of the head and neck in adults progressing on or after platinum-
based therapy. Nivolumab is indicated also in different types of cancer as melanoma, non-
small cell lung cancer, renal cell carcinoma, Hodgking lymphoma, urothelial carcinoma and 
gastro-oesophageal junction cancer 
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb), which 
binds to the programmed death-1 (PD-1) receptor and blocks its interaction with PD-L1 
and PD-L2. The PD-1 receptor is a negative regulator of T-cell activity that has been 
shown to be involved in the control of T-cell immune responses [1]. Engagement of PD-1 
with the ligands PD-L1 and PD-L2, which are expressed in antigen presenting cells and 
may be expressed by tumours or other cells in the tumour microenvironment, results in 
inhibition of T-cell proliferation and cytokine secretion. Nivolumab potentiates T-cell 
responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 
and PD-L2 ligands. 
 
4.4. 
Sponsor  
Grupo Español de Tratamiento de Tumores de Cabeza y Cuello (TTCC) 
 
4.5. 
Ethics Committee 
CEIC Hospital Universitari Germans Trias I Pujol 
 
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4.6. 
Company Responsible of the Monitoring 
APICES 
Av. Antonio López, 16 – 1A  
28320 Pinto (MADRID), SPAIN 
Phone: +34 918166804 
e-mail: ana.moreno@apices.es 
 
4.7. 
Study calendar 
First patient inclusion: Jun 2020 
Last patient inclusion: Nov 2021 
Subject participation duration: 5 years 
Study duration: 6.5 years 
 
 
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5. 
STUDY RATIONALE AND OBJECTIVES  
5.1. 
Background information 
5.1.1. 
Head and Neck Squamous Cell Carcinoma (HNSCC) 
Head and neck cancers are a heterogeneous group of neoplasms that typically originate 
from the mucosal lining of the lip, oral cavity, nasopharynx, larynx, and hypolarynx. 
Biologically, they are generally similar, with 85% of head and neck cancers being 
squamous cell carcinomas; they are, therefore, called head and neck squamous cell 
carcinoma (HNSCC) [4,5]. HNSCC is the fifth most common cancer diagnosed worldwide 
and the eighth most common cause of cancer death [6]. There are 500.000 new cases 
each year worldwide [7]. These cancers are associated with environmental and lifestyle 
risk factors, including smoking, alcohol consumption, exposure to ultraviolet light and 
certain workplace chemicals, and infection with the human papillomavirus [7]. 
In 2020, head and neck cancer (HNC) is expected to affect approximately 833.000 and 
151.000 new patients worldwide and in Europe, respectively [8]. High risk alpha human 
papillomaviruses (HPV), mainly HPV type 16 (HPV16), have been recognized as causally 
related to a subset of oropharyngeal squamous cell carcinomas as well as to a substantial 
fraction of SCCs from unknown primary metastatic to the neck nodes. Both of these 
entities benefit from a significantly better prognosis [9-11]. According to recent estimates, 
worldwide 38.000–45.000 cases of HNC are yearly attributable to HPV [12-13], although 
the geographic prevalence of HPV-related OPSCC is extremely heterogeneous [14-15].  
If detected early, HNSCC is highly curable; however, these cancers are frequently 
aggressive and often are first noticed only when they have spread to the lymph nodes. 
Radiation therapy is the most common form of treatment for HNSCC. Radiotherapy and 
surgery may be used in combination, and the intention of these treatment modalities is 
curative. 
Chemotherapy is generally used to create a hostile environment for metastasis either as 
an additional or adjuvant treatment. Typically, the chemotherapy will combine a platinum-
based therapy (carboplatin or cisplatin) with a taxane (paclitaxel, or docetaxel), sometimes 
including fluorouracil and cetuximab. The 5-year survival rate for patients with HNSCC is 
40% to 50% [15]. 
Metastatic and recurrent HNSCC that is no longer amenable to local surgical/radiation 
therapy causes substantial morbidity and high mortality, with a median PFS of < 6 months 
and median overall survival of less than 12 months. 
 
5.1.2. 
Recurrent or metastatic HNSCC treatment 
The standard of care for recurrent/metastatic HNSCC in first-line was established in 2008 
by the EXTREME study by Vermorken et al [16]. The study randomly assigned 220 of 442 
eligible patients with untreated recurrent or metastatic squamous cell carcinoma of the 
head and neck to receive cisplatin or carboplatin plus fluorouracil every 3 weeks for a 
maximum of 6 cycles and 222 patients to receive the same chemotherapy plus cetuximab 
for a maximum of 6 cycles. Patients with stable disease who received chemotherapy plus 
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cetuximab continued to receive cetuximab until disease progression or unacceptable toxic 
effects. 
Adding cetuximab to platinum-based chemotherapy with fluorouracil (platinum fluorouracil) 
significantly prolonged the median overall survival from 7.4 months in the chemotherapy-
alone group to 10.1 months in the group that received chemotherapy plus cetuximab 
(hazard ratio for death, 0.80; 95% confidence interval, 0.64 to 0.99; P = 0.04). The addition 
of cetuximab prolonged the median progression-free survival time from 3.3 to 5.6 months 
(hazard ratio for progression, 0.54; P<0.001) and increased the response rate from 20% to 
36% (P<0.001). The addition of cetuximab was associated with a 2.7 month increase in 
the median survival and a significant 20% reduction in the relative risk of death, as 
compared with platinum–fluorouracil chemotherapy alone. Secondary efficacy endpoints 
were also significantly improved in the cetuximab group, with a 2.3-month prolongation of 
progression-free survival (a 46% reduction in the risk of disease progression), an 83% 
increase in the response rate, and a 41% reduction in the risk of treatment failure. 
Chemotherapy for incurable recurrent or metastatic HNSCC disease is palliative and 
usually platinum based, and the patients often present with poor physical condition due to 
alcohol and tobacco habits, malnutrition and comorbidities. Consequently, many of them 
are not able to withstand a platinum-based chemotherapy. The addition of taxanes to the 
armamentarium of drugs improve the outcome in this group. An alternative and better 
tolerated regimen for these patients is paclitaxel in combination with cetuximab [17].  
Hitt et al. enrolled 46 patients who were unlikely to benefit from platinum-based 
chemotherapy in a phase II trial combining weekly paclitaxel and cetuximab [17]. 
Cetuximab was administered by i.v. infusion at an initial dose of 400 mg/m2 over 2 h 
followed by weekly doses of 250 mg/m2 over 1 hour. Paclitaxel (80 mg/m2) was 
administered weekly over 1 hour, an hour after cetuximab infusion. The overall response 
rate was 54% (95% CI: 39%–69%) (complete response rate: 22%, disease control rate: 
80%). Median PFS and OS were 4.2 months (95% CI: 2.9–5.5 months) and 8.1 months 
(95% CI: 6.6–9.6 months), respectively. Common grade 3 or 4 adverse events were acne-
like rash (24%), asthenia (17%), and neutropenia (13%). The development of acne-like 
rash was associated with tumor response. Patients who had not previously received 
chemotherapy as part of a multimodal treatment of locally advanced disease had a 
significantly better tumor response than those who had received prior chemotherapy. 
However, the outcome of these patients still remains poor (P = 0.020).  
Additionally, guidelines for the Spanish Society of Medical Oncology (SEOM) includes for 
chemotherapy-naïve patients in recurrent and metastatic disease treatment the weekly 
paclitaxel and cetuximab regimen. If patient cannot be treated with platinum (concomitant 
disease, previous treatment, etc.) or patients have PS 2, the combination ERBITAX 
(paclitaxel plus cetuximab) should be considered [3]. 
5.1.2.1. 
Paclitaxel  
Paclitaxel is a compound extracted from the Pacific yew tree Taxus brevifolia with 
antineoplastic activity. Paclitaxel binds to tubulin and inhibits the disassembly of 
microtubules, thereby resulting in the inhibition of cell division. This agent also induces 
apoptosis by binding to and blocking the function of the apoptosis inhibitor protein Bcl-2 
(B-cell Leukemia 2). 
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Taxanes are among the most active cytotoxic agents in HNSCC, and known to modulate 
antitumor immune responses as well. Similar to cisplatin, paclitaxel does not induce ICD. 
However, concurrent paclitaxel treatment was shown to significantly enhance radiation-
induced ICD in breast cancer cell lines. Similarly, docetaxel treatment itself did not induce 
ATP or HMGB1 secretion by tumor cells. However, calreticulin exposure of tumor cells 
after docetaxel treatment was observed which significantly enhanced tumor cell killing by 
antigen-specific CD8+ cytotoxic T cells [18]. 
In the GORTEC 2008-3 trial [19], 54 patients with previously untreated R/M-HNSCC were 
treated with weekly cetuximab and four 3-week cycles of docetaxel 75 mg/m2 and cisplatin 
75 mg/m2, followed by maintenance cetuximab until disease progression or unacceptable 
toxicity. Toxicity was manageable with granulocyte colony-stimulating factor support. The 
overall response rate was 54%. Median PFS and OS were 7.1 months and 15.3 months, 
respectively. These data compare favorably with the results observed with cisplatin, 5-FU, 
and cetuximab in the EXTREME trial. 
A randomized phase III study compared cisplatin 75 mg/m2 day 1 and paclitaxel 175 
mg/m2 over 3 hours on day 1 every 3 weeks with cisplatin 100 mg/m2 day 1 and FU 1.000 
mg/m2 /24 hours by continuous intravenous infusion days 1 through 4 [20]. Overall survival 
was not different between the two groups. Median survival was 8.1 months (95% CI, 6.1 to 
10.0) and 8.7 months (95% CI, 6.7 to 12.2) respectively. 
In non-randomized phase II trials cetuximab was added to a taxane, either as a single 
agent or in combination with cisplatin. Hitt et al. [17] enrolled 46 patients who were unlikely 
to benefit from platinum-based chemotherapy in a phase II trial combining cetuximab 
administered by i.v. infusion at an initial dose of 400 mg/m2 over 2 hour followed by weekly 
doses of 250 mg/m2 over 1 hour and weekly paclitaxel 80 mg/m2 administered weekly over 
1 hour, an hour after cetuximab infusion. The overall response rate was 54% (95% CI: 
39%–69%) (complete response rate: 22%, disease control rate: 80%). Median PFS and 
OS were 4.2 months (95% CI: 2.9–5.5 months) and 8.1 months (95% CI: 6.6–9.6 months), 
respectively. Common grade 3 or 4 adverse events were acne-like rash (24%), asthenia 
(17%), and neutropenia (13%). The development of acne-like rash was associated with 
tumor response. Patients who had not previously received chemotherapy as part of a 
multimodal treatment of locally advanced disease had a significantly better tumor response 
than those who had received prior chemotherapy (P = 0.020). 
5.1.2.2. 
Cetuximab  
Cetuximab is an IgG1 humanized monoclonal murine antibody targeting the epidermal 
growth factor receptor (EGFR). EGFR is an erbB family receptor tyrosine kinase 
expressed by a wide variety of tumor types. Binding of a ligand to EGFR results in receptor 
dimerization, autophosphorylation, and induction of signaling cascades leading to cell 
proliferation. Cetuximab works by inhibiting ligand binding to EGFR, thereby blocking cell 
growth signaling. Importantly, for colorectal cancer cetuximab is only effective for tumors 
expressing wild-type KRAS, as mutant KRAS provides growth signals that bypass EGFR 
inhibition. However, for HNSCC cetuximab appears to be effective for both KRAS-wild type 
and KRAS-mutant tumors. Cetuximab was approved for HNSCC in 2006 after early phase 
III trials demonstrated that cetuximab improved response to chemotherapy and reduced 
the risk of death for patients who have cetuximab-related skin toxicity. 
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Later studies showed that cetuximab plus platinum-based chemotherapy increases overall 
and progression-free survival (PFS) [16,17], and that 5-year survival is improved for 
patients receiving chemo-radiotherapy who developed skin rash of grade ≥2 severity in 
response to cetuximab. However, a more recent phase III study that included more than 
800 patients found that adding cetuximab to platinum-based chemo-radiotherapy regimens 
did not improve PFS or OS [21], suggesting that routine cetuximab administration may not 
be beneficial to all patients. Therefore, further research is needed to identify patients who 
are most likely to benefit from cetuximab therapy. 
There is accumulating data that the efficacy of cetuximab-based regimens in treatment of 
recurrent/metastatic HNSCC is not only based on the inhibition of EGFR signaling 
pathways but also on the activation of Fcγ receptor-positive NK cells leading to DC 
maturation and activation of cytotoxic T cells [22]. 
5.1.2.3. 
Immunotherapy in HNSCC 
Immunotherapeutic approaches recently have demonstrated clinical efficacy in several 
cancer types, including melanoma, renal cell carcinoma, non-small cell lung cancer [23], 
HNSCC [24], etc. Regarding HNSCC, recently published data of pembrolizumab clinical 
trials showed: improvement in overall survival when compared pembrolizumab with 
standard of care (8.4 months vs 6.9 months ; HR 0·80, 0·65–0·98; p=0·0161) [25] in 
patients with R/M HNSCC that progressed during or after platinum based treatment; in an 
interim analysis of KEYNOTE-048 study, that included patients with R/M HNSCC with no 
prior systemic therapy, improvement in overall survival when compared pembrolizumab 
with EXTREME scheme (cisplatin or carboplatin + fluorouracil + cetuximab) in CPS ≥20 
(14.9 vs 10.7 months; HR 0.61 [95% CI 0.45-0.83]; P = 0.0007) and also in CPS ≥1 (12.3 
vs 10.3 months; HR 0.78 [95% CI 0.64-0.96]; P = 0.0086) [26]; and in KEYNOTE-048 final 
analysis, pembrolizumab + cisplatin or carboplatin + fluorouracil improved overall survival 
vs EXTREME scheme in the CPS ≥20 (14.7 vs 11.0 months; HR 0.60, 95% CI 0.45-0.82, 
P = .0004) and CPS ≥1 (13.6 vs 10.4 months; HR 0.65, 95% CI 0.53-0.80, P < .0001) [27]. 
Tumors may modulate and evade the host immune response through a number of 
mechanisms, including down regulation of tumor-specific antigen expression and 
presentation, secretion of anti-inflammatory cytokines, and upregulation of inhibitory 
ligands. In HNSCC, down-regulation of T-cell function is thought to be mediated by 
multiple mechanisms: i.) Reduced expression of costimulating molecules of the B7-CD28 
family; ii.) Increased expression of PD L1 in tumor cells and tumor associated fibroblasts; 
and, iii.) Loss of HLA-class I and selective down-regulation of HLA-A,B,C locus expression 
resulting in defective antigen presentation [28-30]. In a subset of HPV-infected HNSCC, 
data shows that antigen-processing machinery components are downregulated compared 
to the adjacent normal squamous epithelium with incomplete activation of tumor specific T 
cells or suboptimal target recognition enabling tumor progression [31]. T cell checkpoint 
regulators such as CTLA-4 and programmed death-1 (PD-1, CD279) are cell surface 
molecules that, when engaged by their cognate ligands, induce signaling cascades down 
regulating T cell activation and proliferation. 
PD-L1 expression has been associated with poor prognosis in certain tumor types such as 
renal, esophageal, gastric, ovarian, pancreatic, and lung cancer [32-37]. PD-1 
engagement on T cells by PD-L1-positive APC or PD-L1-positive tumor cells in the tumor 
microenvironment may limit effective immune responses. Conversely, PD-L1 expression 
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may be a positive prognostic factor as it may indicate infiltration of tumor-specific T cells 
that secrete IFN-ɣ, which upregulates PD-L1 expression. Consistent with this hypothesis is 
the co-localization of lymphoid cell infiltrates and PD-L1 staining observed in human 
melanoma lesions [38]. PD-L1 expression in HNSCC has been reported, preliminary 
results from a phase 1 trial in patients with [39] recurrent or metastatic disease observed 
that 77.9% of patients tested (N=104) expressed PD-L1, defined as ≥ 1% of stained cells 
in the tumor microenvironment. 
Recently published guidelines from the Society for Immunotherapy of Cancer [40] defined 
positivity for PD-L1 as ≥1% TPS or ≥ 1 CPS by IHC staining. However, it is important to 
note that expression levels may differ depending on the antibody used and whether 
staining includes tumor alone or tumor plus stroma. The majority of the subcommittee 
agreed that the best use of biomarker testing when treating patients with HNSCC with 
immunotherapy is by combined positive score (CPS) (see annex 12). 
The role of the PD-1 blockade in squamous cell carcinoma of the lung has been 
established in CA209017 study [41] where nivolumab monotherapy in the second-line 
treatment setting demonstrated clinically meaningful survival benefit regardless of PD-L1 
expression compared to standard of care docetaxel. In a similar histology, for squamous 
cell carcinoma of the head and neck primary, the role of PD-1 blockade is evolving. 
CA209141 study, is a randomized, open-label, phase 3 trial that compared nivolumab, a 
fully human anti-programmed death 1 (PD-1) monoclonal antibody, to investigator’s choice 
of systemic therapy in patients with recurrent or metastatic HNSCC who progressed from a 
platinum containing therapy. At a preplanned interim analysis, the median OS was 7.5 
months (95% confidence interval [CI], 5.5 to 9.1) with nivolumab versus 5.1 months (95% 
CI, 4.0 to 6.0) with investigator’s choice. There is a 30% reduction in the risk of death for 
patients on the nivolumab arm (hazard ratio 0.70; 97.73% CI, 0.51 to 0.96; P=0.0101) over 
standard of care. In addition, the overall safety profile of nivolumab was favorable 
compared to standard of care. Clinical benefit seen in this chemotherapy pre-treated 
HNSCC suggests the potential clinical activity of nivolumab in the earlier treatment setting. 
We expect that combination treatment of paclitaxel and immune checkpoint inhibitors 
would also improve the outcome of patients unable for a cisplatin-based first-line 
chemotherapy. 
5.1.2.4. 
Nivolumab 
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb), which 
binds to the programmed death-1 (PD-1) receptor and blocks its interaction with PD-L1 
and PD-L2. The PD-1 receptor is a negative regulator of T-cell activity that has been 
shown to be involved in the control of T-cell immune responses. Engagement of PD-1 with 
the ligands PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be 
expressed by tumours or other cells in the tumour microenvironment, results in inhibition of 
T-cell proliferation and cytokine secretion. Nivolumab potentiates T-cell responses, 
including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2 
ligands. 
Up-regulation of PD-L1 and PD-L2 occurs in tumors. The cross-talk between tumor and T 
cells through the PD-1/ligand interaction in the tumor microenvironment leads to inhibition 
of active T-cell immune surveillance of tumors. Inhibition of PD-1, therefore, can block this 
negative regulatory pathway and allow T cells to regain the ability to attack tumors [42,43]. 
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Nivolumab is currently approved by EMA in different types of cancer (refer to Nivolumab 
SmPC). 
 
Melanoma: nivolumab as monotherapy or in combination with ipilimumab is 
indicated for the treatment of advanced (unresectable or metastatic) melanoma in 
adults. 
Adjuvant treatment of melanoma: nivolumab as monotherapy is indicated for the 
adjuvant treatment of adults with melanoma with involvement of lymph nodes or 
metastatic disease who have undergone complete resection  
Non-Small Cell Lung Cancer (NSCLC): nivolumab in combination with ipilimumab 
and 2 cycles of platinum-based chemotherapy is indicated for the first-line 
treatment of metastatic non-small cell lung cancer in adults whose tumours have 
no sensitising EGFR mutation or ALK translocation 
 
Non-Small Cell Lung Cancer (NSCLC): nivolumab as monotherapy is indicated for 
the treatment of locally advanced or metastatic non-small cell lung cancer after 
prior chemotherapy in adults.Malignant pleural mesothelioma (MPM): nivolumab in 
combination with ipilimumab is indicated for the first-line treatment of adult patients 
with unresectable malignant pleural mesothelioma. 
 
Renal Cell Carcinoma (RCC): nivolumab as monotherapy is indicated for the 
treatment of advanced renal cell carcinoma after prior therapy in adults.  
Renal Cell Carcinoma (RCC): nivolumab in combination with ipilimumab is 
indicated for the first-line treatment of adult patients with intermediate/poor-risk 
advanced renal cell carcinoma. 
Renal Cell Carcinoma (RCC): nivolumab in combination with cabozantinib is 
indicated for the first-line treatment of adult patients with advanced renal cell 
carcinoma (see section 5.1). 
 
Classical Hodgkin Lymphoma (cHL): nivolumab as monotherapy is indicated for 
the treatment of adult patients with relapsed or refractory classical Hodgkin 
lymphoma after autologous stem cell transplant (ASCT) and treatment with 
brentuximab vedotin. 
Squamous Cell Cancer of the Head and Neck (SCCHN): nivolumab as 
monotherapy is indicated for the treatment of recurrent or metastatic squamous cell 
cancer of the head and neck in adults progressing on or after platinum-based 
therapy. 
Urothelial Carcinoma: nivolumab as monotherapy is indicated for the treatment of 
locally advanced unresectable or metastatic urothelial carcinoma in adults after 
failure of prior platinum-containing therapy. 
Adjuvant treatment of urothelial carcinoma: nivolumab as monotherapy is indicated 
for the adjuvant treatment of adults with muscle invasive urothelial carcinoma 
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(MIUC) with tumour cell PD-L1 expression ≥1% who are at high risk of recurrence 
after undergoing radical resection of MIUC. 
Mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) 
colorectal cancer (CRC): nivolumab in combination with ipilimumab is indicated for 
the treatment of adult patients with mismatch repair deficient or microsatellite 
instability-high metastatic colorectal cancer after prior fluoropyrimidine-based 
combination chemotherapy (see section 5.1). 
Oesophageal squamous cell carcinoma (OSCC): nivolumab in combination with 
ipilimumab is indicated for the first-line treatment of adult patients with 
unresectable advanced, recurrent or metastatic oesophageal squamous cell 
carcinoma with tumour cell PD-L1 expression ≥ 1%. 
 
Oesophageal squamous cell carcinoma (OSCC): nivolumab in combination with 
fluoropyrimidine- and platinum-based combination chemotherapy is indicated for 
the first-line treatment of adult patients with unresectable advanced, recurrent or 
metastatic oesophageal squamous cell carcinoma with tumour cell PD-L1 
expression ≥ 1%. 
 
Oesophageal squamous cell carcinoma (OSCC): nivolumab as monotherapy is 
indicated for the treatment of adult patients with unresectable advanced, recurrent 
or metastatic oesophageal squamous cell carcinoma after prior fluoropyrimidine- 
and platinum-based combination chemotherapy. 
 
Adjuvant treatment of oesophageal or gastro-oesophageal junction cancer (OC or 
GEJC): nivolumab as monotherapy is indicated for the adjuvant treatment of adult 
patients with oseophageal or gastro-oesophageal junction cancer who have 
residual pathologic disease following prior neoadjuvant chemoradiotherapy. 
Gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinoma: 
nivolumab in combination with fluoropyrimidine- and platinum-based combination 
chemotherapy is indicated for the first-line treatment of adult patients with HER2-
negative advanced or metastatic gastric, gastro-oesophageal junction or 
oesophageal adenocarcinoma whose tumours express PD-L1 with a combined 
positive score (CPS) ≥ 5. 
 
The most common adverse reactions of nivolumab as monotherapy are fatigue (30%), 
rash (17%), pruritus (13%), diarrhea (13%), and nausea (12%). The majority of adverse 
reactions were mild to moderate (Grade 1 or 2). 
A variety of serious immune-mediated adverse reactions have also been observed in 
patients receiving nivolumab, including pneumonitis, colitis, hepatitis, nephritis, 
hypothyroidism and hyperthyroidism, and other immune-mediated adverse reactions. 
Further details regarding the clinical experience with nivolumab may be found in the 
current version of the approved nivolumab investigator brochure. 
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Approval of nivolumab in Squamous Cell Cancer of the Head and Neck was based on data 
from an international, multi-center, open-label, randomized, phase III trial (CheckMate 141) 
[24]. Eligible patients were 18 years of age or older, had histologically confirmed, 
recurrent/metastatic HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx, and 
had tumor progression on or within 6 months after the last dose of platinum-based 
chemotherapy administered in the locally advanced, recurrent, or metastatic disease 
setting. Patients (361) were randomized 2:1 to receive nivolumab (3 mg/kg every 2 weeks) 
(240) or standard single agent of investigator’s choice (methotrexate 40–60 mg/m2 weekly, 
docetaxel 30–40 mg/m2 weekly, or cetuximab 400 mg/m2 once, then 250 mg/m2 weekly) 
and stratified by prior cetuximab treatment (121). Treatment continued until tumor 
progression or unacceptable toxicity. Patients in the nivolumab arm were allowed to 
continue nivolumab treatment beyond tumor progression if they met predefined, protocol 
specified criteria. 
In a 2-year long-term survival update, the median overall survival was 7.7 months (95% CI, 
5.7 to 8.8) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.2) in the standard-
therapy group [44]. Overall survival was significantly longer with nivolumab than with 
standard therapy, and nivolumab treated patients had a risk of death that was 32% lower 
than the risk among patients assigned to standard therapy (hazard ratio, 0.68; 95% CI, 
0.54 to 0.96; P = 0.01). The estimated rate of overall survival at 2 years among patients 
treated with nivolumab (16.9%; 95% CI, 12.4 to 22.0) was nearly triple that of standard 
therapy (6.0%; 95% CI, 2.7 to 11.3). The response rate among nivolumab-treated patients 
was 13.3% (95% CI, 9.3 to 18.3), including 7 complete responses and 25 partial 
responses. In the standard-therapy group, the response rate was 5.8% (95% CI, 2.4 to 
11.6), including 1 complete response and 6 partial responses.  
Serious adverse reactions occurred in 49% of patients receiving nivolumab. The most 
frequent serious adverse reactions reported in at least 2% of patients receiving nivolumab 
were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. The 
most common adverse reactions occurring in more than 10% of nivolumab-treated patients 
and at a higher incidence than investigator’s choice were cough and dyspnea. The most 
common laboratory abnormalities occurring in 10% or more nivolumab-treated patients 
and at a higher incidence than investigator’s choice were increased alkaline phosphatase, 
increased amylase, hypercalcemia, hyperkalemia, and increased TSH. In the clinical trial, 
13.1% of patients taking nivolumab had severe side effects related to treatment compared 
with 35.1% of patients in the standard therapy group. Fatigue, nausea, rash, decreased 
appetite, and pruritus were the most common side effects in patients treated with 
nivolumab. 
Additional details on clinical experience with nivolumab are provided in the current version 
of the nivolumab Investigator’s Brochure (IB). 
5.2. 
Study rationale 
While there is much excitement around the phenomenon of a chemo-induced anticancer 
immune response and combining biotherapy with immunotherapy, numerous questions 
remain to be addressed in clinical trials. A major challenge is to identify not only the 
optimal immune checkpoint inhibitor as partner for a given chemotherapy schedule but 
also the best chronological sequence for their combined application. 
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Chemotherapy for incurable recurrent or metastatic HNSCC disease is palliative and 
usually platimun based, and the patients often present with poor physical condition due to 
alcohol and tobacco habits, malnutrition and comorbidities. Consequently, many of them 
are not able to withstand a platinum-based chemotherapy. The addition of taxanes to the 
armamentarium of drugs improve the outcome in this group. An alternative and better 
tolerated regimen for these patients is paclitaxel in combination with cetuximab [17]. 
However, the outcome of these patients still remains poor, with a median PFS and OS of 4 
and 8 months respectively.  
Recently, new treatments such as immune-checkpoint inhibitors have shown promising 
activity and good tolerability in patients with R/M HNSCC and has been included in the 
recently published guidelines from the Society for Immunotherapy of Cancer [40]. 
Nivolumab (anti-PD1) has been approved for patients progressing on or after platinum-
based therapy, as it clearly impacts on overall survival. CheckMate 141 study results 
showed a clear improvement in overall survival in the nivolumab group versus the 
standard-therapy group (7.7 months versus 5.1 months), but only patients with ECOG 0-1 
were included [44], therefore it is necessary to evaluate the safety and efficacy of 
treatments with nivolumab in patients with a more compromised performance status than 
those included in that study.  
Preclinical data suggests that paclitaxel may have a role as an immuno-modulator, mainly 
by increasing tumor infiltrating CD8+ lymphocytes. We expect that nivolumab in 
combination with paclitaxel would improve the outcome of patients unable for a cisplatin-
based first-line chemotherapy. 
For patients unable for a cisplatin-based first-line chemotherapy is important to identify an 
appropriate combination of therapy can represent a significant addition to the therapeutic 
armamentarium. The presence of severe comorbidities, age-related frailty or underlying 
severe psychosocial problems may be obstacles for highly intensive treatment plans. Such 
patients may benefit from less complicated or potentially less toxic treatment plans. The 
biology of the patient’s disease must also be considered in selecting or planning a 
combined modality approach. The goals of the addition of engineered monoclonal 
antibodies (MoAbs) to chemotherapy in a treatment plan, must be considered in this 
population to improved survival, optimization of quality of life and control of metastases. 
The most common treatment toxicity grade 3/4 of paclitaxel and cetuximab published by 
Hitt et col. [17], were acne-like rash (24%), asthenia (17%) and neutropenia (13%), with 
grade 3/4 febrile neutropenia in 1 patient. Grade 3 infusion-related reactions were 
observed in two patients during paclitaxel infusion. These reactions were managed with 
medication and treatment delay and both patients then continued in the study until 
progression disease. Grade 3/4 gastrointestinal toxicity and renal toxicity were reported in 
3% and 5% of patients, respectively. Commonly occurring lower grade treatment-related 
adverse events included: grade 1–2 conjunctivitis (15%) and peripheral neuropathy (4%); 
grade 1–3 alopecia (13%), grade 1–2 diarrhea (22%) and vomiting (22%) and grade 1–3 
onycholysis (24%). Grade 1–2 hypomagnesemia was reported in seven patients (15%). 
Only two patients withdrew from the study due to treatment-related toxicity (conjunctivitis 
grade 3 and febrile neutropenia grade 4). No toxic deaths were recorded and in general 
treatment was well tolerated [17]. 
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The toxicity of immunotherapy is dependent on the administered agent and dosage. In 
previous clinical trials, immune checkpoint blockade immunotherapy presented acceptable 
toxicity. Even occasional severe toxicity was manageable through treatment interruption or 
involvement of immunosuppressive drugs. During ipilimumab treatment approximately 60 
% patients showed immune-related adverse events, of them 10–15 % being grade 3–4 
[45]. The blockade of PD-1/-L1 showed less severe ir-AEs in previous phase I studies [46]. 
Diarrhea and skin rash were the most common immune-related adverse events after 
ipilimumab. Other adverse effects included enterocolitis, hypothyroidism, hypophysitis and 
neuropathies [46]. The most common adverse events reported for both nivolumab and 
pembrolizumab were mild fatigue, rash, pruritus and diarrhea, which could be usually 
managed without dose interruption or discontinuation [46]. In Clinical Trial CA209-141, 
13.1% of patients treated with nivolumab had severe side effects related to treatment 
compared with 35.1% of patients in the standard therapy group [24]. Considering the 
different kinds and acceptable adverse events, the combination treatment of paclitaxel and 
immune checkpoint inhibitors seems feasible for HNSCC patients. 
Adverse events (AEs) of these new regimens are described to be mild compared with 
those of classical chemotherapy [47]. Overall, these clinical observations provide a sound 
rationale for investigating immune checkpoint inhibitors with paclitaxel for primary 
treatment of recurrent or metastatic HNSCC unable for cisplatin-based chemotherapy. 
5.3. 
Study objectives 
Primary objective: 
Primary objective of this study is to assess the efficacy of nivolumab plus paclitaxel, in 
terms of two years overall survival (OS), for first-line treatment of recurrent or metastatic 
HNSCC in the platinum ineligible and platinum refractory settings. 
OS is defined as the time between the date of randomization and the date of death. For 
subjects without documentation of death, OS will be censored on the last date the subject 
was known to be alive. 
Secondary objectives: 
Secondary objectives of this study are: 
- 
To evaluate the efficacy of Nivolumab with paclitaxel in patients with 
recurrent or metastatic HNSCC in the platinum ineligible and platinum 
refractory settings by:  
o Progression free survival (PFS) 
o Overall response rate (ORR) using Response Evaluation Criteria In 
Solid Tumors (RECIST 1.1) [2] as determined by investigator criteria 
o Disease control rate (DCR)  
o Duration of response (DoR) 
o Rate of progressive disease at 6 months  
o Five years overall survival (5y-OS) 
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- 
To evaluate the efficacy of study treatment in patients ≥ 70 years and 
according to G8 result. 
- 
To evaluate efficacy (ORR, PFS, OS) based on: PDL1 expression 
measured by Combined Positive Score (CPS), Presence of Human 
Papilomavirus (HPV) in Oropharynx Carcinoma (OPC), cisplatin refractory, 
cisplatin ineligibility and Karnofsky. 
- 
To evaluate safety profile of Nivolumab with paclitaxel by:  
o Percentage of patients with AEs 
o Percentage of patients with Grade 3 and Grade 4 AEs 
o Percentage of patients with SAEs 
o Percentage of patients who discontinued due to AEs 
o Percentage of patients with each AE by grade 
 
6. 
STUDY DESIGN   
6.1. 
Overall design 
This is a randomized, open-label, controlled, multicenter, phase II trial to assess the 
efficacy of nivolumab plus paclitaxel for first-line treatment of recurrent or metastatic 
HNSCC in the platinum ineligible and platinum refractory settings. 
Approximately 141 subjects will be randomized to the two treatment arms in a 2:1 ratio (94 
in experimental arm and 47 in control arm) and stratified by the following factors: 
1. Karnofsky performance status (70% vs 80-100%) 
2. CPS ≥1 vs <1 (DAKO PD-L1 IHC 22C3) (see annex 12). PD-L1 determination 
(CPS, before patient inclusion) will be performed by a central lab (Pathological 
Anatomy Service, Hospital 12 de Octubre, Madrid, Spain) 
3. If oropharyngeal cancer: oropharyngeal cancer HPV+ (p16 IHC & HPV DNA) vs 
oropharyngeal cancer HPV– / non-oropharyngeal cancer). For subjects with 
oropharyngeal cancer, sites defined in annex 8. HPV status of tumor tissue has to 
be locally determined at screening by any of the following methods: p16 IHC, in situ 
hybridization, or polymerase chain reaction based assay. If HPV status by p16 IHC 
is positive result confirmation by PCR is mandatory. 
 
HPV p16 status (OPC), PD-L1 status (CPS) and Karnofsky performance status will be 
needed prior to randomization. Subjects will undergo screening evaluations to determine 
eligibility prior to randomization.  
Once enrolled in the study, patients will be randomized in a 2:1 ratio to receive: 
- 
Arm 1 (experimental): NIVOTAX (Combination of nivolumab + paclitaxel, follow by 
maintenance with nivolumab).  
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Combination treatment: Nivolumab 240 mg will be administered via IV infusion 
every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly.  
After 12 weeks from the start of the combined treatment paclitaxel will be stopped.  
Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks 
after the last administration of nivolumab 240 mg. Once nivolumab is administered 
at 480 mg, paclitaxel can no longer be administered. 
Nivolumab will be continued alone until disease progression, unacceptable toxicity 
or withdrawal of consent up to a maximum of 24 months. 
- 
Arm 2 (standard): ERBITAX (Combination of cetuximab + paclitaxel, follow by 
maintenance with cetuximab).  
Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) 
administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) 
administered via IV infusion. 
After 12 weeks from the start of the combined treatment paclitaxel will be stopped 
and weekly cetuximab will be continued alone until disease progression, 
unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.  
ERBITAX has been chosen as a control group since it is the standard treatment in 
Spain for this patients and to have a contemporary reference with a profile of 
patients equal to that of the experimental arm. 
 
 
Patient will start study treatment within 48 hours of randomization. 
The premedication used for paclitaxel, nivolumab and cetuximab will be according to each 
participating site standard of care.  
In Arm 1 paclitaxel premedication must be administered during or after the observation 
period (30 minutes following nivolumab infusion).  
Tumor progression and response endpoints will be assessed using RECIST 1.1 criteria. 
Tumor assessments performed as standard of care prior to obtaining informed consent 
and within 28 days prior to initiation of study treatment do not have to be repeated at 
screening. Screening assessments must include CT scans (with oral or IV contrast) of the 
chest and abdomen and CT scans (with oral or IV contrast) or MRI (with contrast) of the 
head and neck region. If a CT scan with contrast is contraindicated (e.g., in patients with 
contrast allergy or impaired renal clearance), a non-contrast CT scan of the chest may be 
performed and MRI with contrast scans of the abdomen and head and neck region must 
be performed. All measurable and non-measurable lesions should be assessed and 
documented at screening. If both a CT scan with contrast is contraindicated (e.g., in 
patients with impaired renal clearance or contrast allergy) and MRI is contradicted (e.g., in 
patients with claustrophobia), non-contrast CT scans of the chest, abdomen, and head and 
neck region may be performed only upon prior approval from the coordinating 
investigators. 
An evaluation of disease response using the RECIST version 1.1 will be performed at 
screening/baseline (within 28 days before the first study drug administration), at week 9 
and then every 12 weeks until disease progression. 
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Dose modification (interruption or reduction) of cetuximab or paclitaxel should be done 
according to SmPC (see sections 9.4.4 and 9.4.5). 
Dose reductions will be not be allowed for nivolumab.  Only dose interruption for a 
maximum of 6 weeks, are allowed (see section 9.4.3.). 
Cetuximab has to be permanently discontinued in case of administration interruption for 4 
consecutive infusions due to any relevant circumstance. Principal investigator and study 
coordinators could assess the possibility of treatment reintroduction if cetuximab 
administration benefit is clearly documented. 
Study Scheme 
 
 
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Study Treatment 
 
Patient will start study treatment within 48 hours of randomization. 
Tumor progression and response endpoints will be assessed using RECIST 1.1 criteria. 
Since the combination of paclitaxel and nivolumab in HNSCC has not yet been studied, 
the sponsor will establish a study data monitoring committee for reviewing safety data of 
the combination. This committee will consist of the two coordinating investigators and at 
least 5 of the participating investigators who will review the available safety information.  
The study data monitoring committee will evaluate the safety profile of the combination 
once the first 10 patients included in the nivolumab arm have finished the combined 
treatment with paclitaxel. Additionally, the study data monitoring committee will review the 
available safety information every three months. It is not considered necessary to make 
more frequent reviews since both drugs are widely used in the participating oncology 
departments, there is sufficient experience in their use and the safety profile of both drugs 
is clearly defined. 
During the periodic reviews, the study data monitoring committee together with the 
sponsor will review the available safety data (adverse events, serious adverse events, 
dropouts) and make a recommendation on whether or not to continue recruiting patients in 
the study, depending on the safety data from patients included. In any case, if an 
unexpected event related to patient safety is detected, it will be notified to the participating 
investigators and will be evaluated by the sponsor and the study data monitoring 
committee, which could increase the frequency of safety reviews if deemed appropriate. 
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6.2. 
Primary endpoint 
Primary endpoint of the study is two years overall survival. 
OS is defined as the time between the date of randomization and the date of death. For 
subjects without documentation of death, OS will be censored on the last date the subject 
was known to be alive. 
 
6.3. 
Secondary endpoints 
PFS is defined as the time from randomization to the date of first documented disease 
progression, as assessed by the investigator using RECIST 1.1 criteria, or death due to 
any cause, whichever occurs first. Subjects who died without a reported progression will 
be considered to have progressed on the date of their death. Subjects who did not 
progress or die will be censored on the date of their last evaluable tumor assessment. 
Subjects who did not have any on study tumor assessments and did not die will be 
censored on the date they were randomized. Subjects who started any subsequent anti-
cancer therapy without a prior reported progression will be censored at the last evaluable 
tumor assessment prior to/on initiation of the subsequent anti-cancer therapy. 
 
ORR is defined as the number of subjects with a best overall response (BOR) of a 
complete response (CR) or partial response (PR) divided by the number of randomized 
subjects for each treatment group. The BOR is defined as the best response designation, 
as determined investigator assessment, recorded between the date of randomization and 
the date of progression, as assessed by investigator per RECIST 1.1 or the date of 
subsequent anticancer therapy, whichever occurs first. For subjects without evidence of 
RECIST 1.1 progression or subsequent anticancer therapy, all available response 
designations will contribute to the BOR assessment. For subjects who continue treatment 
beyond progression, the BOR will be determined based on response designations up to 
the time of initial RECIST 1.1 progression. 
 
Disease control rate (DCR) is defined as the number of subjects with a best overall 
response (BOR) of a complete response (CR), partial response (PR) or stable disease 
(SD) divided by the number of randomized subjects for each treatment group. 
 
Duration of Response (DoR) is defined as the time between the date of first confirmed 
response to the date of the first documented tumor progression (per RECIST 1.1), or 
death due to any cause, whichever occurs first. Subjects who neither progress nor die will 
be censored on the date of their last evaluable tumor assessment. Subjects who started 
any subsequent anti-cancer therapy without a prior reported progression will be censored 
at the last evaluable tumor assessment prior to or on initiation of the subsequent anti-
cancer therapy. DoR will be evaluated for responders (confirmed CR or PR) only. 
 
Rate of PD is defined as the number of subjects with PD at 6 months divided by the 
number of randomized subjects for each treatment group. 
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Efficacy (ORR, PFS, OS) will be evaluated based on:  PDL1 expression measured by 
Combined Positive Score (CPS), Presence of Human Papilomavirus (HPV) in Oropharynx 
Carcinoma (OPC), cisplatin refractory, cisplatin ineligibility and Karnofsky-PS. 
All randomized subjects will be monitored by radiographic assessment at week 9 (± 7 
days) and then every 12 weeks (± 7 days).  RECIST 1.1 criteria will be used for the 
assessment.  
 
Subjects will be evaluated for safety if they have received any study drug. Toxicity 
assessments will be continuous during the treatment phase and the safety follow-up 
phase. Adverse events and laboratory values will be graded according to the NCI-CTCAE 
version 5.0. Subjects will be followed for drug-related toxicities until these toxicities 
resolve, return to baseline or are deemed irreversible. All adverse events will be 
documented for minimum of 100 days after the last dose of study medications. On-study 
weight, Karnofsky performance status, and vital signs should be assessed at each on-
study visit prior to dosing. Vital signs should also be taken as per institutional standard of 
care prior to, during and after infusions. The start and stop time of the study therapy 
infusions should be documented. 
Physical examinations are to be performed as clinically indicated. If there are any new or 
worsening clinically significant changes since the last exam, report changes on the 
appropriate non-serious or serious adverse event page. 
Laboratory toxicities (eg, suspected drug induced liver enzyme evaluations) will be 
monitored during the follow-up phase via on site/local labs until all study drug related 
toxicities resolve, return to baseline, or are deemed irreversible. 
The safety analysis will be performed in all treated subjects. Descriptive statistics of 
safety will be presented using the NCI CTCAE version 5.0 by treatment arm. All AEs, 
drug-related AEs and SAEs will be tabulated using the worst grade per NCI CTCAE v 5.0 
criteria by system organ class and preferred term.  
Percentage of patients with AEs, percentage of patients with Grade 3 and Grade 4 AEs, 
percentage of patients with SAEs, percentage of patients who discontinued due to AEs, 
incidence of deaths and percentage of patients with each AE per grade will be provided.  
 
7. 
PATIENT SELECTION 
Patients diagnosed with HNSCC who are unable for first-line cisplatin-based 
chemotherapy and not previously treated for recurrent/metastatic disease will be include in 
the study. 
Patients will be distributed in the following way: 
- 
Group 1: Platinum resistant population (one third of the patients – 47 
patients):  
Patients who have experienced disease progression or relapse 
during or within 6 months of receiving platinum-based therapy 
administered as neoadjuvant, adjuvant therapy or as concomitant 
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chemotherapy with radiotherapy and have received at least 200 
mg/m2  of cisplatin. 
- 
Group 2: Platinum sensitive but unable for cisplatin-based therapy  
according to one of these criteria (one third of the patients – 47 patients): 
1. Karnofsky grade 70% or 
2. Impaired renal function, creatinine clearance >30 mL/min  and <80 mL/min 
GFR could be assessed by direct measurement (EDTA or creatinine 
clearance) if available or by calculation from serum or plasma creatinine, or 
3. Class III heart failure according to the New York Heart Association (see 
annex 9), or 
4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or  
5. History of allergic reactions to cisplatin, carboplatin, or other platinum-
containing compounds. 
If the patient meets more than one of the first three criteria, the patient 
cannot be included in the study. (Criteria 1, 2 and 3 cannot coincide in the same 
patient; criteria 4 and 5 can go alone or in combination with any other). 
- 
Group 3: Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for 
locally advanced disease (one third of the patients – 47 patients) (a patient 
who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles 
induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN 
cancer). The interval from the last cycle of cisplatin and the start of first line 
treatment for R/M disease is >6 months. 
 
Once the planned recruitment in groups 1 or 3 is completed, sponsor will 
evaluate the number of patients recruited in each of the other groups as well as 
the remaining recruitment time to confirm whether the proportion of patients to 
be included in each group is maintained. 
7.1. 
Inclusion criteria 
Each patient must meet all the following inclusion criteria to be enrolled in the study: 
1. Voluntary written consent must be given before performance of any study-related 
procedure not part of standard medical care.  
2. Histologically confirmed HNSCC (oral cavity, oropharynx, hypopharynx, larynx) not 
amenable to therapy with curative intent (surgery or radiation therapy with or 
without chemotherapy).  
3. Patients not previously treated for recurrent/metastatic disease. 
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4. Radiographically measurable disease as defined by RECIST version 1.1. 
Previously irradiated lesions can only be considered as measurable disease if 
disease progression according to RECIST version 1.1. 
5. Patients unable for cisplatin-based chemotherapy, defined “unable” by: 
a. Karnofsky 70% or  
b. Karnofsky 80-100% and amenable to chemotherapy, but: 
1) Impaired renal function, creatinine clearance >30 mL/min  and <80 
mL/min GFR could be assessed by direct measurement (EDTA or 
creatinine clearance) if available or by calculation from serum or 
plasma creatinine (see annex 5), or  
2) Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or  
3) Class III heart failure according to the New York Heart Association 
(see annex 9), or 
4) History of allergic reactions to cisplatin, carboplatin, or other 
platinum-containing compounds or 
5) Prior dose of cisplatin ≥225 mg/m² for locally advanced disease (a 
patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 
3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced 
primary HN cancer can be included), or 
6) Disease progression or relapse during or within 6 months of 
receiving platinum-based therapy administered as neoadjuvant, 
adjuvant therapy or as concomitant chemotherapy with 
radiotherapy and have received at least 200 mg/m2 of cisplatin.  
6. Male or female patients aged ≥18 years. 
Patients aged ≥70 years old can only be included with a G8 (Geriatric 8) (see 
annex 10) health status screening score ≥ 14. 
a. Female patients: 
i. Are postmenopausal for at least 1 year before the Screening visit, or 
ii. Are surgically sterile, or 
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iii. If they are of childbearing potential, agree to practice one highly 
effective method of contraception and one additional effective 
(barrier) method, at the same time (see annex 6) from the time of 
signing the informed consent through 180 days after the last dose 
of study drug, or 
iv. Agree to practice true abstinence, when this is in line with the 
preferred and usual lifestyle of the subject. (Periodic abstinence 
[eg, calendar, ovulation, symptothermal, postovulation methods] 
withdrawal, spermicides only, and lactational amenorrhea are not 
acceptable methods of contraception. Female and male condoms 
should not be used together). 
v. Women of childbearing potential (WOCBP) must have a negative 
serum or urine pregnancy test within 72 hours prior to the start of 
study drug. 
vi. Women must not be breastfeeding 
b. Male patients, even if surgically sterilized (ie, status postvasectomy), who: 
i. Agree to practice effective barrier contraception during the entire 
study treatment period and through 6 months after the last dose of 
study drug, OR 
Agree to practice true abstinence, when this is in line with the preferred and 
usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods] withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. 
Female and male condoms should not be used together).Investigators shall 
counsel WOCBP and male subjects who are sexually active with WOCBP 
on the importance of pregnancy prevention and the implications of an 
unexpected pregnancy. 
7. Clinical laboratory values as specified below within 28 days before the first dose of 
study drug: 
a. Total bilirubin must be ≤2 × the upper limit of normal (ULN). 
b. Magnesium ≥ lower limit of normal. 
c. Calcium ≥ lower limit of normal. 
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d. ALT and AST must be ≤3 × ULN unless liver metastases are present, in 
which case they must be ≤5x ULN. 
e. Hemoglobin must be ≥9 g/dL, absolute neutrophil count (ANC) must be 
≥1.500/µL, WBC must be ≥2.000/µL and platelet count must be 
≥100.000/µL. 
8. Subjects who have received radiation as primary therapy are eligible if radiation 
therapy treatment was completed > 4 weeks prior to inclusion 
9. Documentation of PD-L1 status by IHC performed by the central lab at 
randomization. A pre-treatment tumor tissue sample should be sent.  
A representative formalin-fixed paraffin-embedded (FFPE) tumor specimen (at 
least 5 mm3 in which more than 60% of the sample is tumor) in paraffin block or 
unstained, freshly cut, serial sections (preferably at least 5) from an FFPE tumor 
specimen, are preferred.  A newly obtained biopsy (within 6 months prior to start of 
study treatment) is preferred but an archival sample is acceptable, if several tumor 
samples are available, testing should be performed on the most recently obtained 
tumor sample. 
This specimen should be accompanied by the associated pathology report 
anonymized. Freshly cut, serial sections must have been cut no more than 14 days 
prior to analysis by central lab. Slides that have been cut more than 14 days prior 
to analysis by central lab should not be used and new slides should be made. 
PD-L1 expression determined by using Combined Positive Score (CPS) (see 
annex 12) before patient randomization (DAKO PD-L1 IHC 22C3) will be 
performed by a central lab (Anatomic Pathology Department, Hospital 12 de 
Octubre, Madrid, Spain) 
10. Documentation of HPV p16 status (OPC) is required for HNSCC tumor of the 
oropharynx. For subjects with oropharyngeal cancer, sites are defined in annex 8. 
HPV status of tumor tissue has to be locally determined at screening by any of the 
following methods: p16 IHC, in situ hybridization, or polymerase chain reaction 
based assay. If HPV status by p16 IHC is positive result confirmation by PCR is 
mandatory. 
 
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7.2. 
Exclusion criteria 
Patients meeting any of the following exclusion criteria will not to be enrolled in the study: 
1. Male or female patients aged < 18 years. Patients aged ≥>70 years old can only be 
included with a G8 (Geriatric 8) health status screening score < 14. 
2. Karnofsky <70%. 
3. Patients that meets more than one of the following criteria: 
a. Karnofsky 70%,  
b. Impaired renal function, creatinine clearance >30 mL/min  and <80 mL/min 
GFR could be assessed by direct measurement (EDTA or creatinine 
clearance) if available or by calculation from serum or plasma creatinine 
(see annex 5),  
c. Class III heart failure according to the New York Heart Association (annex 
9). 
4. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy 
except for alopecia, vitiligo, hear loss, and the laboratory values defined in the 
inclusion criteria. 
  
5. Histologically confirmed squamous cell carcinoma of unknown primary, of the 
nasopharynx or non-squamous histologies (eg, mucosal melanoma). 
6. Active brain metastases or leptomeningeal metastases. 
7. Carcinomatous meningitis. 
8. 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. 
9. Diagnosis of immunodeficiency or any condition requiring systemic treatment with 
either corticosteroids (>10 mg daily prednisone equivalents) or other 
immunosuppressive medications within 14 days of treatment. 
10. History of pneumonitis requiring treatment with steroids; history of idiopathic 
pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia, or evidence 
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of active pneumonitis on screening chest CT scan; history of radiation pneumonitis 
in the radiation field (fibrosis) is permitted. 
11. Patients with a history of interstitial lung disease cannot be included if they have 
symptomatic ILD (Grade 3-4) and/or poor lung function.  
12. Prior therapy with experimental antitumor vaccines; any T-cell co-stimulation 
agents or inhibitors of checkpoint pathways, such as anti-PD-1, anti-PD-L1, anti-
PD-L2, anti-CD137, or anti-CTLA-4 antibody; or other agents specifically targeting 
T cells are prohibited.  
13. Any serious medical or psychiatric illness, including drug or alcohol abuse, that 
could, in the investigator’s opinion, potentially interfere with the completion of 
treatment according to this protocol. 
14. Life-threatening illness unrelated to cancer. 
15. Female patients who are lactating and breast-feeding or a positive serum 
pregnancy test during the screening period. 
16. Systemic anticancer treatment or radiotherapy less than 4 weeks or 5 half-lives, 
whichever is longer, before the first dose of study treatment or not recovered from 
acute toxic effects from prior chemotherapy and radiotherapy. 
17. Prior treatment with investigational agents ≤21 days (≤4 weeks for monoclonal 
antibodies with evidence of PD) or ≤5 their half-lives (whichever is shorter) before 
the first dose of study treatment. A minimum of 10 days should elapse from prior 
therapy to initiating protocol therapy. 
18. Major surgery within 14 days before the first dose of study drug and not recovered 
fully from any complications from surgery. 
19. Systemic infection requiring IV antibiotic therapy or other serious infection within 14 
days before the first dose of study drug. 
20. Known human immunodeficiency virus (HIV) positive (testing not required), or 
known acquired immunodeficiency syndrome (AIDS). 
21. Patients with positive test for hepatitis B virus or hepatitis C virus indicating 
presence of virus, eg, Hepatitis B surface antigen (HBsAg) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA. negative). 
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22. Active secondary malignancy that requires treatment. 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. 
23. Any clinically significant co-morbidities, such as uncontrolled pulmonary disease, 
known impaired cardiac function or clinically significant cardiac disease (specified 
below), active central nervous system disease, active infection, or any other 
condition that could compromise the patient’s participation in the study. 
Patients with any of the following cardiovascular conditions are excluded: 
a. Acute myocardial infarction within 6 months before starting study drug. 
b. Evidence of current uncontrolled cardiovascular conditions including cardiac 
arrhythmias, angina, pulmonary hypertension, or electrocardiographic 
evidence of acute ischemia or active conduction system abnormalities. 
c. Friderichia corrected QT interval (QTcF) >450 milliseconds (msec) (men) or 
>475 msec (women) on a 12-lead ECG during the Screening period. 
d. Abnormalities on 12-lead ECG including, but not limited to, changes in 
rhythm and intervals that in the opinion of the investigator are considered to 
be clinically significant. 
24. Patients with history of hypersensitivity reactions to study drugs (nivolumab, 
cetuximab or paclitaxel) or any of their excipients. 
25. Symptomatic peripheral neuropathy of Grade ≥ 2 based on the CTCAE v5.0. 
26. Pulmonary embolism, deep vein thrombosis, or other significant thromboembolic 
event ≤ 8 weeks prior to starting the study treatment. 
27. History of severe skin disorder that in the opinion of the investigator may interfere 
with study conduct. 
 
7.3. 
Randomization procedures 
After the subject’s initial eligibility is established and informed consent has been obtained, 
the subject must be enrolled into the study through the e-CRF to obtain the subject 
number. Every subject that signs the informed consent form must be assigned a subject 
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number. The investigator or designee will register the subject for enrollment by following 
the enrollment procedures. The date that informed consent was obtained is required for 
enrollment.  
Once enrolled in the eCRF, enrolled subjects that have met all eligibility criteria will be 
ready to be randomized. Karnofsky, CPS score ≥1 / <1 (PD-L1) and HPV p16 result 
(positive, negative or not oropharyngeal cancer) will be entered by the site directly into the  
eCRF for randomization.  
Enrollment will stop once 141 subjects have been randomized. 
Patient will start study treatment within 48 hours of randomization. 
 
7.4. 
Blinding procedures 
Not applicable. Open label study. 
 
8. 
WITHDRAWAL CRITERIA 
8.1. 
Reasons for Withdrawal 
Subjects who request to discontinue study drug will remain in the study and must continue 
to be followed for protocol specified follow-up procedures except when a subject 
specifically withdraws consent for any further contact with him/her. The withdrawal of 
consent should be explained in detail in the medical records by the investigator and 
entered on the appropriate CRF page.  
All reasonable efforts must be made to locate subjects to determine and report their 
ongoing status. Lost to follow-up is defined by the inability to reach the subject after a 
minimum of three documented phone calls or emails. All attempts should be documented 
in the subject’s medical records. If it is determined that the subject has died, the site will try 
to obtain the date and cause of death. 
8.2. 
Discontinuation of study drug 
Subjects MUST discontinue study treatment for any of the following reasons: 
- 
Subject’s request to stop study treatment 
- 
Any clinical adverse event (AE), laboratory abnormality or intercurrent 
illness which, in the opinion of the investigator, indicates that continued 
participation in the study is not in the best interest of the subject 
- 
Progression disease 
- 
Interruption of nivolumab for 6 weeks or more.  
- 
Termination of the study by the sponsor 
- 
Loss of ability to freely provide consent  
- 
Pregnancy 
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8.3. 
Handling of Withdrawals 
In the case of pregnancy, the investigator must immediately notify the sponsor or designee 
of this event. In most cases, the study drug will be permanently discontinued. Please 
contact the sponsor or designee within 24 hours of awareness of the pregnancy.  
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures. The only exception is when a subject withdraws consent for all study 
procedures including post-treatment study follow-up. 
If study drug is discontinued prior to progression disease, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
eCRF. 
8.4. 
Reserve and Replacement Subjects 
Subjects who discontinue study drug or withdraw consent should not be replaced.  
 
9. 
INVESTIGATIONAL PRODUCT 
Nivolumab, cetuximab and paclitaxel are the investigational medicinal products in this 
clinical trial.  
The sponsor, by means of manufacturer, will supply free of charge, nivolumab for the 
conducting of the clinical trial. Cetuximab and paclitaxel will be provided by each 
participant site as they are the usual treatment in Spain for these patients.  
9.1. 
Investigational product description 
9.1.1. 
Description 
Nivolumab  
Nivolumab is a clear to opalescent, colourless to pale yellow liquid that may contain few 
light particles. The solution has a pH of approximately 6.0 and an osmolality of 
approximately 340 mOsm/kg. 
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb), which 
binds to the programmed death-1 (PD-1) receptor and blocks its interaction with PD-L1 
and PD-L2. The PD-1 receptor is a negative regulator of T-cell activity that has been 
shown to be involved in the control of T-cell immune responses. Engagement of PD-1 with 
the ligands PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be 
expressed by tumours or other cells in the tumour microenvironment, results in inhibition of 
T-cell proliferation and cytokine secretion. Nivolumab potentiates T-cell responses, 
including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2 
ligands. In syngeneic mouse models, blocking PD-1 activity resulted in decreased tumour 
growth. 
Nivolumab as monotherapy is indicated for the treatment of recurrent or metastatic 
squamous cell cancer of the head and neck in adults progressing on or after platinum-
based therapy. Nivolumab is indicated also in different types of cancer as melanoma, non-
small cell lung cancer, renal cell carcinoma, Hodgkin lymphoma urothelial carcinoma and 
gastro-oesophageal junction cancer 
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Cetuximab 
Cetuximab 5 mg/mL solution for infusion is a colourless solution supplied in vials 
containing 20 mL of solution.  
Cetuximab is a chimeric monoclonal IgG1 antibody that is specifically directed against the 
epidermal growth factor receptor (EGFR).  
EGFR signalling pathways are involved in the control of cell survival, cell cycle 
progression, angiogenesis, cell migration and cellular invasion/metastasis.  Cetuximab 
binds to the EGFR with an affinity that is approximately 5- to 10-fold higher than that of 
endogenous ligands. Cetuximab blocks binding of endogenous EGFR ligands resulting in 
inhibition of the function of the receptor. It further induces the internalisation of EGFR, 
which can lead to down-regulation of EGFR. Cetuximab also targets cytotoxic immune 
effector cells towards EGFR-expressing tumour cells (antibody dependent cell-mediated 
cytotoxicity, ADCC).  
The protein product of the proto-oncogene RAS (rat sarcoma) is a central down-stream 
signal-transducer of EGFR. In tumours, activation of RAS by EGFR contributes to EGFR-
mediated increased proliferation, survival and the production of pro-angiogenic factors.  
Cetuximab inhibits the proliferation and induces apoptosis of human tumour cells that 
express EGFR. In vitro cetuximab inhibits the production of angiogenic factors by tumour 
cells and blocks endothelial cell migration. In vivo cetuximab inhibits expression of 
angiogenic factors by tumour cells and causes a reduction in tumour neo-vascularisation 
and metastasis. 
Paclitaxel 
Paclitaxel 6 mg/ml, concentrate for solution for infusion is a clear colourless to slightly 
yellow solution free from visible particles with a pH in range of 3.0 – 5.5 and an osmolarity 
of > 4000 mOsm/l. 
Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from 
tubulin dimers and stabilises microtubules by preventing depolymerization. This stability 
results in the inhibition of the normal dynamic reorganisation of the microtubule network 
that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel 
induces abnormal arrays or bundles of microtubules throughout the cell cycle and multiple 
asters of microtubules during mitosis.  
9.1.2. 
Packaging 
Nivolumab 
Nivolumab 10 mg/mL concentrate for solution for infusion. One vial of 10 mL contains 100 
mg of nivolumab. 10 mL of concentrate in a 10 mL vial (Type I glass) with a stopper 
(coated butyl rubber) and a grey flip-off seal (aluminium).  
Nivolumab will be labelled with the study protocol code, batch number, content, expiry 
date, storage conditions, investigator and sponsor name. The study medication will be 
labelled in accordance with annex 13 of the European Good Manufacturing Practices.  
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Cetuximab 
Each mL of solution for infusion contains 5 mg cetuximab. Each vial of 20 mL contains 100 
mg cetuximab.  
Cetuximab 5 mg/mL solution for infusion is supplied in vials containing 20 mL of solution in 
a vial (Type I glass) with a stopper (halobutyl rubber) and a seal (aluminium/polypropylen).  
Paclitaxel 
Paclitaxel 6 mg/ml Concentrate for Solution for Infusion. 
Paclitaxel 6 mg/ml, concentrate for solution for infusion is a clear colourless to slightly 
yellow solution free from visible particles with a pH in range of 3.0 – 5.5 and an osmolarity 
of > 4000 mOsm/l. 
Paclitaxel is supplied in type I glass vials (closed with Omniflex Plus rubber stopper and 
sealed with aluminium flip off seal).  
9.1.3. 
Shipping, Storage and Disposal 
Nivolumab  
Nivolumab must be stored in a refrigerator (2°C to 8°C). The vials must be kept in the 
original package in order to protect from light. Nivolumab should not be frozen. 
The unopened vial can be stored at controlled room temperature up to 25°C with room 
light for up to 48 hours. 
Nivolumab injection it is preferred to administer the drug product immediately. If not used 
immediately, the solution may be stored under refrigeration conditions (2°C-8°C) and 
protected from light for up to 7 days, including the product administration period or as 
described in the instructions provided to the clinical site. The infusion solution may be 
stored at room temperature (up to 25ºC) and room light for a maximum of 8 hours, 
including the product administration period. 
Do not store any unused portion of the infusion solution for reuse. Any unused medicine or 
waste material should be disposed of in accordance with local requirements. 
If the study drugs are destroyed at the hospital site, the investigator is responsible for 
ensuring that the appropriate procedures are followed when destroying them, as per 
corresponding institutional regulations, guidelines, and procedures. Satisfactory records of 
the destruction of the drugs should also be maintained so that these procedures can be 
verified. Any unused study drugs can be destroyed only once the clinical trial monitor has 
inspected them and carried out the drug accountability. 
All unused or partially used study drugs can be destroyed on site, as long as the site has a 
standard operating procedure to this effect. 
Cetuximab  
Cetuximab must be stored in a refrigerator (2°C to 8°C). Cetuximab should not be frozen. 
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Chemical and physical in-use stability of cetuximab 5 mg/mL has been demonstrated for 
48 hours at 25ºC.  
Cetuximab does not contain any antimicrobial preservative or bacteriostatic agent. From a 
microbiological point of view, the product shall be used immediately after opening. If not 
used immediately, in-use storage times and conditions prior to use are the responsibility of 
the user and would normally not be longer than 24 hours at 2 to 8ºC, unless opening has 
taken place in controlled and validated aseptic conditions. 
Do not store any unused portion of the infusion solution for reuse. Any unused medicine or 
waste material should be disposed of in accordance with local requirements. 
If the study drugs are destroyed at the hospital site, the investigator is responsible for 
ensuring that the appropriate procedures are followed when destroying them, as per 
corresponding institutional regulations, guidelines, and procedures. Satisfactory records of 
the destruction of the drugs should also be maintained so that these procedures can be 
verified. Any unused study drugs can be destroyed only once the clinical trial monitor has 
inspected them and carried out the drug accountability. 
All unused or partially used study drugs can be destroyed on site, as long as the site has a 
standard operating procedure to this effect. 
Paclitaxel 
Do not store above 25°C. Keep the vial in the outer carton in order to protect from light. 
Freezing does not adversely affect the unopened vials. 
After opening before dilution: Chemical and physical in-use stability has been 
demonstrated for 28 days at 25°C following multiple needle entries and product 
withdrawal. From a microbiological point of view, once opened the product may be stored 
for a maximum of 28 days at 25°C. Other in-use storage times and conditions are the 
responsibility of the user. 
After dilution: Chemical and physical in-use stability of the solution prepared for infusion 
has been demonstrated at 5°C and at 25°C for 7 days when diluted in 5% Dextrose 
solution, and for 14 days when diluted in 0.9% Sodium Chloride Injection. From a 
microbiological point of view, the product should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the 
user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken 
place in controlled and validated aseptic conditions. 
9.2. 
Dosage and administration 
Patient will start study treatment within 48 hours of randomization. 
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Nivolumab plus paclitaxel 
Patients will receive nivolumab 240 mg via IV infusion through a 0.2-micron to 1.2-micron 
pore size, low-protein binding (polyethersulfone membrane) in-line filter.  
Nivolumab will be administered as an intravenous infusion over 30 minutes every 2 weeks 
during paclitaxel treatment (first 12 weeks of treatment).  
Paclitaxel IV infusion will start at least 30 minutes after completion the nivolumab infusion.  
Paclitaxel premedication must be administered during or after the observation period (30 
minutes following nivolumab infusion). 
Paclitaxel will be administered as 60 minutes IV infusion every week at a dose of 80 mg/m² 
during 12 weeks. 
Nivolumab  
Once paclitaxel cycles are completed, nivolumab will be switch to 480 mg administered as 
an intravenous infusion over 60 minutes every 4 weeks until disease progression, 
unacceptable toxicity or withdrawal of consent up to a maximum of 24 months, which 
occur first.  
Patient will be monitored for an observation period of at least 30 minutes after nivolumab 
infusion is completed. 
Maintenance treatment with nivolumab 480 mg will start two weeks after the last 
administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel 
can no longer be administered. 
Cetuximab plus paclitaxel 
Cetuximab is administered once a week. The initial dose is 400 mg/m2 over 2 h.  
A close monitoring of patients, particularly during the first administration, is required. 
Special attention is recommended for patients with reduced performance status and pre-
existing cardio-pulmonary disease. 
All subsequent weekly doses are 250 mg/m2 each.  
From second administration, cetuximab will be administered as an intravenous infusion 
over 60 minutes every week during paclitaxel treatment (first 12 weeks of treatment).   
Cetuximab will be administered first. 
Paclitaxel IV infusion will start one hour after completion the cetuximab infusion. 
Premedication used for paclitaxel and cetuximab will be according to each participating 
site standard of care.  
Paclitaxel will be administered as 60 minutes IV infusion every week at a dose of 80 mg/m² 
during 12 weeks. 
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Cetuximab 
Once paclitaxel cycles are completed, cetuximab treatment will be administered at same 
dose as an intravenous infusion over 60 minutes every week until progression disease, 
intolerable toxicity, patient withdrawal or during 24 months, which occur first.  
After completion of the cetuximab infusion, patient will be monitored according to site 
standard of care. 
9.3. 
Treatment duration 
In arm 1, after 12 infusions of paclitaxel, nivolumab will be switch to 480 mg administered 
as an intravenous infusion over 60 minutes every 4 weeks until disease progression, 
unacceptable toxicity or withdrawal of consent up to a maximum of 24 months. 
Maintenance treatment with nivolumab 480 mg will start two weeks after the last 
administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel 
can no longer be administered. 
In arm 2, after 12 infusions of paclitaxel, cetuximab will be administered via IV infusion 
over 60 minutes every week until disease progression, unacceptable toxicity or withdrawal 
of consent up to a maximum of 24 months. 
Maintenance treatment with weekly cetuximab will continue after the end of the 
combination treatment.  
During maintenance treatment nivolumab or cetuximab will be administered up to a 
maximum of 24 months from start of combination treatment (C1D1).  
9.4. 
Criteria for dose adjustments 
Dose reductions will not be allowed for nivolumab.  
Dose modification (delay, interruption or reduction) of cetuximab or paclitaxel should be 
done according to SmPC (see sections 9.4.4 and 9.4.5 for dose reductions). 
Patients on the study will be evaluated weekly during the first 12 weeks of study treatment 
and every 2 weeks thereafter. After 12 weeks of treatment, in cases in which either 
nivolumab, cetuximab or paclitaxel monotherapy continues following discontinuation of the 
other drug due to toxicities, patients will be evaluated every 4 weeks until PD or treatment 
discontinuation. 
Toxicities are to be assessed according to the NCI CTCAE version 5.0. The causal 
relationship of each AE should be assessed in relation to nivolumab, paclitaxel or 
cetuximab so that dose modifications can be made accordingly. Administration and dose 
modification of nivolumab will follow prescribing information for nivolumab and also the 
guidance described in this section (see section 9.4.4). Dose modification guidelines for 
hematologic and non-hematologic toxicities will be performed based on the type and 
severity of AEs, causality determination by investigators, and safety and tolerability profiles 
of each of the study drugs. Only dose interruption and discontinuation for a maximum of 
6 weeks, not dose reductions, are allowed for nivolumab.  
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Per the dose modification guidelines, patients who have the paclitaxel or cetuximab held 
because of treatment-related or possibly related AEs may resume study drug after 
resolution of the AE; they may either maintain the same dose level or have doses of study 
drugs reduced by dose reduction allowed only for each (paclitaxel, cetuximab) according 
to SmPC. When a dose reduction of paclitaxel or cetuximab occurs, dose should not be 
reescalated. 
If one study drug is delayed because of toxicity attributed to its use, the other study drug 
will be administered as scheduled unless otherwise specified.  
Study drug(s) can be held at the investigator’s discretion for high-grade, non-drug-related 
toxicities if it is considered to be necessary in the clinical management of the event. 
However, when study drug(s) resumes after resolution of the non-drug-related event, it 
should be done according SmPC. If multiple toxicities are noted, the dose adjustments 
and/or delays should be made according to the most severe toxicity guidelines and the 
causal relationship to one or both study drugs.  
When the dose of study drug(s) is withheld based on toxicity, clinical and laboratory re-
evaluation should be repeated at least weekly or more frequently until the toxicity resolves 
to ≤Grade 1 or baseline, or to an acceptable level according to the investigator’s 
assessment. Upon recovery, study drug(s) may be reinitiated either at the same dose level 
or at a reduced dose level (dose reduction not allowed for nivolumab). When a dose 
reduction of paclitaxel or cetuximab is required, no re-escalation of dose will be permitted. 
For treatment-related, Grade 4 non-hematologic toxicities, dose reduction of paclitaxel 
more than 2 dose levels or treatment delay for >6 weeks for nivolumab or > 4 weeks for 
cetuximab, in general, require that study treatment will be permanently discontinued. If, in 
the opinion of the investigator and the sponsor (coordinating investigator), it is in the 
patient’s best interest to continue study treatment, then the study drug(s) can be resumed 
at the same dose after recovery of the toxicity or toxicities to Grade 1 or baseline. 
However, no exceptions should be made in the case of adverse reactions that result in 
nivolumab discontinuation as required per the most recent nivolumab SmPC. In particular, 
the study discontinuation required due to the immune-related AEs or infusion reactions 
associated with the use of nivolumab should not be overridden. 
For transient lab value abnormalities that, based on investigator assessment, are not 
clinically significant or are most probably related to disease and not the study treatment, 
continuation of therapy without following the dose modification guidelines is permissible 
upon discussion with the coordinating investigator. 
In general, the study drug(s) will resume only after the resolution of AEs to ≤Grade 1 or 
baseline or as specified in these dose modification guidelines. However, retreatment with 
study drug(s) could start when the AEs are resolved to a level deemed acceptable by the 
investigator based on consideration of the individual patient situation and 
discussions/agreement with the coordinating investigator. 
In general, dose modification guidelines must follow the recommendations of nivolumab, 
paclitaxel and cetuximab SmPC. However, in individual patient cases, following discussion 
and agreement between the investigator and the coordinating investigator, alternative 
dose modifications may be recommended to maximize exposure to study treatment while 
protecting patient safety. However, nivolumab discontinuation should not be overridden. 
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9.4.1. 
Nausea and/or Vomiting 
A patient who develops nausea and/or vomiting will be actively managed by employing 
optimal antiemetic treatment based on local standard practice. 
Additionally, antiemetics may be used prophylactically as clinically indicated following the 
occurrence of a first event of study drug-related or possibly related nausea and/or 
vomiting. An optimal antiemetic regimen is defined as one that employs both a 5-HT3 
antagonist and a corticosteroid given in standard doses and according to standard 
schedules. 
9.4.2. 
Anemia, Thrombocytopenia, and/or Neutropenia 
Hemoglobin and blood counts should be monitored regularly as outlined in the protocol 
with additional testing obtained according to standard clinical practice. Administration of 
nivolumab, cetuximab or paclitaxel should be modified according investigator brochure and 
summary of product characteristics. RBC transfusion and use of erythropoietin to manage 
severe anemia, platelet transfusion to prevent and minimize bleeding in case of severe 
thrombocytopenia, and myeloid growth factor (eg, G-CSF, GM-CSF) support to treat 
severe and/or febrile neutropenia are permitted per ESMO/SEOM guidelines, as 
necessary. 
However, it should be noted that prophylactic use of myeloid growth factors is not 
permitted.  
9.4.3. 
Nivolumab dose adjustments 
Dose reductions will not be allowed for nivolumab. Only dose interruption for a maximum 
of 6 weeks, are allowed.  
 
9.4.3.1. 
Criteria to Resume Nivolumab Treatment 
Subjects may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to 
Grade 1 or baseline, with the following exceptions: 
• 
Subjects may resume treatment in the presence of Grade 2 fatigue. 
• 
Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity. 
• 
For subjects with Grade 2 AST/ALT and/or total bilirubin values, dosing may 
resume when laboratory values return to baseline and management with 
corticosteroids, if needed, is complete. 
• 
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline 
before treatment is resumed. Subjects with persistent Grade 1 pneumonitis after 
completion of a steroid taper over at least 1 month may be eligible for retreatment if 
discussed with and approved by the coordinating investigator.  
• 
Subjects with drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement may resume treatment after consultation with the 
coordinating investigator.  
• 
Adrenal insufficiency requires discontinuation regardless of control with hormone 
replacement. 
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9.4.3.2. 
Immune-Mediated Adverse Reactions 
Immune-mediated AEs can occur with nivolumab, both during treatment and following 
discontinuation. For any suspected immune-mediated AEs, other causes should be 
excluded. Based on the severity of the adverse reaction, nivolumab should be permanently 
discontinued or withheld, high-dose corticosteroids should be administered, and if 
appropriate, hormone-replacement therapy should be initiated. Upon improvement to 
Grade 1 or less, a corticosteroid taper should be initiated and continued over at least 1 
month. Consideration should be given to restarting nivolumab after completion of the 
corticosteroid taper based on the severity of the event. For more information related to the 
management of immune mediated adverse reactions associated with nivolumab, see 
Annex 13. 
9.4.3.3. 
Other Immune-Mediated Adverse Reactions 
Nivolumab can cause other clinically significant and potentially fatal immune-mediated 
adverse reactions. Immune-mediated adverse reactions may occur after discontinuation of 
nivolumab therapy. For any suspected immune-mediated adverse reactions, exclude other 
causes. Based on the severity of the adverse reaction, permanently discontinue or 
withhold nivolumab, administer high-dose corticosteroids, and if appropriate, initiate 
hormone-replacement therapy. See the current nivolumab IB version for more 
information related to other immune-mediated adverse reactions.  
9.4.3.4. 
Nivolumab Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to 
be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgia, hypotension, hypertension, bronchospasm, or other allergic-like reactions. 
Infusion reactions should be graded according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 guidelines. 
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines, as appropriate: 
For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated): 
- Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 
mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg, at least 30 
minutes before subsequent nivolumab/nivolumab placebo administrations. 
For Grade 2 symptoms (moderate reaction required therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for < 24 hours): 
- Stop the study drug infusion, begin an IV infusion of normal saline, and treat the 
participant with diphenhydramine 50 mg IV (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg; remain at bedside and monitor participant 
until resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also be 
administered, as appropriate. If the infusion is interrupted, then restart the infusion at 50% 
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of the original infusion rate when symptoms resolve; if no further complications ensue after 
30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor the 
participant closely. If symptoms recur, then no further study medication will be 
administered at that visit. 
- For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 
mg should be administered at least 30 minutes before nivolumab/nivolumab placebo 
infusions. 
If necessary, corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used. 
For Grade 3 or 4 symptoms (severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[eg, renal impairment, pulmonary infiltrates]; Grade 4: Life threatening; pressor or 
ventilatory support indicated): 
- Immediately discontinue infusion of study drug. Begin an IV infusion of normal saline and 
treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored 
until the Investigator is comfortable that the symptoms will not recur. Study drug will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor the participant until recovery of 
the symptoms. 
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given 
(eg, oral antihistamine or corticosteroids). 
9.4.4. 
Cetuximab dose adjustments 
Cetuximab has to be permanently discontinued in case of administration interruption for 4 
consecutive infusions due to any relevant circumstance. Principal investigator and study 
coordinators could assess the possibility of treatment reintroduction if cetuximab 
administration benefit is clearly documented.  
 
9.4.4.1. 
Skin reaction  
If a patient experiences grade 3 skin toxicity (according to NCI-CTCAE v 5.0), cetuximab 
infusion may be delayed up to four consecutive infusions while maintaining the same dose. 
The investigator can establish a concomitant treatment with moisturizers and/or topical 
and/or oral antibiotics and/or topical corticosteroids. If skin toxicity decreases to grade ≤2 
before the next cetuximab infusion, treatment can be restarted. If new episodes of grade 3 
skin toxicity occur for a second or third time, treatment with cetuximab should be 
temporarily discontinued for up to 4 consecutive weeks by reducing the doses to 200 
mg/m2 and 150 mg/m2, respectively. Dose reductions of cetuximab are permanent. 
Treatment with cetuximab should be discontinued if four consecutive infusions are 
suspended or if a new episode of grade 3 skin toxicity occur for the fourth time. 
 
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The patient should be monitored weekly until rash resolution. If the patient is benefiting 
from treatment with cetuximab, the principal investigator and/or coordinating investigator 
can evaluate the possibility that the patient continues receiving cetuximab. 
 
If the patient has a grade 4 skin toxicity, treatment with cetuximab should be discontinued. 
If the infusion of cetuximab is suspended for 4 consecutive weeks due to toxicity to 
cetuximab, or for intercurrent disease (eg infection) that requires discontinuation of study 
treatment, treatment with cetuximab should be definitely interrupted, except when the 
patient is benefiting from cetuximab treatment. In that case, the principal investigator 
and/or coordinating investigator can evaluate the possibility that the patient continues 
receiving cetuximab. 
 
9.4.4.2. 
Allergic reactions 
If the patient has a hypersensitivity reaction, the investigator must establish the therapeutic 
measures corresponding to the best available medical practice. Based on previous 
experience with hypersensitivity reactions, the following treatment guidelines may apply: 
 
Treatment modifications in case of allergic or hypersensitivity reaction to cetuximab 
 
Grade 1  
The infusion rate may be decreased to 50% and monitor closely monitor the patient for any 
worsening. The total infusion time of cetuximab should not exceed 4 hours. 
 
Grade 2 
Stop cetuximab infusion. Bronchodilators, oxygen, etc., should be administered according 
to the best available medical practice. Resume the infusion at 50% of the previous infusion 
rate once the severity of the allergic reaction has disappeared or decreased to grade 1 and 
closely monitor the patient for any worsening. 
 
Grade 3 or Grade 4 
Immediately stop cetuximab infusion. Adrenaline, bronchodilators, antihistamines, 
glucocorticoids, intravenous fluids, vasoconstrictors, oxygen, etc., should be administered 
when clinically indicated. Stop cetuximab treatment immediately. 
 
9.4.4.3. 
Cetuximab administration after hypersensitivity reactions 
Once the infusion rate of cetuximab is decreased due to the occurrence of an allergic or 
hypersensitivity reaction, this infusion rate should be maintained during subsequent 
infusions. If a patient has a second allergic or hypersensitivity reaction with the slowest 
infusion rate, treatment with cetuximab should be discontinued. If at any time a patient 
experiences a grade 3 or 4 allergic or hypersensitivity reaction, cetuximab should be 
definitively interrupted. 
 
9.4.4.4. 
Cetuximab dose modifications or delayed administration for another 
reason 
If a patient has a concomitant disease (eg, an infection) that, in the opinion of the 
investigator and/or coordinating investigator, forces the treatment interruption, this 
concomitant disease must be cured within a period of time less than the corresponding to 
four consecutive infusions of cetuximab. If treatment with cetuximab is delayed, a loading 
dose is not administered but the planned dose is administered. If the administration of 
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cetuximab is interrupted for a long period of time, the patient is withdrawn from the study 
except for patients who are getting benefit with cetuximab that will be evaluated by 
principal investigator and coordinating investigator. 
 
9.4.5. 
Paclitaxel dose adjustments 
Safety assessments should be performed within 24 hours prior to the administration of 
paclitaxel. In addition, patients should be carefully examined on the day paclitaxel is 
administered. 
 
Paclitaxel should not be delayed due to toxicity related to cetuximab or nivolumab. 
Paclitaxel modifications are based on the observed toxicities and are graded according to 
NCI-CTCAE v 5.0. The dose of paclitaxel is modified according to the time at which the 
toxicity appears. The doses of paclitaxel should be modified according to the neutrophil 
and platelet count, and according to the worst grade of non-hematological toxicity. 
 
Dose modifications are permanent and are based on the dose administered in the last 
infusion. Once the dose is reduced, this dose should be maintained for all following 
paclitaxel administrations. 
 
9.4.5.1. 
Previous requirements for paclitaxel administration 
The decision to administer paclitaxel is based on neutrophil and platelet counts and the 
severity of mucositis or other non-hematologic toxicities observed on the day the treatment 
has to be administered. 
 
To administer paclitaxel, the following conditions must be met: 
 
• Neutrophils ≥ 1,500 / mm³. 
• Platelets ≥ 100,000 / mm³. 
• No presence of mucositis grade ≥2 or any other non-hematological toxicity 
grade 3-4 (except alopecia or nausea and / or vomiting). 
 
If a patient cannot receive paclitaxel due to toxicity, the dose is interrupted for a week. If 
after one week delay the patient continues unable to receive paclitaxel, the treatment is 
delayed another week. If patient cannot receive paclitaxel for 28 days, paclitaxel treatment 
will be discontinued and patient can receive cetuximab or nivolumab monotherapy 
according to the treatment arm. 
 
In case of grade 2 mucositis, although neutrophils and platelets are at normal values, 
administration of paclitaxel is interrupted one week. In case of mucositis grade 3-4, 
paclitaxel is interrupted and the doses are reduced in the following administrations. In case 
of treatment delays, all evaluations will be performed as planned. 
 
9.4.5.2. 
Paclitaxel dose reductions 
Three levels of paclitaxel dose reduction have been planned: 70 mg/m²; 60 mg/m²; and 50 
mg/m². If a new dose reduction is required with the administration of 50 mg/m², the 
administration of paclitaxel is definitely interrupted and patient can continue with cetuximab 
or nivloumab monotherapy. 
 
A dose level of paclitaxel will be reduced in case of: 
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• Febrile neutropenia grade 3-4 
• Thrombocytopenia grade 3-4 
• Mucositis grade 3-4 
• Neuropathy grade 2  
• Any other grade 3-4 toxicity 
• Interruption of paclitaxel for 2 consecutive weeks due to toxicity 
• Interruption of paclitaxel one week after administration of paclitaxel, twice in 
a row. 
 
Once a paclitaxel dose reduction due to toxicity is made, the dose of paclitaxel will not be 
increased at any time during the study. 
 
9.4.5.3. 
Paclitaxel interruption  
In the event of the following toxicities, paclitaxel treatment will be definitively interrupted, 
and patient can receive monotherapy treatment: 
 
• Grade 3-4 neurological toxicity 
• Second or third degree atrioventricular block or cardiac arrhythmia, with the 
exception of asymptomatic isolated extrasystoles 
• Severe hypersensitivity reaction 
• Paclitaxel interruption of 28 days due to toxicity 
• If patient is receiving administration of 50 mg/m² of paclitaxel and a new 
dose reduction is required. 
 
9.5. 
Accountability  
Nivolumab will be provided by the sponsor. Cetuximab and paclitaxel are commercialised 
drugs which will be provided by the pharmacy department of the participating trial sites. 
The monitor will oversee study drugs in the hospital’s pharmacy. Nivolumab accountability 
will be documented and the quantities delivered, dispensed, returned and destroyed will be 
verified. Cetuximab and paclitaxel compliance will be assessed through the administration 
sheets available at the pharmacy department of the participating trial sites. 
All inventory forms for the study medication must be available for inspection by authorised 
representatives of the sponsor or by inspectors from regulatory authorities. The 
investigator is responsible for the accountability of all used and unused study supplies at 
their site. 
Accountability forms for study medication must be available for review by authorised 
representatives of the sponsor or by inspectors from regulatory authorities.  
9.6. 
Auxiliary Medicinal Products 
Not applicable.  
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9.7. 
Concomitant medication 
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate prophylactic or supportive care except for those medications identified 
as “prohibited”.  
Premedication used for paclitaxel, nivolumab and cetuximab will be according to each 
participating site standard of care. In Arm 1 paclitaxel premedication must be administered 
during or after the observation period (30 minutes following nivolumab infusion).  
Therapies that are required to manage AEs and control cancer symptoms are allowed 
based on standard clinical practice, unless specifically excluded. Supportive care agents, 
such as erythropoietin, G-CSF, blood products (red blood cell and platelet transfusions), 
and pain medications are permitted as needed per European Society for Medical Oncology 
(ESMO) guidelines, SEOM guidelines or local institutional practice. Nivolumab is 
associated with immune-related AEs, which may be managed per clinical judgment of the 
investigator in accordance with the institutional guideline and the most recent nivolumab 
investigator brochure. 
The Investigator must be informed as soon as possible about any medication taken from 
the time of screening until the end of the clinical phase of the study (end of study visit). 
Patients must be instructed not to take any medications, including over-the-counter 
products, without first consulting with the Investigator.  
All concomitant medications should be reported to the investigator and recorded on the 
appropriate eCRF. 
Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily 
prednisone equivalent, are permitted in the absence of active autoimmune disease. 
Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). A brief (less than 3 weeks) course of 
corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-
autoimmune conditions (eg, delayed type hypersensitivity reaction caused by a contact 
allergen) is permitted. 
9.8. 
Prohibited drugs  
The following medications and procedures are prohibited during the study: 
- 
Any antineoplastic therapy other than nivolumab, paclitaxel or cetuximab.  
- 
Chronic use of corticosteroids at daily doses greater than the equivalent of 10 mg 
of prednisone as part of any anticancer treatment regimens. Physiologic 
replacement doses of systemic corticosteroids are permitted, even if >10 mg/day 
prednisone or equivalents. 
- 
Radiation therapy. Palliative radiotherapy for pain control in a pre-existing lesion 
may be considered after discussion with the sponsor and coordinating investigator. 
- 
Prophylactic use of myeloid growth factors or granulocyte macrophage-colony 
stimulating factor. In case of neutropenia drugs administration should be stopped 
till recovery and subsequent dose reduction according to protocol.  Supportive care 
agents, such as erythropoietin, G-CSF, blood products (red blood cell and platelet 
transfusions), and pain medications are permitted as needed per European Society 
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for Medical Oncology (ESMO) guidelines, SEOM guidelines or local institutional 
practice. 
- 
Immunosuppressive medications within 14 days of start study treatment. 
 
9.9. 
Precautions  
The metabolism of paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes 
CYP2C8 and CYP3A4. Caution should be exercised when administering paclitaxel 
concomitantly with medicines known to inhibit either CYP2C8 or CYP3A4 (e.g. 
ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, 
clopidogrel, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) because toxicity of 
paclitaxel may be increased due to higher paclitaxel exposure. Administering paclitaxel 
concomitantly with medicines known to induce either CYP2C8 or CYP3A4 (e.g. rifampicin, 
carbamazepine, phenytoin, efavirenz, nevirapine) is not recommended because efficacy 
may be compromised because of lower paclitaxel exposures. 
Paclitaxel should be administered with caution in patients receiving protease inhibitors as 
concomitant therapy. 
Caution should be used regarding the use of herbal medications as there may be as yet 
unknown interactions with study medication. Discontinuation of the use of herbal 
medications prior to study enrollment is encouraged. 
 
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10. 
STUDY SCHEDULE 
Study Procedures 
Screening 
(Days -28 to -1) 
Paclitaxel combination 
treatment (12 weeks) 
(±3 days) 
Monotherapy treatment 
phase (±3 days) 
EOT 
/withdrawal 
visit 
(±3 days)19 
Safety follow-
up visit 
(+30 days ±7 
days)20 
Follow-up 
(every  
12 weeks  
±7 days) 
 
 
Every week 
Every 2 weeks 
 
 
 
Informed Consent Form 
X 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Vital signs2 
X 
X 
X 
X 
X 
 
Demographic3 
X 
 
 
 
 
 
Physical examination4 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
 
Karnofsky PS 
X 
X 
X 
X 
X 
 
HPV status 5 
X 
 
 
 
 
 
12-lead ECG 
X 
If clinically indicated 
 
Hematology6 
X 
X18 
X18 
X 
X 
 
Serum chemistry7 
X 
X18 
X18 
X 
X 
 
Thyroid panel8 
X 
X18 
X18 
X 
X 
 
Coagulation 
X 
 
 
 
X 
 
Urinalysis9 
X 
If clinically indicated 
X 
 
Serology 10 
X 
 
 
 
 
 
Pregnancy test11 
X 
X  
X 
X 
X 
X11 
Tumor Tissue Sample (PD-L1)12
X 
 
 
 
 
 
Tumor assessment13 
X 
X13 
X13 
X 
X 
 
Nivolumab administration14 
 
Q2w 
Q4w 
 
 
 
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Study Procedures 
Screening 
(Days -28 to -1) 
Paclitaxel combination 
treatment (12 weeks) 
(±3 days) 
Monotherapy treatment 
phase (±3 days) 
EOT 
/withdrawal 
visit 
(±3 days)19 
Safety follow-
up visit 
(+30 days ±7 
days)20 
Follow-up 
(every  
12 weeks  
±7 days) 
 
 
Every week 
Every 2 weeks 
 
 
 
Cetuximab administration15 
 
Q1w 
Q1w 
 
 
 
Paclitaxel administration16 
 
Q1w 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
 
Anticancer treatments 
 
 
 
 
 
X 
Overall survival 
 
 
 
 
 
X17 
1. All subjects must first read, understand, and sign the approved ICF before any study-specific screening procedures are performed. 
2. Vital signs include heart rate, respiratory rate, blood pressures, and temperature. Measure vital signs before dosing (-10 minutes) and postdose (+10 minutes) of 
nivolumab. Blood pressure should be determined with the patient in a seated position after the patient has been sitting quietly for 5 minutes. Oxygen saturation will also be 
measured when vital signs are taken. 
3. Sex, age, and self-reported race/ethnicity. 
4. Includes evaluation of the head, eyes, ears, nose, and throat and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and 
neurologic systems.  
5. OPC HPV status of tumor tissue has to be locally determined at screening by any of the following methods: p16 IHC, in situ hybridization, or polymerase chain reaction 
based assay. If HPV status by p16 IHC is positive result confirmation by PCR is mandatory. 
6. Include absolute red blood cell count (RBC), hemoglobin, hematocrit, platelet count, white blood cell count (WBC), with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils). Hematology will be performed every 4 weeks during monotherapy treatment, except in case of a clinically significant alteration that will be 
performed at investigator criteria. 
7. Chemistry panel including: ALT, AST, total bilirubin, creatinine or creatinine clearance, alkaline phosphatase, BUN or serum urea level, Ca, Mg, Na, K, Cl, LDH, Glucose, 
amylase, lipase, phosphate. Chemistry panel will be performed every 4 weeks during monotherapy treatment, except in the case of a clinically significant alteration (eg 
magnesium) that will be performed at investigator criteria. 
8. Thyroid panel including: TSH, Free T4, Free T3 or Total T3, will be determined every 8 weeks.  
9. Urinalysis: pH, protein, glucose, ketones, blood, leucocytes, nitrite and specific gravity. 
10. Serology: Hepatitis B surface antigen (HBsAg), and hepatitis C antibody (HC Ab) or Hepatitis C RNA (HCV RNA). Patients with positive test for hepatitis B virus or 
hepatitis C virus indicating presence of virus, eg, Hepatitis B surface antigen (HBsAg) positive, or Hepatitis C antibody positive (except if HCV-RNA negative) will not be 
included. 
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11. A serum or urine pregnancy test will be performed for women of childbearing potential at Screening (72 hours prior to start study treatment for women of childbearing 
potential), every 4 weeks, at the end of study treatment, in the safety follow-up visit. In arm 1 pregnancy test will be performed also every 4 weeks until 5 months (150 days) 
after the last dose of nivolumab. 
12. A Tumor sample prior to therapy is mandatory for PD-L1 testing (to be shipped to Central Lab). If a recent tumor sample is not available at screening, a fresh biopsy will 
be taken at any point prior to randomization. A newly obtained biopsy (within 6 months prior to start of study treatment) is preferred but an archival sample is acceptable, if 
several tumor samples are available, testing should be performed on the most recently obtained tumor sample. Sufficient tumor tissue should be submitted either one full 
block (5mm3 and more than 60% tumor tissue) or minimum of 5 slides, obtained from core biopsy, punch biopsy, excisional biopsy or surgical specimen. Freshly cut, serial 
sections must have been cut no more than 14 days prior to analysis by central lab. Slides that have been cut more than 14 days prior to analysis by central lab should not be 
used and new slides should be made. 
13. Response assessments will be performed at screening, at week 9 and every 12 weeks (+/- 7 days). The same imaging modality and/or the same methods for disease 
measurement must be used throughout the study. Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to 
initiation of study treatment do not have to be repeated at screening. Screening assessments must include CT scans (with oral or IV contrast) of the chest and abdomen and 
CT scans (with oral or IV contrast) or MRI (with contrast) of the head and neck region. If a CT scan with contrast is contraindicated (e.g., in patients with contrast allergy or 
impaired renal clearance), a non-contrast CT scan of the chest may be performed and MRI with contrast scans of the abdomen and head and neck region must be 
performed. All measurable and non-measurable lesions should be assessed and documented at screening. If both a CT scan with contrast is contraindicated (e.g., in 
patients with impaired renal clearance or contrast allergy) and MRI is contradicted (e.g., in patients with claustrophobia), non-contrast CT scans of the chest, abdomen, and 
head and neck region may be performed only upon prior approval from the coordinating investigators. 
14. A 240 mg dose of Nivolumab will be administered as an intravenous infusion over 30 minutes every 2 weeks during paclitaxel treatment (first 12 weeks of treatment), and 
paclitaxel infusion will start at least 30 minutes after completion of the nivolumab infusion. Paclitaxel premedication must be administered during or after the observation 
period (30 minutes following nivolumab infusion). After that, a 480 mg dose over 60 minutes will be administered every 4 weeks until progression disease, intolerable toxicity, 
patient withdrawal or during 24 months, which occur first. 
15. A 250 mg/m2 dose of cetuximab (initial dose is 400 mg/m2 as an intravenous infusion over 120 minutes) will be administered as an intravenous infusion over 60 minutes 
every week during paclitaxel treatment (first 12 weeks of treatment), one hour before paclitaxel infusion. Cetuximab and paclitaxel premedication will be administered 
according standard of care at each participating site. After that, cetuximab treatment will be administered at same dose every week until progression disease, intolerable 
toxicity, patient withdrawal or during 24 months, which occur first. 
16. Paclitaxel will be administered IV, at least 30 minutes after completion of the nivolumab infusion (arm 1), at a dose of 80 mg/m² (infusion duration 60 minutes) until 
disease progression or unacceptable toxicity; and one hour after cetuximab infusion (arm 2) at a dose of 80 mg/m² (infusion duration 60 minutes) until disease progression or 
unacceptable toxicity. 
17. Patient will be followed for at least 5 years or until he/she dies. 
18. Hematology and serum chemistry can be done in the 72 hours prior to treatment administration. 
19. End of treatment / withdrawal visit will be performed once the principal investigator determines patient discontinuation of study treatment (±3 days). 
20. Safety follow up visit will be performed 30 days (±7 days) after the last administration of study treatment or prior to start another new therapy, whichever occurs first.  
DocuSign Envelope ID: 834F441E-BB57-4466-A6ED-3D12263D7324


Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
CONFIDENTIAL 
MWP-301-E3 EN Protocol template for Clinical Trials Rev04.0  
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10.1. 
Pre-study visit (screening) 
Screening procedures will be performed up to 28 days before day 1, unless otherwise specified. 
All subjects must first read, understand, and sign the approved ICF before any study-specific 
screening procedures are performed. After signing the ICF, completing all screening 
procedures, and being deemed eligible for entry, subjects will be enrolled in the study. 
Procedures that are performed prior to the signing of the ICF and are considered standard of 
care may be used as screening assessments if they fall within the 28-day screening window.  
The following procedures will be performed during the screening visit: 
● Informed consent. 
● Review of eligibility criteria. 
● Medical history.  
● Demographics. 
● Physical exam.  
● Weight and height  
● Karnofsky Performance Status  
● Vital signs. 
● 12-lead ECG.  
● Tumor tissue sample prior to therapy is mandatory for PD-L1 testing (to be shipped to 
Central Lab for CPS). If a recent tumor sample is not available at screening, a fresh 
biopsy will be taken at any point prior to randomization. A newly obtained biopsy (within 
6 months prior to start of study treatment) is preferred but an archival sample is 
acceptable, if several tumor samples are available, testing should be performed on the 
most recently obtained tumor sample. Sufficient tumor tissue (5 mm3 in which more than 
60% of the sample is tumor tissue) should be submitted either one full block or minimum 
of 5 slides, obtained from core biopsy, punch biopsy, excisional biopsy or surgical 
specimen. Freshly cut, serial sections must have been cut no more than 14 days prior to 
analysis by central lab. Slides that have been cut more than 14 days prior to analysis by 
central lab should not be used and new slides should be made. 
● HPV status of tumor tissue has to be locally determined at screening for subjects with 
oropharyngeal cancer by any of the following methods: p16 IHC, in situ hybridization, or 
polymerase chain reaction based assay. If HPV status by p16 IHC is positive result 
confirmation by PCR is mandatory.  
● Review of prior/concomitant medications.  
● Review of adverse events.  
● Tumor assessment. Tumor assessments performed as standard of care prior to 
obtaining informed consent and within 28 days prior to initiation of study treatment do 
not have to be repeated at screening. Screening assessments must include CT scans 
(with oral or IV contrast) of the chest and abdomen and CT scans (with oral or IV 
contrast) or MRI (with contrast) of the head and neck region. If a CT scan with contrast 
is contraindicated (e.g., in patients with contrast allergy or impaired renal clearance), a 
non-contrast CT scan of the chest may be performed and MRI with contrast scans of the 
abdomen and head and neck region must be performed. All measurable and non-
measurable lesions should be assessed and documented at screening. If both a CT 
scan with contrast is contraindicated (e.g., in patients with impaired renal clearance or 
contrast allergy) and MRI is contradicted (e.g., in patients with claustrophobia), non-
contrast CT scans of the chest, abdomen, and head and neck region may be performed 
only upon prior approval from the coordinating investigators. Response assessments for 
solid tumors will be performed at screening, at week 9 and every 12 weeks (+/- 7 days). 
The same imaging modality and/or the same methods for disease measurement must 
be used throughout the study.  
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Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
CONFIDENTIAL 
MWP-301-E3 EN Protocol template for Clinical Trials Rev04.0  
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● Clinical laboratory tests for: 
o Hematology. CBC w/ differential. 
o Serum chemistry. ALT, AST, total bilirubin, alkaline Phosphatase, BUN or serum 
urea level, Ca, Mg, Na, K, Cl, LDH, Glucose, amylase, lipase, phosphate. 
o Serum creatinine or Creatinine clearance. 
o TSH, free T3 or total T3 and free T4. 
o Coagulation panel. 
o 
Serum or urine pregnancy test (within 72 hours prior to start study treatment for 
women of childbearing potential, including women who have had a tubal ligation).  
o Serology: Hepatitis B surface antigen (HBV sAg), and hepatitis C antibody (HCV Ab) 
or Hepatitis C RNA (HCV RNA). Subjects who test positive for hepatitis C but have 
undetectable HCV RNA are allowed to enroll.  
o Urinalysis:  blood, glucose, ketones, PH, protein, specific gravity, leucocytes, nitrite. 
 
Clinical laboratory tests could be done in the 72 hours prior any study treatment administration 
on Day 1 Cycle 1. 
 
10.2. 
Paclitaxel combination treatment visits (first 12 weeks of treatment) 
The following procedures will be performed during the study treatment visits until week 12: 
Day 1 and every week (± 3 days) 
● Physical exam. Includes evaluation of the head, eyes, ears, nose, and throat and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  
● Weight. 
● Karnofsky Performance Status 
● Vital signs. 
● 12-lead ECG, if clinically indicated.  
● Review of concomitant medications.  
● Review of adverse events.  
● Clinical laboratory tests for: 
o Hematology. CBC w/ differential. 
o Serum chemistry. ALT, AST, total bilirubin, alkaline Phosphatase, BUN or serum 
urea level, Ca, Mg, Na, K, Cl, LDH, Glucose, amylase, lipase, phosphate. 
o Serum creatinine or Creatinine clearance. 
o TSH, Free T3 or total T3 and free T4, every 8 weeks. 
o 
Serum or urine pregnancy test every 4 weeks (+/- 7 days) for women of 
childbearing potential.  
o Urinalysis:  blood, glucose, ketones, PH, protein, specific gravity, leucocytes, nitrite, 
if clinically indicated. 
● Tumor assessment at week 9 (+/- 7 days) and every 12 weeks (+/- 7 days) thereafter. 
The same imaging modality and/or the same methods for disease measurement must 
be used throughout the study.  
 
Clinical laboratory tests could be done in the 72 hours prior to any study treatment 
administration.  
 
 
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Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
CONFIDENTIAL 
MWP-301-E3 EN Protocol template for Clinical Trials Rev04.0  
Page 70/117 
 
10.3. 
Monotherapy treatment visits (cetuximab or nivolumab) 
The following procedures will be performed during the monotherapy treatment visits every 2 
weeks: 
● Physical exam. Physical exam. Includes evaluation of the head, eyes, ears, nose, and 
throat and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems.  
● Weight. 
● Karnofsky Performance Status. 
● Vital signs. 
● 12-lead ECG, if clinically indicated.  
● Review of concomitant medications.  
● Review of adverse events.  
● Clinical laboratory tests (every 4 weeks [-72 hours]) for: 
o Hematology. CBC w/ differential. 
o Serum chemistry. ALT, AST, total bilirubin, alkaline Phosphatase, BUN or serum 
urea level, Ca, Mg, Na, K, Cl, LDH, Glucose, amylase, lipase, phosphate. 
o Serum creatinine or Creatinine clearance. 
o TSH, Free T3 or total T3 and free T4, every 8 weeks. 
o 
Serum or urine pregnancy test every 4 weeks (+/- 7 days) for women of 
childbearing potential.  
o Urinalysis:  blood, glucose, ketones, PH, protein, specific gravity, leucocytes, nitrite, 
if clinically indicated. 
● Tumor assessment every 12 weeks (+/- 7 days). The same imaging modality and/or the 
same methods for disease measurement must be used throughout the study.  
 
Clinical laboratory tests could be done in the 72 hours prior to any study treatment 
administration (every 4 weeks). 
 
10.4. 
End of treatment / Withdrawal visit  
End of treatment / withdrawal visit will be performed once the principal investigator determines 
patient discontinuation of study treatment (±3 days). 
The following procedures will be performed: 
● Physical exam.  
● Weight. 
● Karnofsky Performance Status. 
● Vital signs. 
● 12-lead ECG, if clinically indicated.  
● Review of concomitant medications.  
● Review of adverse events.  
● Clinical laboratory tests for: 
o Hematology. CBC w/ differential. 
o Serum chemistry. ALT, AST, total bilirubin, alkaline Phosphatase, BUN or serum 
urea level, Ca, Mg, Na, K, Cl, LDH, Glucose, amylase, lipase, phosphate. 
o Serum creatinine or Creatinine clearance. 
o TSH, Free T3 or total T3 and free T4. 
DocuSign Envelope ID: 834F441E-BB57-4466-A6ED-3D12263D7324


Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
CONFIDENTIAL 
MWP-301-E3 EN Protocol template for Clinical Trials Rev04.0  
Page 71/117 
o 
Serum or urine pregnancy test for women of childbearing potential.  
● Tumor assessment: For study withdrawal not due to progression disease, tumor 
assessment will be done if clinically indicated.  
 
10.5. 
Safety follow-up visit  
Safety follow up visit will be performed 30 days (±7 days) after the last administration of study 
treatment or prior to start another new therapy, whichever occurs first. 
The following procedures will be performed: 
● Physical exam. 
● Weight. 
● Karnofsky Performance Status. 
● Vital signs. 
● 12-lead ECG, if clinically indicated.  
● Review of concomitant medications.  
● Review of adverse events.  
● Clinical laboratory tests for: 
o Hematology. CBC w/ differential. 
o Serum chemistry. ALT, AST, total bilirubin, alkaline Phosphatase, BUN or serum 
urea level, Ca, Mg, Na, K, Cl, LDH, Glucose, amylase, lipase, phosphate. 
o Serum creatinine or Creatinine clearance. 
o TSH, Free T3 or total T3 and free T4. 
o Urinalysis: blood, glucose, ketones, PH, protein, specific gravity, leucocytes, nitrite. 
o 
Serum or urine pregnancy test for women of childbearing potential.  
o Coagulation panel. 
 
10.6. 
Follow-up visits  
Follow-up visits will be performed every 12 weeks (±7 days).  
The following procedures will be performed: 
● Assessments for disease progression. Tumor assessment will be performed until 
disease progression or until the patient receives another anticancer therapy. 
● Anticancer therapy. 
● Survival status. 
● Review of adverse events. AEs and SAEs related to study treatment will be monitored 
until resolution or end of study. 
● Serum or urine pregnancy test every 4 weeks (+/- 7 days) for women of childbearing 
potential until 5 months after the last dose of nivolumab or 4 weeks after the last dose of 
cetuximab. 
 
Telephone follow-up visits may be performed if it is not necessary to do any specific study 
assessment. 
 
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Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
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CONFIDENTIAL 
MWP-301-E3 EN Protocol template for Clinical Trials Rev04.0  
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11. 
ASSESSMENT OF SAFETY / ADVERSE EVENTS 
Safety information should be collected in clinical studies in an efficient and consistent way. 
Adverse events must be identified and notified rapidly to identify possible risks to patients and 
satisfy regulatory requirements for notification of adverse events. 
Subjects will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline or are deemed irreversible. All adverse events will be documented for minimum of 100 
days after the last dose of study medications. 
11.1. 
Definitions 
11.1.1. 
Adverse event (AE) 
An AE is any undesired experience that occurs in a patient participating in clinical research that 
is associated in time with the use of a medicinal product, whether or not it is considered to be 
related to the investigational products. Therefore, an adverse event can be any unintentional 
unfavorable sign (including an anomalous laboratory result), symptom or disease that is 
associated in time with the use of a medicinal product, whether or not it is considered to be 
related to the product. Pre-existing diseases that worsen during the study shall be notified as 
Adverse Events. 
AEs include pre- or post-treatment events that occur as a result of study procedures (e.g. 
invasive procedures or modification of the patient’s previous medication). 
11.1.2. 
Serious adverse event (SAE) 
A SAE is an undesired medical experience that, at any dose: 
- 
Results in death. 
- 
Is life-threatening: (NOTE: The term "life-threatening" refers to the fact 
that the patient is at risk of death as a result of this event, not that death might 
have occurred if the SAE had been more intense). 
- 
Results in the patient’s hospitalization or prolongs a previous 
hospitalization (NOTE: In general, hospitalization means that the patient has 
remained [generally at least overnight] in the hospital or emergency room for 
observation or treatment that could not have been given/administered in the 
doctor’s office or outpatient clinic. Complications that occur during a 
hospitalization are AEs. If a complication prolongs hospitalization or satisfies any 
of the other criteria for seriousness, then the event will be considered SAE. 
When any doubt exists as to whether a "hospitalization" has taken place or was 
necessary, the AE will be considered serious. The hospitalization to implement 
scheduled treatment of a disease present before the subject entered the study 
and that has not worsened with respect to baseline is not considered an AE). 
- 
results in  disability or incapacity (NOTE: Disability refers to an important 
alteration in a person’s capacity to carry out his or her own daily living tasks, not 
minor clinical ailments such as headaches, nausea, vomiting, diarrhea, flu or 
accidental injuries (such as a sprained ankle), that can interfere with the 
functions of daily life, but do not alter them in an important way). 
- 
results in  a congenital anomaly or birth defect. 
- 
is medically important (meaning important adverse events that are not 
immediately life-threatening or do not cause death or require patient 
DocuSign Envelope ID: 834F441E-BB57-4466-A6ED-3D12263D7324


Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
CONFIDENTIAL 
MWP-301-E3 EN Protocol template for Clinical Trials Rev04.0  
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hospitalization but can endanger the patient or may require some type of 
intervention to prevent one of the results cited above). 
- 
Suspected transmission of an infectious agent (eg, pathogenic or 
nonpathogenic) via the study drug is an SAE. 
  
11.1.3. 
Additional considerations 
Alterations in laboratory parameters (hematology, biochemistry or urine analysis), as well as 
anomalous results of other studies (such as ECGs, radiology, measurements of vital 
constants), including those that deteriorate in relation to baseline, should be recorded as AEs or 
SAEs if, in the medical and scientific opinion of the investigator, they are clinically relevant. 
On the contrary, clinically significant alterations in safety parameters that are associated with 
the study disease are not characterized as AEs or SAEs unless the investigator thinks that they 
are more serious than would be expected considering the state of the patient. 
Lack of efficacy (i.e., disease progression) is a disease-related event and should not be 
classified as a SAE. Death as a result of disease progression is also excluded from the 
definition of SAEs.  
11.2. 
Characteristics of an adverse event 
11.2.1. 
Causality assessment 
The investigator has the obligation to establish the relation of causality between the 
investigational product administration and (the event) of each AE/SAE. "A reasonable 
possibility" is proposed to define cases in which there are facts/proof or arguments suggesting 
a causal relation, more than a relation that cannot be excluded. The investigator will use his or 
her clinical judgment to determine the relation. Alternative causes, such as the natural history of 
underlying diseases, concomitant treatment, other risk factors and the temporal relation 
between the event and the investigational drug will be considered and investigated. The 
investigator will also consult the investigator's brochure/summary of product characteristics in 
making the evaluation. 
There may be situations in which a SAE occurs and the investigator has only minimal 
information to include in the initial report to the Sponsor. Nevertheless, it is very important that 
the investigator evaluate the causality of each event before the initial transmission of data to the 
Sponsor. The investigator can change his or her opinion about causality based on the 
information that appears during follow-up, which is why the SAE report may have to be 
modified. The evaluation of causality is one of the criteria that determine whether a case is 
compliant or not with the criteria of notification of the Health Authorities. 
11.2.2. 
Expectedness  
Unexpected Adverse Events: An unexpected AE is defined as any event not generally taken 
into consideration and not described in the approved or subsequent documents (e.g., not listed 
in the SPC, protocol, or the informed consent). 
Expected Adverse Events: An expected AE is any adverse event side effect whose nature and 
intensity have been previously observed and documented for the study product (eg. in the 
Investigator Brochure, SPC or PIL). Expected AEs do not generally include intended effects of 
medications. 
Expectedness of the reported Adverse Events will be classified by APICES. 
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Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
CONFIDENTIAL 
MWP-301-E3 EN Protocol template for Clinical Trials Rev04.0  
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11.2.3. 
Severity 
The severity of any AEs will be graded using the CTCAE vs 5.0 (see Annex 4). If the CTCAE 
has no code that matches, the following guide should be used:  
Grade 
Description 
0 
No adverse event 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only 
2 
Moderate; minimal, local or noninvasive intervention indicated  
3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated 
4 
Life-threatening consequences; urgent intervention indicated  
5 
Death related to adverse event 
 
Grading of AEs is based on specific clinical criteria that will require evaluation by the study site 
Investigator. Should an AE stop and then restart, it will be considered two separate events and 
the severity assessed as described above.  
 
11.3. 
Reporting procedures 
11.3.1. 
Reporting of adverse events (AEs)  
The investigator will try to obtain information about any adverse events that have occurred in all 
visits by examining or directly interrogating the patient. All serious adverse events that occur 
during the clinical trial, whether or not they are related to the study drug, must be 
communicated immediately by telephone and by e-mail to the clinical trial monitor. All 
information referring to adverse events must be recorded in the respective section of the CRF. 
All adverse events that occur during the period comprehended from the time of enrollment of 
the patient in the study (signing of the consent form) to 100 days after discontinuation of the 
investigational products will be recorded. SAEs related to disease progression or worsening of 
disease symptoms will not be reportable. When one or more signs or symptoms correspond to 
a disease, the main diagnosis or syndrome will be notified. All adverse events will be followed 
until resolution or stabilization, or until it is determined that the study treatment or the patient’s 
participation in the study has not been the cause. All adverse events still present at the end of 
the study period will be monitored until their final outcome is determined. 
11.3.2. 
Reporting of serious adverse events (SAEs)  
The investigator will notify APICES of all serious adverse events that occur during the study 
within 24 h of receiving knowledge of the same.  
ATT. SAFETY DEPARTMENT 
E-mail: safety@apices.es 
The investigator will collect information about the SAE on the respective SAE form. The 
minimum initial information for the notification of an adverse event must include the following: 
• Adverse event and date of onset of the adverse event 
• Sex and age (or date (month-year) of birth) of the patient 
• Information about treatment received 
• Name and address of the notifying physician 
• Relation of causality with the study medication. 
 
When the SAE is notified with the minimum initial information, the complete SAE notification 
form with all the information will be sent in the next two working days.  
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Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
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CONFIDENTIAL 
MWP-301-E3 EN Protocol template for Clinical Trials Rev04.0  
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Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. 
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be 
reported as SAE. 
All SAEs must be collected that occur during the screening period and within 100 days of 
discontinuation of dosing. If applicable, SAEs must be collected that relate to any later protocol 
specified procedure (eg, a follow-up skin biopsy). 
The Sponsor Institution must report all SAEs, and all follow up information to BMS on an SAE 
Report Form within 24 hours of becoming aware of the initial event or follow-up information.  
BMS SAE, Select Adverse Event and Pregnancy Reporting Information 
e-mail: mailto:worlwide.safety@bms.com 
Fax Number: + 1 609-818-3804 
 
 
The sponsor/CRO will reconcile the clinical database AE cases (case level only) transmitted to 
BMS Global Pharmacovigilance (Worldwide.Safety@bms.com).  
The sponsor/CRO will request from BMS Worldwide Patient Safety (WWPS), 
aepbusinessprocess@bms.com the SAE reconciliation report and include the BMS protocol 
number every 3 months and prior to data base lock or final data summary. WWPS will send the 
sponsor/CRO the report to verify and confirm all SAEs have been transmitted to BMS WWPS. 
The data elements listed on the WWPS reconciliation report will be used for case identification 
purposes. If the sponsor determines a case was not transmitted to BMS WWPS, the case 
should be sent immediately to BMS (Worldwide.Safety@bms.com). 
 
11.3.3. 
Reporting of serious adverse events (SAEs) to Health Authorities 
The sponsor is responsible for notifying to the Spanish Health Authorities of all suspected 
serious adverse reactions and, simultaneously, unexpected, associated with investigational 
medicinal products of which he has knowledge, which occurred in the clinical trial. This 
communication shall be made within the time limits established by Spanish legislation. 
Additionally, suspected serious adverse reactions and, simultaneously, unexpected occurred 
outside the study should be notified in accordance with the criteria established in the guidelines 
of the European Commission.  
In addition to this, the sponsor must inform without undue delay within fifteen calendar days to 
the Spanish Health Authorities and the IEC, any information affecting significantly the risk / 
benefit ratio of the trial. Such notification shall be made in accordance with the guidelines of the 
European Commission or, where appropriate, with the procedures set forth in the instructions 
for the conduct of clinical trials in Spain published by the Spanish Health Authorities. 
11.3.4. 
Follow-up of AEs and SAEs 
After the initial notification of an AE or SAE, the investigator is required to follow up each case 
and obtain more data on the patient’s state. All the AEs and SAEs documented in previous 
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Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
CONFIDENTIAL 
MWP-301-E3 EN Protocol template for Clinical Trials Rev04.0  
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visits must be reviewed in subsequent visits. All AEs and SAEs must be monitored until their 
resolution, stabilization, explanation of the event by another cause, or until the follow-up period 
ends. This is applicable to all the patients, including those who withdraw early. 
The investigator will include in the follow-up any additional research that may clarify the nature 
and/or causality of the AE or SAE. This might include additional laboratory tests or studies, 
histopathologic examinations, or the consultation of other healthcare professionals. Any co-
investigator can ask the investigator to carry out additional evaluations to definitively clarify the 
nature and/or the causality of AEs or SAEs. If the patient dies while participating in the study or 
during a follow-up period agreed upon mutually, the investigator will provide a copy of any 
postmortem finding requested, including histopathology. 
11.3.5. 
AEs or SAEs that occur after the study ends 
Post-study AEs or SAEs are defined as any event that occurs outside the period of detection 
defined in the protocol. The investigator is not required to actively seek out AEs or SAEs in 
patients who have participated in the clinical trial in the past. Nevertheless, if the investigator 
comes to know of the existence of any AE or SAE, including the death of the patient at any time 
after a patient has left the study, and this AE or SAE is considered related to the study drug, the 
investigator must notify the sponsor promptly. 
11.3.6. 
Immune-mediated  adverse events  
Selected Adverse Events (serious or non-serious) that are of scientific and medical concern 
specific to the nivolumab treatment require ongoing monitoring and rapid communication by the 
Investigator to the Sponsor Institution and BMS. Nivolumab Immune-mediated AEs (IMAE) are 
adverse events  (that include pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, 
rash, and endocrine (adrenal insufficiency, hypothyroidism/thyroiditis, hyperthyroidism, diabetes 
mellitus, and hypophysitis) for which subjects received immunosuppressive medication for 
treatment of the event, with the exception of endocrine events (hypothyroidism/thyroiditis, 
hyperthyroidism, hypophysitis, diabetes mellitus, adrenal insufficiency), which are included 
regardless of treatment since these events are often managed without immunosuppression. 
IMAEs, regardless of causality, can occur within 100 days of the last dose.  
A summary of the IMAEs category and their respective preferred terms (PTs) are provided 
below: 
IMAE 
PTs included 
Pneumonitis  
Pneumonitis, Interstitial lung disease 
Diarrhea/Colitis 
Diarrhea, Colitis, Enterocolitis 
Hepatitis 
 
Hepatotoxicity, Hepatitis, Hepatitis acute, Autoimmune hepatitis, 
AST increased, ALT increased, Bilirubin increased, ALP increased 
Adrenal insufficiency  
Adrenal insufficiency 
Hypothyroidism/Thyroiditis 
 
Hypothyroidism, Thyroiditis Thyroiditis acute (collapsed with 
thyroiditis for frequency), Autoimmune thyroiditis (collapsed with 
thyroiditis for frequency) 
Hyperthyroidism 
Hyperthyroidism 
Hypophysitis 
Hypophysitis 
Diabetes mellitus 
Diabetes mellitus, Diabetic ketoacidosis 
Nephritis and renal dysfunction 
Nephritis, Nephritis allergic, Tubulointerstitial nephritis, Acute renal 
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EudraCT No.: 2019-002922-60 
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APICES Project No.: TTCC277007 
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failure, Renal failure, Increased creatinine 
Rash 
Rash, Rash maculopapular 
 
 
11.3.7. 
Special Situation Reports 
The following Special Situation should be collected even in the absence of an AE: 
a. Data related to medicinal product usage during pregnancy or breastfeeding 
b. Data related to overdose, abuse, misuse and medication error (including 
potential and intercepted medication errors) 
c. Data related to a Suspected Transmission of Infectious Agent by Medicinal 
Product (STIAMP) 
d. Occupational exposure  
e. Lack of efficacy 
f. Medication error  
The investigator will notify the sponsor on the SAE form all special situations detailed above 
that occur during the study within 24 h of receiving knowledge of the same.  
ATT. APICES SAFETY DEPARTMENT 
Email: safety@apices.es  
 
 
11.3.8. 
Pregnancy 
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 6 
months after product administration for WOCBP, 6 months after product administration for male 
participants with partners who are WOCBP, the investigator must immediately notify the 
APICES Monitor/designee of this event and complete and forward a Pregnancy Form to 
APICES Designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures.  
In most cases, the study treatment will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for participant safety). Please call the APICES Medical Monitor 
within 24 hours of awareness of the pregnancy. 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the pregnancy 
form. 
DocuSign Envelope ID: 834F441E-BB57-4466-A6ED-3D12263D7324


Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
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11.4. 
Study data monitoring committee 
Since the combination of paclitaxel and nivolumab has not yet been studied in HNSCC, the 
sponsor will establish a study data monitoring committee for reviewing safety data of the 
combination. This committee will consist of the two coordinating investigators and at least 5 of 
the participating investigators who will review the available safety information.  
The study data monitoring committee will evaluate the safety profile of the combination once 
the first 10 patients included in the nivolumab arm have finished the combined treatment with 
paclitaxel. Additionally, the study data monitoring committee will review the available safety 
information every three months. It is not considered necessary to make more frequent reviews 
since both drugs are widely used in the participating oncology departments, there is sufficient 
experience in their use and the safety profile of both drugs is clearly defined. 
During the periodic reviews, the study data monitoring committee together with the sponsor will 
review the available safety data (adverse events, serious adverse events, dropouts) and make 
a recommendation on whether or not to continue recruiting patients in the study, depending on 
the safety data from patients included. In any case, if an unexpected event related to patient 
safety is detected, it will be notified to the participating investigators and will be evaluated by 
the sponsor and the study data monitoring committee, which could increase the frequency of 
safety reviews if deemed appropriate. 
 
12. 
STATISTICAL CONSIDERATIONS 
12.1. 
General considerations 
A brief summary of the general statistical analysis methods is provided below; full details will 
be provided in a separate Statistical Analysis Plan (SAP), which will be finalized prior to 
database lock.  
12.2. 
Sample size 
Sample size has been calculated based on the primary objective of this clinical trial, to evaluate 
2-year overall survival.  
Previous studies shown that the two year OS in patients with recurrent or 
metastatic head and neck squamous cell carcinoma was about 16%. To accept the treatment 
efficacy we will assume that the 2-year OS with nivolumab in combination with weekly paclitaxel 
will be at least 26%. A sample size of 94 evaluable patients achieves 80% power at a 0.05 
significance level (alpha) to accept the efficacy of nivolumab in combination with weekly 
paclitaxel. An accrual time of 18 months and follow-up time of 24 months (treatment and follow-
up time) have been considered in the sample size calculation. Sample size was calculated for the 
experimental arm. 94 patients will be included in the experimental arm and 47 in the control arm. Total 
sample size is 141 patients. Patients will be randomized in a 2:1 ratio.  
Sample size has been calculated with one-sample survival method. The test statistic for 
survival probability is assumed to be based on the non-parametric estimate of the survival 
distribution. For median survival, a Brookmeyer-Crowley like test assumed*. 
A control group has been included to have a contemporary reference with a profile of patients 
equal to that of the experimental arm. 
* Brookmeyer R and Crowley, JJ. A confidence interval for the median survival time. Biometrics, 38, 29-41, 1982. 
12.3. 
Analytical Populations 
The populations used for analysis will include the following: 
DocuSign Envelope ID: 834F441E-BB57-4466-A6ED-3D12263D7324


Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
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- 
Intent-to-treat (ITT) efficacy population: all patients who are randomized will 
analyze for efficacy endpoints. This is the primary dataset for analyses of study 
conduct, study population, and efficacy. 
- 
Safety population: all patients who received at least one dose of the study 
treatment and had at least one valid post baseline safety assessment. 
 
12.4. 
Analysis of Primary Objective 
Primary objective of this study is to assess the efficacy of nivolumab plus paclitaxel, in terms of 
two years overall survival (OS), for first-line treatment of recurrent or metastatic HNSCC in the 
platinum ineligible and platinum refractory settings. 
OS is defined as the time between the date of randomization and the date of death. For 
subjects without documentation of death, OS will be censored on the last date the subject was 
known to be alive. 
OS in each treatment group will be estimated using KM method for all randomized subjects. 
Median values along with two-sided 95% CI will be calculated. OS rates at 2 and 5 years will be 
estimated for each treatment arm. 
 
12.5. 
Analysis of Secondary Objectives 
12.5.1. 
Secondary Efficacy evaluations 
Demographics and baseline characteristics will be summarized by treatment arm as 
randomized using descriptive statistics using the efficacy population. 
 
Efficacy analyses will be performed by treatment arm and also in patients ≥ 70 years.  
 
ORR and DCR will be performed by treatment arm using RECIST criteria v1.1. Number of 
responses and or stable disease, percentage and 95% CI will be calculated.  
 
Duration of response (DoR), PFS and OS in each treatment group will be estimated using 
Kaplan Meier method. Median survival time along with 95% CI will be provided.  
 
The distribution of PD-L1 expression (CPS) will be examined using descriptive statistics. 
 
Frequency of BOR and ORR by CPS score ≥1 / <1 (PD-L1) subgroups for each treatment 
group will be tabulated.  
 
Cox regression on univariate models will be used to calculate the risk reduction (OS and PFS). 
Hazard ratio (HR) with 95% CIs will be reported to evaluate the impact of treatment arm and 
stratification variables (CPS (≥1 / <1), HPV (positive vs negative) and Karnofsky PS (70% vs 
80-100%)) on the time-to-event efficacy endpoints. 
12.5.2. 
Secondary Safety evaluations 
The safety analysis will be performed in all treated subjects. Descriptive statistics of safety will 
be presented using the NCI CTCAE version 5.0 by treatment arm. All AEs, drug-related AEs, 
SAEs and drug-related SAEs will be tabulated using the worst grade per NCI CTCAE v 5.0 
criteria by system organ class and preferred term.  
 
DocuSign Envelope ID: 834F441E-BB57-4466-A6ED-3D12263D7324


Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
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Percentage of patients with AEs, percentage of patients with Grade 3 and Grade 4 AEs, 
percentage of patients with SAEs, percentage of patients who discontinued due to AEs and 
incidence of deaths will be provided.  
 
13. 
DATA HANDLING AND QUALITY ASSURANCE 
 
13.1. 
Monitoring of the trial 
The clinical monitors are employees of APICES, and representatives of the sponsor. As such, 
they have the obligation to follow the trial closely so that all aspects of the trial are carefully 
monitored for compliance with applicable government regulations and with ICH E6(R2) 
guidelines.  
The clinical monitors will visit the study sites and Investigators at intervals as defined in the 
monitoring plan, in addition to maintaining necessary contact through telephone, e-mail, and 
letter. The clinical monitors will maintain current personal knowledge of the trial through 
observation, review of trial records and source documentation, and discussion of the conduct 
of the trial with the study site Investigators and staff. 
13.2. 
Audits 
The sponsor may choose to schedule and conduct periodic audits of ongoing clinical studies. 
Audits are independent of, and separate from, routine monitoring or quality control functions 
and are conducted to assure accuracy and compliance with the protocol, governing regulatory 
authorities and/or ICH E6(R2) guidelines. 
13.3. 
Reporting of serious breaches 
Serious breaches of the authorized protocol or of the Royal Decree 1090/2015 occurring in 
Spain must be reported by the sponsor without undue delay and no later than seven calendar 
days from becoming aware of the breach to the Spanish Agency of Medicines and Medical 
Devices (AEMPS) and the CEIm. 
To this end, a serious breach shall be defined as a breach that may significantly affect the 
safety and rights of the trial subjects or the reliability and robustness of the data generated in 
the clinical trial. 
Only serious breaches should be notified to the AEMPS and the CEIm, and the breaches that 
do not constitute a serious breach should not be notified. 
Each study site Investigator must document and explain in the subject’s source documentation 
any breaches from the approved protocol and / or the Royal Decree 1090/2015. Investigators 
may implement a breach to eliminate an immediate hazard to trial subjects without prior IEC 
informed consent approval, but the breach must be reported to the monitor/CRA within 1 
working day. Such incidents will be evaluated for potential safety hazards of the ongoing study, 
and if deemed appropriate, a protocol amendment will be issued.  
The monitor/CRA will document breaches throughout the course of monitoring visits. The 
monitor will notify the Investigator during a visit and a “Breach Form” will be completed and 
signed by the investigator and by the monitor.  
13.4. 
Data Management 
APICES will be responsible for processing and quality control of the data. Data will be handled 
in accordance with the Data Management Plan, Standard Operating Procedures and 
applicable regulatory guidelines. 
DocuSign Envelope ID: 834F441E-BB57-4466-A6ED-3D12263D7324


Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
CONFIDENTIAL 
MWP-301-E3 EN Protocol template for Clinical Trials Rev04.0  
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Data management based on GCP refers to activities defined to achieve safe routines for 
efficient entry of subject information into a database, avoiding errors. The routines include 
procedures for handling of eCRFs, database set-up and management, data entry and 
verification, data validation, quality control (QC) of database, and documentation of the 
performed activities, including information of discrepancies in the process. The database, the 
data entry screens and the program, will be designed in accordance with the clinical study 
protocol by APICES. 
13.5. 
Electronic Case Report Forms (eCRFs) 
Data collection for this study will consist of electronic data capture for all eCRF information. 
APICES will supply the eCRF. 
All study site Investigators agree to maintain accurate eCRFs and source documentation as 
part of the case histories.  
All information is to be filled in the subject’s eCRF. If an enroled subject is not randomized into 
the study (ie, fails screening), only minimum data (such as demographics and consent date) 
and the reason for failing screening should be reported on the eCRF. In general, no queries for 
missing data on these subjects will be issued for procedures indicated as ‘Not done’. 
For randomized subjects, information captured on the source documents will be entered into 
the subject’s eCRF by study site personnel and monitored at the study site. If an item is not 
available or is not applicable, this fact should be indicated by a missing reason. Blank spaces 
should not be present unless otherwise directed. Any corrections should be made using the 
procedure outlined in the Case Report Form Completion Guide of the study manual and will be 
recorded in the eCRF. 
Each completed eCRF must be reviewed, signed, and dated by the study site Investigator in a 
timely manner. The completed eCRF will be reviewed by the study Monitor as soon as practical 
after completion. A copy of the final, approved and signed eCRF will be provided to the site 
and should be stored in the appropriate files. 
13.6. 
Web-based eCRF 
Clinical data (including AEs and concomitant medications) will be entered into an Electronic 
Data Capture (EDC) application. The data system is password protected and includes internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete or inaccurate. Clinical data will be entered directly from the source documents. 
Roles and rights of the study site personnel responsible for entering the study data into the 
eCRF will be determined in advance. Only authorized study site personnel designated by each 
study site Investigator will complete data collection. Appropriate training and security measures 
will be completed with the Investigator and all authorized study site personnel, prior to the 
study initiation, and before any study data is entered into the system. 
13.7. 
Entering of Data into the eCRF 
The eCRFs should always reflect the latest observations on the subjects participating in the 
study. Therefore, the eCRFs should be completed as soon as possible during or after the 
subject’s visit. Each study site Investigator must verify that all data entries in the eCRFs are 
accurate and correct. 
If some assessments are not done, or if certain information is not available, not applicable or 
unknown, the Investigator or authorized designee should indicate this in the eCRF. The 
investigator will approve the data using an electronic signature, and this approval is used to 
confirm the accuracy of the data recorded. 
DocuSign Envelope ID: 834F441E-BB57-4466-A6ED-3D12263D7324


Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
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13.8. 
The Query Process 
Each monitor will review the eCRFs and evaluate them for completeness and consistency. 
Each eCRF will be compared with the respective source documents to ensure that there are no 
discrepancies between critical data. All entries, corrections and alterations are to be made by 
the Investigator or his/her authorized designee. The monitor cannot enter data in the eCRFs.  
Once clinical data of the eCRF have been submitted to the central server, corrections to the 
data fields will be audit trailed (ie, the reason for any change, the name of the person who 
performed the change, and time and date will be logged). If additional corrections are needed, 
the responsible monitor or Data Manager will raise a query in the EDC application. The 
appropriate investigational staff will answer queries generated in the application. This process 
is audit trailed meaning that the name of investigational staff, time, and date is logged. 
13.9. 
Source Documents 
The eCRF is essentially considered a data entry form and should not constitute the original (or 
source) medical records unless otherwise specified. Source documents are all documents 
used by the Investigator or hospital that relate to the subject’s medical history, that verify the 
existence of the subject, the inclusion and exclusion criteria, and all records covering the 
subject’s participation in the study. They include enrolment and randomization log, 
investigational product accountability log, laboratory notes, memoranda, material dispensing 
records, subject files, etc. 
Each Investigator is responsible for maintaining source documents. These will be made 
available for inspection by the study monitor at each monitoring visit. All supportive 
documentation submitted with the eCRF, such as laboratory data should be clearly identified 
with the study, visit and subject number. Any personal information (e.g., subject name, initials) 
should be removed or rendered illegible to preserve individual confidentiality. 
13.10. 
User ID 
eCRF records will be automatically appended with the identification of the creator, by means of 
their unique User ID. Specified records will be electronically signed by the Investigator to 
document his/her review of the data and acknowledgement that the data are accurate. This will 
be facilitated by means of the Investigator’s unique User ID and password; date and time 
stamps will be added automatically at time of electronic signature. If an entry in an eCRF 
requires change, the correction should be made in accordance with the relevant software 
procedures. 
13.11. 
Audit Trail 
To meet regulatory requirements, the eCRF data will be electronically stored at sites. All 
changes will be fully recorded in a protected audit trail, and a reason for the change will be 
required. Once all data have been entered, verified, and validated, the database will be locked 
to prevent any further changes in the clinical study data.  
13.12. 
Inspection of Records 
The Investigators and institutions involved in the trial will permit trial-related monitoring, audits, 
IEC review, and regulatory inspection(s) by providing direct access to all trial records. In the 
event of an audit, the Investigator agrees to allow the sponsor, representatives of the sponsor, 
and the governing regulatory agency access to all trial records. 
The Investigator should promptly notify the sponsor of any inspections scheduled by any 
regulatory authorities and promptly forward copies of any inspection reports received to the 
sponsor. 
DocuSign Envelope ID: 834F441E-BB57-4466-A6ED-3D12263D7324


Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
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13.13. 
Trial Record Retention 
Essential documents and eCRF data should be retained during 25 years. 
 
14. 
ADMINISTRATIVE CONSIDERATIONS 
The following administrative items are meant to guide each study site Investigator in the 
conduct of the study but may be subject to change based on industry and government SOPs or 
working practice documents or guidelines.  
14.1. 
Legal Considerations 
The current clinical trial will be conducted in accordance with the protocol, the principles 
established in the current revised version of the Declaration of Helsinki (Annex 1) and the 
applicable regulatory requirements, particularly the ICH Tripartite Harmonized Guidelines for 
good clinical practice (1996), the Regulation (EU) 536/2014 relative to clinical trials on 
medicinal products for human use and the locally applicable regulations (e.g., In Spain, the 
Royal Decree on Clinical Trials 1090/2015).  
14.2. 
Ethics committee review 
ICH guidelines require that approval be obtained from Health Authorities and an Ethics 
Committee before human subjects can participate in research studies. Prior to the trial onset, 
the protocol, informed consent, advertisements to be used for subject recruitment (if 
applicable), and any other written information regarding this trial to be provided to the subject 
will be approved by the Ethics Committee. The clinical study will only be started when both the 
Health Authorities and an Ethics Committee have considered that the expected benefits for the 
trial subject and society justify the risks; in addition, the trial will only be continued if compliance 
with this criterion is constantly supervised. 
APICES will obtain Ethics Committee approvals on behalf of the sponsor and investigators. All 
regulatory approvals should be signed by the Ethics Committee Chairman or designee and 
must identify the Ethics Committee name and address, the clinical protocol by title and/or 
protocol number and the date approval and/or favorable opinion was granted. Documentation 
of all Health Authorities and Ethics Committee approvals and of the Ethics Committee 
compliance with ICH E6(2) will be maintained by the site and will be available for review.  
14.3. 
Modifications of the protocol 
Any change in the approved protocol will require a Protocol amendment. The Investigator must 
not make any change in the study without favourable opinion from the Ethics Committee and 
authorization from the Health Authorities, except as necessary to eliminate an impending and 
obvious risk for the subjects except when necessary to remove an apparent, immediate hazard 
to subjects. Protocol changes introduced to eliminate an impending and obvious risk may be 
implemented immediately, but must subsequently be documented in an amendment, reported 
to the Ethics Committee and be submitted to the relevant Health Authorities within the required 
timeframe.  
Any substantial amendments to the protocol must be submitted in writing to the Ethics 
Committee and the Health Authorities for approval before the changes proposed in the 
amendment are implemented. Depending on the magnitude of the change, the recruitment 
may be temporally halted. 
The sponsor does not have to notify non-substantial amendments to the Health Authorities or 
the Ethics Committee. However, any non-substantial amendments will be recorded and 
contained in the documentation when it is subsequently submitted, for example in the 
DocuSign Envelope ID: 834F441E-BB57-4466-A6ED-3D12263D7324


Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
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subsequent notification of a substantial amendment. Documentation of any non-substantial 
amendments will be available on request for inspection at the trial site or the sponsor premises 
as appropriate. 
14.4. 
Informed consent 
A written informed consent in compliance with ICH E6 guidelines shall be obtained from each 
subject before being included in the study or performing any study specific procedures.  
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki. The consent form and any revision(s) should be 
approved by the Ethics Committee prior to being provided to potential subjects. 
The written Informed Consent Form (ICF) should be prepared in the local language(s) of the 
potential subject population. 
An approved informed consent form will be provided by the sponsor to investigative site.  
Before a subject’s participation in the study, it is the Principal Investigator’s (or their designee) 
responsibility to obtain freely given consent in writing, from the subject after adequate 
explanation of the aims, methods, anticipated benefits, and potential risks of the study and 
before any protocol-specific screening procedures or any study drugs are administered. 
Subjects must have the opportunity to ask questions and receive answers and will have 
adequate time to decide whether or not to participate in the study. Once the Investigator is 
assured that the subject understands the implications of participating in the trial, the subject will 
be asked to give consent to participate in the trial by signing the informed consent. 
The ICF should be signed and personally dated by the subject and by the physician who 
conducted the informed consent discussion (Principal Investigator or designee). The subject’s 
written informed consent should also be documented in the subject’s medical records. 
The Investigator shall provide a copy of the signed informed consent to the subject. A second 
original form shall be maintained in the Investigator study file at the site. 
If the informed consent is revised during the course of the trial, all active participating subjects 
must sign the revised form approved by the Ethics Committee. 
The subject participating in a clinical trial, or his/her legal representative, may withdraw consent 
at any time without giving any reason and without this involving any penalty or prejudice for the 
participating subject. 
14.5. 
Confidentiality  
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. Each Investigator will ensure that all site 
personnel involved will respect the confidentiality of any information about trial subjects. 
Management of personal data from subjects participating in the trial, particularly as regards 
consent, will comply with Regulation (EU) 2016/679 of the European Parliament and of the 
Council of 27 April 2016 on the protection of natural persons with regard to the processing of 
personal data and on the free movement of such data and local laws. 
At each site, all records will be kept in a secure storage area with limited access. Clinical 
information will not be released without the written permission of the subject. Subject identity is 
confidential and may only be known by the Investigator, trial personnel, appointed auditors and 
monitors, and Health Authorities. 
DocuSign Envelope ID: 834F441E-BB57-4466-A6ED-3D12263D7324


Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
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Each Investigator and all employees and coworkers involved with this trial may not disclose or 
use for any purpose other than performance of the trial, any data, record, or other unpublished, 
confidential information disclosed to those individuals for the purpose of the trial. Prior written 
agreement from the sponsor or its designee must be collected for the disclosure of any said 
confidential information to other parties. 
14.6. 
Insurance  
The sponsor has contracted an insurance policy to cover the responsibilities of the investigator 
and other parties participating in the study, according to the applicable legislation. 
- 
Insurance company: Chubb European Group SE 
- 
Policy Number: ESLSC238983 
14.7. 
Publications  
The sponsor commits to responsible publication of both the positive and negative results from 
its clinical trials as required by all governing regulatory and health authorities.  
Investigators will not publish the global study results (all sites) unless the sponsor has not done 
so in a suitable time period after the clinical study report (CSR) has been available. Should the 
Investigator(s) independently seek to publish results of this study which occur at their study 
site(s), they must inform the study sponsor of any/all drafts (including, but not limited to papers, 
manuscripts or abstracts) at least 60 days before submission to the congress, meeting or 
journal. The sponsor and Investigator(s) will agree with all aspects related to any proposed 
publications with regards to the following: 1) any proposed publications will be drafted in 
agreement with international recommendations, such as those from the International 
Committee of Medical Journal Editors (ICMJE) and all elements of the Consort Statement 
(2010), to maintain integrity of the trial results in all communications; 2) any proposed 
publications will state the Clinical Research Ethics Committees which approved the trial and 
the funding sources of the trial; 3) any proposed publications will occur before disclosure of 
results to lay people; 4) any proposed publications will not report premature or partial data prior 
to completion of the analysis of the overall results of the trial. 
The order of the authors in the publication will be determined according to the sponsor 
standard operating procedures. 
DocuSign Envelope ID: 834F441E-BB57-4466-A6ED-3D12263D7324


Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
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15. 
SPONSOR’S SIGNATURE PAGE 
 
 
Study title: Phase II multicenter randomized trial to assess the efficacy and safety of first line 
nivolumab in combination with paclitaxel in subjects with R/M HNSCC unable for cisplatin-
based chemotherapy (NIVOTAX) 
Study code: TTCC-2019-01 / CA209-7HE / TCC277007 
Version number and date: 5.0 - October, 19th, 2022 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable regulations and ICH guidelines. 
 
 
 
 
Position  
(pre-printed name) 
 Signature 
 Signature date 
 (DD-Mmm-YYYY) 
 
 
 
Position  
(pre-printed name) 
 Signature 
 Signature date 
 (DD-Mmm-YYYY) 
 
 
Position  
(pre-printed name) 
 Signature 
 Signature date 
 (DD-Mmm-YYYY) 
 
 
Position  
(pre-printed name) 
 Signature 
 Signature date 
 (DD-Mmm-YYYY) 
 
DocuSign Envelope ID: 834F441E-BB57-4466-A6ED-3D12263D7324
Ricard Mesía
21-oct.-2022
Ico
Pi
28-oct.-2022
Lara Iglesias


Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
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16. 
INVESTIGATOR’S SIGNATURE PAGE 
 
 
Study title: Phase II multicenter randomized trial to assess the efficacy and safety of first line 
nivolumab in combination with paclitaxel in subjects with R/M HNSCC unable for cisplatin-
based chemotherapy (NIVOTAX) 
Study code: TTCC-2019-01 / CA209-7HE / TCC277007 
Version number and date: 5.0 - October, 19th, 2022 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable regulations and ICH guidelines. 
 
 
 
 
Principal Investigator’s signature 
 
Signature date 
(DD-Mmm-YYYY) 
 
 
 
 
 
Investigator’s name (capital letters) 
 
 
 
 
 
Investigator’s signature 
 
Signature date 
(DD-Mmm-YYYY) 
 
 
 
 
 
Investigator’s name (capital letters) 
 
 
 
 
 
Investigator’s signature 
 
Signature date 
(DD-Mmm-YYYY) 
 
 
 
 
 
Investigator’s name (capital letters) 
 
 
 
 
 
DocuSign Envelope ID: 834F441E-BB57-4466-A6ED-3D12263D7324


Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
APICES Project No.: TTCC277007 
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17. 
REFERENCES  
 
1. 
 Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 
and its ligands in regulating autoimmunity and infection. Nat Immunol 2007;8(3):239-45) 
2. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New Response Evaluation Criteria in 
Solid Tumours: Revised RECIST Guideline (version 1.1). Eur J Cancer 45:228–247. 
3. 
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Joseph AW, D'Souza G. Epidemiology of human papillomavirus-related head and 
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O'Rorke MA, Ellison MV, Murray LJ, Moran M, James J, Anderson LA. Human 
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15. 
Castellsagué X, Alemany L, Quer M, Halec G, Quirós B, Tous S, et al. HPV 
Involvement in Head and Neck Cancers: Comprehensive Assessment of Biomarkers in 
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cancer. N Engl J Med 2008;359:1116-27  
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Hitt R.; Irigoyen A.; Cortes-Funes H.; Grau J.J.; Garcia-Saenz J.A.; Cruz-Hernandez 
J.J. Phase II study of the combination of cetuximab and weekly paclitaxel in the first-line 
treatment of patients with recurrent and/or metastatic squamous cell carcinoma of head 
and neck. Ann Oncol. 2012;23(4):1016-1022. 
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Guigay J, Fayette J, Dillies AF, Sire C, Kerger JN, Tennevet I, et al. Cetuximab, 
docetaxel, and cisplatin as first-line treatment in patients with recurrent or metastatic 
head and neck squamous cell carcinoma: a multicenter, phase II GORTEC study. Ann 
Oncol. (2015) 26:1941–7. 
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Gibson MK, Li Y, Murphy B, Hussain MH, DeConti RC, Ensley J, Forastiere AA; 
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an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 
2005;23:3562–3567. 
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Ang KK, Zhang Q, Rosenthal DI. Randomized phase III trial of concurrent 
accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and 
neck carcinoma: RTOG 0522. J Clin Oncol. 2014;32(27):2940–50.] 
22. 
Srivastava RM, Lee SC, Andrade Filho PA, Lord CA, Jie HB, Davidson HC, Lopez-
Albaitero A, Gibson SP, Gooding WE, Ferrone S, et al. Cetuximab-activated natural 
killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in 
head and neck cancer patients. Clin Cancer Res. 2013;19(7):1858–72. 
23. 
Mellman I, Coukos G & Dranoff G. Cancer immunotherapy comes of age. Nature 
2011 Dec 22;29 4 8 0:480-89 
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Ferris RL, Blumenschein Jr. G, Fayette J, Guigay J, Colevas AD, Licitra L, et al. 
Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 
2016;375:1856–67. 
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Cohen EEW, Soulières D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, et al. 
Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or 
metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, 
open-label, phase 3 study. Lancet 2018; 393: 156-157. 
26. 
Burtness B, Harrington KJ, Greil R, et al. KEYNOTE-048: phase 3 study of first-line 
pembrolizumab (P) for recurrent/metastatic head and neck squamous cell carcinoma 
(R/M HNSCC). Presented at: European Society of Medical Oncology 2018 Congress; 
October 19-23, 2018; Munich, Germany. Abstract LBA8_PR. 
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Rischin D, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G, et al. 
Protocol-specified final analysis of the phase 3 KEYNOTE-048 trial of pembrolizumab 
(pembro) as first-line therapy for recurrent/metastatic head and neck squamous cell 
carcinoma (R/M HNSCC). J Clin Oncol. (2019) 37. doi: 
10.1200/JCO.2019.37.15_suppl.6000. 
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28. 
Alberts AE, Strauss L, Liao T, et al. T cell-tumor interaction directs the development 
of immunotherapies in head and neck cancer. Clinical and Developmental Immunology 
2010 doi:10.1155/2010/236378 epub. 
29. 
Leibowitz MS, Pedro A, Fiho A, Ferrone S, Ferris RL. Deficiency of activated STAT 1 
head and neck cancer cells mediates TAP1-dependent escape from cytotoxic T 
lymphocytes. Cancer Immunol Immunotherapy 2011;60:525-535 
30. 
Cho YA, Hong SD. Relation between expression of PDL-1 and tumor infiltrating 
lymphocytes in oral squamous cell carcinoma. Oral Oncology 2011;12:1148 
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Albers A, Abe K, Hunt J, et al. Antitumor activity of human papillomavirus type 16 E7-
specific T cells against virally infected squamous cell carcinoma of the head and neck. 
Cancer Res 2005;65(23):11146-55. 
32. 
Dong H, Chen L. B7-H1 pathway and its role in the evasion of tumor immunity. J Mol 
Med 2003;81(5):281-7 
33. 
Thompson RH, Kuntz SM, Leibovich BC, et al. Tumor B7-H1 is associated with poor 
prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res 
2006;66(7):3381-5 
34. 
Ohigashi Y, Sho M, Yamada Y, et al. Clinical significance of programmed death-1 
ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. 
Clin Cancer Res 2005;11(8):2947-53. 
35. 
Wu C, Zhu Y, Jiang J, et al. Immunohistochemical localization of programmed death-
1 ligand- 1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem 
2006;108(1):19-24. 
36. 
Nomi T, Sho S, Akahori T, et al. Clinical significance and therapeutic potential of the 
programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. 
Clin Cancer Res 2007;13(7):2151-7 
37. 
Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: 
immunoselection and immunosubversion. Nat Rev Immunol 2006;6:715-27. 
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Taube, J. Anders RA, Young GD, et al. Colocalization of inflammatory response with 
B7-H1 expression in human melanocytic lesions supports an adaptive resistance 
mechanism of immune escape. Sci Transl Med 2012;4(127):127ra37 
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Seiwert TY. A phase Ib study of MK-3475 in patients with human papillomavirus 
(HPV)-associated and non-HPV-associated head and neck (H/N) cancer. J Clin Oncol. 
32:5s, 2014 suppl; abstr 6011 
40. 
Cohen et al. The Society for Immunotherapy of Cancer consensus statement on 
immunotherapy for the treatment of squamous cell carcinoma of the head and neck 
(HNSCC)Journal for ImmunoTherapy of Cancer (2019) 7:184  
41. 
Brahmer J, Reckamp K, Baas P et al. Nivolumab versus docetaxel in squamous-cell 
non-smallcell lung cancer. N Engl J Med 2015;373:123-35. 
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Keating GM. Nivolumab: A Review in Advanced Squamous Non-Small Cell Lung 
Cancer. Drugs 2015;75(16):1925-34. 
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Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev 
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44. 
Ferris RL, Blumenschein G, Fayette J, Guigay J, Colevas AD, Licitra L et al. 
Nivolumab vs investigator's choice in recurrent or metastatic squamous cell carcinoma 
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of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses 
by tumor PD-L1 expression. Oral Oncology. 2018 Jun;81:45-51. 
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Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez 
R, Robert C, Schadendorf D, Hassel JC, et al. Improved survival with ipilimumab in 
patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23. 
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Gangadhar TC, Vonderheide RH. Mitigating the toxic effects of anticancer 
immunotherapy. Nat Rev Clin Oncol. 2014;11(2):91–9. 
47. 
Guan M, Zhou YP, Sun JL, Chen SC. Adverse events of monoclonal antibodies used 
for cancer therapy. Biomed Res Int. 2015;2015:428169 
 
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Annex 1. Declaration of Helsinki  
WMA Declaration of Helsinki - Ethical Principles for 
Medical Research Involving Human Subjects 
Adopted by the 
18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd General Assembly, Edinburgh, Scotland, October 2000 
Note of Clarification, added by the WMA General Assembly, Washington 2002 
Note of Clarification, added by the WMA General Assembly, Tokyo 2004 
59th General Assembly, Seoul, Republic of Korea, October 2008 
64th General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles.  
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of 
my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient's best interest when providing medical 
care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician’s knowledge 
and conscience are dedicated to the fulfilment of this duty.  
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, effectiveness, 
efficiency, accessibility and quality. 
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7. Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. The responsibility for the protection of research subjects 
must always rest with the physician or other health care professionals and never with the 
research subjects, even though they have given consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable international 
norms and standards. No national or international ethical, legal or regulatory requirement 
should reduce or eliminate any of the protections for research subjects set forth in this 
Declaration. 
11. Medical research should be conducted in a manner that minimises possible harm to the 
environment.  
12. Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately 
qualified physician or other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14. Physicians who combine medical research with medical care should involve their 
patients in research only to the extent that this is justified by its potential preventive, 
diagnostic or therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the patients who 
serve as research subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risks, Burdens and Benefits 
16. In medical practice and in medical research, most interventions involve risks and 
burdens. 
Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected by 
the condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher. 
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18. Physicians may not be involved in a research study involving human subjects unless 
they are confident that the risks have been adequately assessed and can be satisfactorily 
managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof 
of definitive outcomes, physicians must assess whether to continue, modify or immediately 
stop the study. 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research. 
Scientific Requirements and Research Protocols 
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
22. The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, potential conflicts of 
interest, incentives for subjects and information regarding provisions for treating and/or 
compensating subjects who are harmed as a consequence of participation in the research 
study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, the 
sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research is to 
be performed as well as applicable international norms and standards but these must not be 
allowed to reduce or eliminate any of the protections for research subjects set forth in this 
Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse 
events. No amendment to the protocol may be made without consideration and approval by 
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the committee. After the end of the study, the researchers must submit a final report to the 
committee containing a summary of the study’s findings and conclusions. 
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent 
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in a 
research study unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any 
possible conflicts of interest, institutional affiliations of the researcher, the anticipated 
benefits and potential risks of the study and the discomfort it may entail, post-study 
provisions and any other relevant aspects of the study. The potential subject must be 
informed of the right to refuse to participate in the study or to withdraw consent to participate 
at any time without reprisal. Special attention should be given to the specific information 
needs of individual potential subjects as well as to the methods used to deliver the 
information. 
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-given 
informed consent, preferably in writing. If the consent cannot be expressed in writing, the 
non-written consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
27. When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent must be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
28. For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for them 
unless it is intended to promote the health of the group represented by the potential subject, 
the research cannot instead be performed with persons capable of providing informed 
consent, and the research entails only minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent 
is able to give assent to decisions about participation in research, the physician must seek 
that assent in addition to the consent of the legally authorised representative. The potential 
subject’s dissent should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research group. In 
such circumstances the physician must seek informed consent from the legally authorised 
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representative. If no such representative is available and if the research cannot be delayed, 
the study may proceed without informed consent provided that the specific reasons for 
involving subjects with a condition that renders them unable to give informed consent have 
been stated in the research protocol and the study has been approved by a research ethics 
committee. Consent to remain in the research must be obtained as soon as possible from 
the subject or a legally authorised representative. 
31. The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek informed 
consent for its collection, storage and/or reuse. There may be exceptional situations where 
consent would be impossible or impracticable to obtain for such research. In such situations 
the research may be done only after consideration and approval of a research ethics 
committee. 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best  proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention  
and the patients who receive any intervention less effective than the best proven one, 
placebo, or no intervention will not be subject to additional risks of serious or irreversible 
harm as a result of not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments 
should make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial. This information must also be disclosed to participants 
during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a 
duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. All parties should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as positive 
results must be published or otherwise made publicly available. Sources of funding, 
institutional affiliations and conflicts of interest must be declared in the publication. Reports 
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of research not in accordance with the principles of this Declaration should not be accepted 
for publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally authorised representative, may use an 
unproven intervention if in the physician’s judgement it offers hope of saving life, re-
establishing health or alleviating suffering. This intervention should subsequently be made 
the object of research, designed to evaluate its safety and efficacy. In all cases, new 
information must be recorded and, where appropriate, made publicly available. 
 
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Annex 2. List of Sites / Principal Investigators  
 
Attached in a separate file. 
 
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Annex 3. Informed Consent Form 
 
Attached in a separate file. 
 
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Annex 4. NCI-CTC AE Criteria 
 
Common terminology criteria for classification of adverse events version 5.0 (NCI CTC 
AEv5.0) are available at the following Internet address: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_
Quick_Reference_8.5x11.pdf 
 
 
 
 
 
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Annex 5 Cockcroft-Gault Equation 
 
 
For male subjects: 
Creatinine clearance = 
(140 - age[years]) x weight [kg]    OR  
(140 - age[years]) x weight [kg]   
 
72 x (serum creatinine[mg/dL]) 
 
0.81 x (serum creatinine [µmol/L]) 
 
 
For female subjects: 
Creatinine clearance = 
0.85 (140 − age[years]) x weight [kg 
OR 
0.85 (140 − age[years]) x weight [kg]  
 
72 x (serum creatinine[mg/dL]) 
 
0.81 x (serum creatinine[µmol/L]) 
 
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16(1):31-
41. 
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Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
Version 5.0 dated on 19/October/2022 
 
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Annex 6 Methods of Contraception Considered to be Effective 
Acceptable Methods Considered Highly Effective 
Birth control methods that can achieve a failure rate of less than 1% per year when 
used consistently and correctly are considered as highly effective. Such methods 
include: 
- 
combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
- 
progestogen-only hormonal contraception associated with inhibition of 
ovulation: 
o oral 
o injectable 
o implantable 
- 
intrauterine device (IUD) 
- 
intrauterine hormone-releasing system (IUS) 
- 
bilateral tubal occlusion 
- 
vasectomised partner 
- 
sexual abstinence 
 
Methods that are Considered Less Highly Effective 
Acceptable birth control methods that result in a failure rate of more than 1% per 
year include: 
- 
progestogen-only oral hormonal contraception, where inhibition of 
ovulation is not the primary mode of action 
- 
male or female condom with or without spermicide 
- 
cap, diaphragm or sponge with spermicide 
 
 
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Protocol code: TTCC-2019-01 / CA209-7HE 
 
EudraCT No.: 2019-002922-60 
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Annex 7 ECOG and Karnofsky performance status 
 
Karnofsky Status 
Karnofsky 
Grade 
ECOG 
Grade 
ECOG Status 
Normal, no complaints 
100 
0 
Fully active, able to carry on all pre-disease 
performance without restriction 
Able to carry on normal 
activities. Minor signs or 
symptoms of disease 
90 
1 
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, 
office work 
Normal activity with effort 
80 
1 
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, 
office work 
Care for self. Unable to carry 
on normal activity or to do 
active work 
70 
2 
Ambulatory and capable of all selfcare but 
unable to carry out any work activities. Up and 
about more than 50% of waking hours 
Requires occasional 
assistance, but able to care 
for most of his needs 
60 
2 
Ambulatory and capable of all selfcare but 
unable to carry out any work activities. Up and 
about more than 50% of waking hours 
Requires considerable 
assistance and frequent 
medical care 
50 
3 
Capable of only limited selfcare, confined to 
bed or chair more than 50% of waking hours 
Disabled. Requires special 
care and assistance 
40 
3 
Capable of only limited selfcare, confined to 
bed or chair more than 50% of waking hours 
Severly disabled. 
Hospitalisation indicated 
though death nonimminent 
30 
4 
Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair 
Very sick. Hospitalisation 
necessary. Active supportive 
treatment necessary 
20 
4 
Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair 
Moribund 
10 
4 
Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair 
Dead 
0 
5 
Dead 
http://www.ncbi.nlm.nih.gov/pubmed/7165009 
https://oncologypro.esmo.org/Oncology-in-Practice/Practice-Tools/Performance-Scales
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Annex 8 Head and neck squamous cell carcinomas 
 
- 
oral cavity: 
o anterior two thirds of the tongue 
o tongue unspecified, 
o lip 
o gum 
o floor of the mouth 
o hard palate 
o palate unspecified 
o other oral cavity—including buccal mucosa and retromolar area 
o oral cavity unspecified 
- 
oropharynx: 
o base of the tongue 
o soft palate 
o tonsil 
o uvula 
o other parts of the oropharynx 
o Waldeyer’s ring 
o oropharynx unspecified 
- 
larynx: 
o glottis 
o supraglottis 
o subglottis 
o other and unspecified larynx subsites 
o Hypopharynx cases are classified as belonging to the larynx, 
including pyriform sinus 
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Annex 9 New York Heart Association Classification of Cardiac 
Disease 
 
 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of minimal 
cardiovascular disease 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain 
Objective evidence of 
moderately severe 
cardiovascular disease 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or the 
anginal syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased. 
Objective evidence of severe 
cardiovascular disease 
Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for Diagnosis 
of Diseases of the Heart and Great Vessels. Ninth Ed. Boston, MA: Little, Brown & Co; 1994:253-256. 
 
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Annex 10 G8 questionnaire 
 
 
Bellera CA, Rainfray M, Mathoulin-Pélissier S, et al. Screening older cancer patients: first 
evaluation of the G-8 geriatric screening tool. Ann Oncol 2012; 23: 2166–72. 
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Annex 11  RECIST Criteria 
 
The RECIST criteria can be accessed at the following internet address: 
http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf 
 
 
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Annex 12  Combined Positive Score (CPS) 
 
 
                               Number of PD-L1 stained cells 
                               (tumor cells, lymphocytes, macrophages) 
CPS = -------------------------------------------------------------------------- X 100 
                               Total number of viable tumor cells 
 
Reported as a number (capped at 100) 
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Annex 13 Management algorithms for immune-mediated adverse reactions 
 
 
 
 
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SAP_001.pdf: 
 
 
 
 
NIVOTAX Statistical Analysis Plan 
 
 
 
Phase II multicenter randomized trial to assess the 
efficacy and safety of first line nivolumab in combination 
with paclitaxel in subjects with R/M HNSCC unable for 
cisplatin-based chemotherapy (NIVOTAX)” 
 
NCT: NCT04282109 
 
 
 
 
 
 
  
Date: 21-Oct-2022 


16 Antonio López Av, 1st floor 
Pinto (MADRID) 28320 
Tlf.: 91 816 68 04 
www.apices.es 
STP-703-E1 Statistical Analysis Plan template Rev02.3 
 
“Phase II multicenter randomized trial to 
assess the efficacy and safety of first line 
nivolumab in combination with paclitaxel in 
subjects with R/M HNSCC unable for 
cisplatin-based chemotherapy (NIVOTAX)” 
 
NIVOTAX Study 
 
APICES Project No. TTC277007 
 
Statistical Analysis Plan 
 
Version 1.0 
October 21st, 2022 
 
 
 
 
 
 
Prepared by: 
 
 
 
 
 
 
 
 
(Name) 
 
Signature/Date 
 
 
 
 
Reviewed by: 
 
 
 
 
 
 
 
 
(Name) 
 
Signature/Date 
 
 
 
 
Approved by: 
 
 
 
 
 
 
 
 
(Name) 
 
Signature/Date 
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E
APICES
14-nov.-2022
Santiago Martín
APICES
14-nov.-2022
Laura Fuentes
TTCC
Marisa Durán
15-nov.-2022


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 2/28 
Version 1.0: October 21st, 2022 
 
1. HISTORY OF REVISION (Documentation of changes) 
SECTIONS 
VERSION 
DATE REVISED 
REVISED BY 
DESCRIPTION OF CHANGES 
5.3 
0.1 
19-Sep-2022 
Carmen 
Montalbán 
Figure 1 modified 
6.2 
0.1 
19-Sep-2022 
Carmen 
Montalbán 
Variable analysis G8 added. 
ECOG-PS calculation added, 
definition variables modified 
7.1; 7.2; 7.3 
0.1 
19-Sep-2022 
Carmen 
Montalbán 
Definitions added/ modified 
7.4 
0.1 
19-Sep-2022 
Carmen 
Montalbán 
Section added 
9.4 
0.1 
19-Sep-2022 
Carmen 
Montalbán 
New variable added to listing 
9.5 
0.1 
19-Sep-2022 
Carmen 
Montalbán 
Abbreviatures meaning added 
(SOC & PT) 
9.6 
0.1 
19-Sep-2022 
Carmen 
Montalbán 
Section suppressed 
 
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“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 3/28 
Version 1.0: October 21st, 2022 
 
INDEX 
 
1. 
HISTORY OF REVISION (Documentation of changes) ....................................................................... 2 
2. 
INTRODUCTION .................................................................................................................................. 4 
3. 
SYNOPSIS ........................................................................................................................................... 4 
3.1. 
Study title ..................................................................................................................................... 4 
3.2. 
Study Code .................................................................................................................................. 4 
3.3. 
Protocol ........................................................................................................................................ 4 
3.4. 
Sponsor ........................................................................................................................................ 4 
3.5. 
Design and study treatment ......................................................................................................... 4 
3.6. 
Objectives .................................................................................................................................... 7 
3.7. 
Inclusion Criteria .......................................................................................................................... 8 
3.8. 
Exclusion Criteria ....................................................................................................................... 10 
3.9. 
Total number of subjects ............................................................................................................ 12 
4. 
GENERAL CONSIDERATIONS ......................................................................................................... 13 
5. 
STUDY POPULATIONS ..................................................................................................................... 13 
5.1. 
Definition of study populations to analyse ................................................................................. 13 
5.2. 
Study recruitment period ............................................................................................................ 13 
5.3. 
Disposition of subjects ............................................................................................................... 14 
5.4. 
Early withdrawal ......................................................................................................................... 15 
5.5. 
Deaths ........................................................................................................................................ 15 
6. 
SUBJECT DESCRIPTION .................................................................................................................. 15 
6.1. 
Demographic and baseline description. General considerations .............................................. 15 
6.2. 
Subject Characteristics .............................................................................................................. 15 
7. 
TREATMENT ADMINISTRATION ...................................................................................................... 18 
7.1. 
Treatment description. General considerations ......................................................................... 18 
7.2. 
Combination treatment administration ....................................................................................... 18 
7.2.1. 
NIVOTAX arm ........................................................................................................................ 18 
7.2.1.1. 
NIVOTAX dose intensity ........................................................................................................ 19 
7.2.2. 
ERBITAX arm ........................................................................................................................ 20 
7.2.2.1. 
ERBITAX dose intensity ........................................................................................................ 21 
7.2.3. 
End of paclitaxel treatment (combination treatment administration) ..................................... 21 
7.3. 
Monotherapy treatment administration ...................................................................................... 21 
7.3.1. 
NIVOTAX arm ........................................................................................................................ 21 
7.3.1.1. 
NIVOTAX dose intensity ........................................................................................................ 22 
7.3.2. 
ERBITAX arm ........................................................................................................................ 22 
7.3.2.1. 
ERBITAX dose intensity ........................................................................................................ 23 
7.4. 
Post-study anticancer treatments .............................................................................................. 23 
8. 
EFFICACY ASSESSMENT ................................................................................................................ 23 
8.1. 
Primary endpoint ........................................................................................................................ 23 
8.2. 
Secondary endpoints ................................................................................................................. 24 
9. 
SAFETY ASSESSMENT .................................................................................................................... 26 
9.1. 
Safety assessment. General considerations ............................................................................. 26 
9.2. 
Adverse Events .......................................................................................................................... 26 
9.3. 
Adverse Reactions (toxicities) .................................................................................................... 27 
9.4. 
Adverse Events of Special Interest (AESI) ................................................................................ 27 
9.5. 
Serious Adverse Events ............................................................................................................. 28 
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“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 4/28 
Version 1.0: October 21st, 2022 
 
2. INTRODUCTION 
This statistical analysis plan (SAP) describes the final statistical analysis for NIVOTAX study.  
3. SYNOPSIS 
3.1. Study title 
Phase II multicenter randomized trial to assess the efficacy and safety of first line nivolumab in 
combination with paclitaxel in subjects with R/M HNSCC unable for cisplatin-based chemotherapy 
(NIVOTAX). 
3.2. Study Code   
TTCC-2019-01 / CA209-7HE  
3.3. Protocol 
Previous protocol versions / amendments (number and date):  
- 
1.0 dated on November 18th, 2019.  
- 
2.0 dated on March 3rd, 2020.  
- 
3.0 dated on July 10th, 2020.  
Current version (number and date):  
- 
4.0 dated on November 4th, 2021. 
3.4. Sponsor 
Grupo Español de Tratamiento de Tumores de Cabeza y Cuello (TTCC). 
3.5. Design and study treatment  
This is a randomized, open-label, controlled, multicenter, phase II trial to assess the efficacy of nivolumab 
plus paclitaxel for first-line treatment of recurrent or metastatic HNSCC in the platinum ineligible and 
platinum refractory settings.  
Approximately 141 subjects will be randomized to the two treatment arms in a 2:1 ratio (94 in experimental 
arm and 47 in control arm) and stratified by the following factors:  
1. Karnofsky performance status (70% vs 80-100%).  
2. CPS ≥1 vs < 1 (DAKO PD-L1 IHC 22C3) (see annex 12 of protocol v4.0). PD-L1 determination 
(CPS, before patient inclusion) will be performed by a central lab (Pathological Anatomy Service, 
Hospital 12 de Octubre, Madrid, Spain).  
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“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 5/28 
Version 1.0: October 21st, 2022 
 
3. Oropharyngeal cancer: oropharyngeal cancer HPV+ (p16 IHC & HPV DNA) vs oropharyngeal 
cancer HPV–(p16 IHC/ HPV DNA) / non-oropharyngeal cancer).  
 
HPV status of tumor tissue has to be locally determined at screening by any of the following methods: 
p16 IHC, in situ hybridization or polymerase chain reaction-based assay. If HPV status by p16 IHC is 
positive, result confirmation by PCR is mandatory.  
HPV p16 status (OPC), PD-L1 status (CPS) and Karnofsky performance status will be needed prior to 
randomization. Subjects will undergo screening evaluations to determine eligibility prior to randomization.  
Once enrolled in the study, patients will be randomized in a 2:1 ratio to receive:  
 
Arm 1 (experimental): NIVOTAX (Combination of nivolumab + paclitaxel, follow by maintenance 
with nivolumab).  
Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 
80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined 
treatment paclitaxel will be stopped.  
Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last 
administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer 
be administered.  
Nivolumab will be continued alone until disease progression, unacceptable toxicity, or withdrawal of 
consent up to a maximum of 24 months.  
 
- Arm 2 (standard): ERBITAX (Combination of cetuximab + paclitaxel follows by maintenance with 
cetuximab).  
Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion 
weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion.  
After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab 
will be continued alone until disease progression, unacceptable toxicity, or withdrawal of consent up to a 
maximum of 24 months.  
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“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 6/28 
Version 1.0: October 21st, 2022 
 
 
 
 
 
 
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“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 7/28 
Version 1.0: October 21st, 2022 
 
3.6. Objectives 
Primary objective:  
 
Primary objective of this study is to assess the efficacy of nivolumab plus paclitaxel, in terms of two 
years overall survival (OS), for first-line treatment of recurrent or metastatic HNSCC in the platinum 
ineligible and platinum refractory settings.  
OS is defined as the time between the date of randomization and the date of death. For subjects 
without documentation of death, OS will be censored on the last date the subject was known to be 
alive.  
Secondary objectives:  
 
To evaluate the efficacy of Nivolumab with paclitaxel in patients with recurrent or metastatic HNSCC 
in the platinum ineligible and platinum refractory settings by:  
o 
Progression free survival (PFS).  
o 
Overall response rate (ORR) using Response Evaluation Criteria In Solid Tumors (RECIST 
1.1) as determined by investigator criteria.  
o 
Disease control rate (DCR).  
o 
Duration of response (DoR).  
o 
Rate of progressive disease at 6 months.  
o 
Five years Overall Survival (5y-OS).  
 
To evaluate the efficacy of study treatment in patients ≥ 70 years and according to G8 result.  
 
To evaluate efficacy (ORR, PFS, OS) based on: PDL1 expression measured by Combined Positive 
Score (CPS), Presence of Human Papilomavirus (HPV) in Oropharynx Carcinoma (OPC), cisplatin 
refractory, cisplatin ineligibility and Karnofsky Performance Status Scale.  
 
To evaluate safety profile of Nivolumab with paclitaxel by: 
o 
Percentage of patients with AEs.  
o 
Percentage of patients with Grade 3 and Grade 4 AEs.  
o 
Percentage of patients with SAEs.  
o 
Percentage of patients who discontinued due to AEs.  
o 
Percentage of patients with each AE by grade.  
 
 
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“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 8/28 
Version 1.0: October 21st, 2022 
 
3.7. Inclusion Criteria 
Each patient must meet all the following inclusion criteria to be enrolled in the study:  
1. Voluntary written consent must be given before performance of any study-related procedure not 
part of standard medical care.  
2. Histologically confirmed HNSCC (oral cavity, oropharynx, hypopharynx, larynx) not amenable to 
therapy with curative intent (surgery or radiation therapy with or without chemotherapy).  
3. Patients not previously treated for recurrent/metastatic disease.  
4. Radiographically measurable disease as defined by RECIST version 1.1. Previously irradiated 
lesions can only be considered as measurable disease if disease progression according to 
RECIST version 1.1.  
5. Patients unable for cisplatin-based chemotherapy, defined “unable” by:  
a. Karnofsky 70% or  
b. Karnofsky 80-100% and amenable to chemotherapy, but:  
1) Impaired renal function, creatinine clearance >30 mL/min and <80 mL/min GFR could 
be assessed by direct measurement (EDTA or creatinine clearance) if available or by 
calculation from serum or plasma creatinine (see annex 5), or  
2) grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or  
3) Class III heart failure according to the New York Heart Association (annex 9), or  
4) History of allergic reactions to cisplatin, carboplatin, or other platinum-containing 
compounds or  
5) Prior dose of cisplatin ≥225 mg/m² for locally advanced disease (a patient who 
received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with 
cisplatin ≥75/m2) for locally advanced primary HN cancer can be included), or  
6) Disease progression or relapse during or within 6 months of receiving platinum-based 
therapy administered as neoadjuvant, adjuvant therapy or as concomitant 
chemotherapy with radiotherapy and have received at least 200 mg/m2 of cisplatin.  
 
6. Male or female patients aged ≥18 years.  
Patients aged ≥70 years old can only be included with a G8 (Geriatric 8) (see protocol annex 10) 
health status screening score ≥ 14.  
a. Female patients:  
i. 
Are postmenopausal for at least 1 year before the Screening visit, or  
ii. 
Are surgically sterile, or  
iii. 
If they are of childbearing potential, agree to practice one highly effective method of 
contraception and one additional effective (barrier) method, at the same time, from the 
time of signing the informed consent through 180 days after the last dose of study drug, 
or  
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 9/28 
Version 1.0: October 21st, 2022 
 
iv. 
Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be 
used together).  
v. 
Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test within 72 hours prior to the start of study drug.  
vi. 
Women must not be breastfeeding.  
 
b. Male patients, even if surgically sterilized (ie, status postvasectomy), who:  
i. 
Agree to practice effective barrier contraception during the entire study treatment period 
and through 6 months after the last dose of study drug, OR  
ii. 
Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be 
used together). Investigators shall counsel WOCBP and male subjects who are sexually 
active with WOCBP on the importance of pregnancy prevention and the implications of 
an unexpected pregnancy.  
7. Clinical laboratory values as specified below within 28 days before the first dose of study drug:  
a. Total bilirubin must be ≤2 × the upper limit of normal (ULN).  
b. Magnesium ≥ lower limit of normal.  
c. Calcium ≥ lower limit of normal.  
d. ALT and AST must be ≤3 × ULN unless liver metastases are present, in which case they 
must be ≤5x ULN.  
e. Hemoglobin must be ≥9 g/dL, absolute neutrophil count (ANC) must be ≥1.500/μL, WBC 
must be ≥2.000/μL and platelet count must be ≥100.000/μL.  
8. Subjects who have received radiation as primary therapy are eligible if radiation therapy treatment 
was completed > 4 weeks prior to inclusion.  
9. Documentation of PD-L1 status by IHC performed by the central lab at randomization. A pre-
treatment tumor tissue sample should be sent.  
A representative formalin-fixed paraffin-embedded (FFPE) tumor specimen (at least 5mm3 in which 
more than 60% of the sample is tumor) in paraffin block or unstained, freshly cut, serial sections 
(preferably at least 5) from an FFPE tumor specimen, are preferred. A newly obtained biopsy (within 
6 months prior to start of study treatment) is preferred but an archival sample is acceptable, if 
several tumor samples are available, testing should be performed on the most recently obtained 
tumor sample  
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 10/28 
Version 1.0: October 21st, 2022 
 
This specimen should be accompanied by the associated pathology report anonymized. Freshly 
cut, serial sections must have been cut no more than 14 days prior to analysis by central lab. Slides 
that have been cut more than 14 days prior to analysis by central lab should not be used and new 
slides should be made.  
PD-L1 expression determined by using Combined Positive Score (CPS) (see annex 12) before 
patient randomization (DAKO PD-L1 IHC 22C3) will be performed by a central lab (Anatomic 
Pathology Department, Hospital 12 de Octubre, Madrid, Spain).  
10. Documentation of HPV p16 status (OPC) is required for HNSCC tumor of the oropharynx. For 
subjects with oropharyngeal cancer, sites are defined in annex 8. HPV status of tumor tissue has 
to be locally determined at screening by any of the following methods: p16 IHC, in situ hybridization, 
or polymerase chain reaction-based assay. If HPV status by p16 IHC is positive result confirmation 
by PCR is mandatory.  
3.8. Exclusion Criteria 
Patients meeting any of the following exclusion criteria will not to be enrolled in the study:  
1. Male or female patients aged <18 years. Patients aged ≥70 years old should not be included with 
a G8 (Geriatric 8) health status screening score < 14.  
2. Karnofsky <70%.  
3. Patients that meet more than one of the following criteria:  
a. Karnofsky 70%,  
b. Impaired renal function, creatinine clearance >30 mL/min and <80 mL/min GFR could be 
assessed by direct measurement (EDTA or creatinine clearance) if available or by 
calculation from serum or plasma creatinine,  
c. Class III heart failure according to the New York Heart Association.  
4. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy except for 
alopecia, vitiligo, hear loss and the laboratory values defined in the inclusion criteria.  
5. Histologically confirmed squamous cell carcinoma of unknown primary, of the nasopharynx or non-
squamous histologies (eg, mucosal melanoma).  
6. Active brain metastases or leptomeningeal metastases.  
7. Carcinomatous meningitis.  
8. 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.  
9. Diagnosis of immunodeficiency or any condition requiring systemic treatment with either 
corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications 
within 14 days of treatment.  
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 11/28 
Version 1.0: October 21st, 2022 
 
10. History of pneumonitis requiring treatment with steroids; history of idiopathic pulmonary fibrosis, 
drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening 
chest CT scan; history of radiation pneumonitis in the radiation field (fibrosis) is permitted.  
11. Patients with a history of interstitial lung disease cannot be included if they have symptomatic ILD 
(Grade 3-4) and/or poor lung function.  
12. Prior therapy with experimental antitumor vaccines; any T-cell co-stimulation agents or inhibitors of 
checkpoint pathways, such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody; or other agents specifically targeting T cells are prohibited.  
13. Any serious medical or psychiatric illness, including drug or alcohol abuse, that could, in the 
investigator’s opinion, potentially interfere with the completion of treatment according to this 
protocol.  
14. Life-threatening illness unrelated to cancer.  
15. Female patients who are lactating and breast-feeding or a positive serum pregnancy test during 
the screening period.  
16. Systemic anticancer treatment or radiotherapy less than 4 weeks or 5 half-lives, whichever is 
longer, before the first dose of study treatment or not recovered from acute toxic effects from prior 
chemotherapy and radiotherapy.  
17. Prior treatment with investigational agents ≤21 days (≤4 weeks for monoclonal antibodies with 
evidence of PD) or ≤5 their half-lives (whichever is shorter) before the first dose of study treatment. 
A minimum of 10 days should elapse from prior therapy to initiating protocol therapy.  
18. Major surgery within 14 days before the first dose of study drug and not recovered fully from any 
complications from surgery.  
19. Systemic infection requiring IV antibiotic therapy or other serious infection within 14 days before 
the first dose of study drug.  
20. Known human immunodeficiency virus (HIV) positive (testing not required) or known acquired 
immunodeficiency syndrome (AIDS).  
21. Patients with positive test for hepatitis B virus or hepatitis C virus indicating presence of virus, eg, 
Hepatitis B surface antigen (HBsAg) positive, or Hepatitis C antibody (anti-HCV) positive (except if 
HCV-RNA negative).  
22. Active secondary malignancy that requires treatment. 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  
23. Any clinically significant co-morbidities, such as uncontrolled pulmonary disease, known impaired 
cardiac function or clinically significant cardiac disease (specified below), active central nervous 
system disease, active infection, or any other condition that could compromise the patient’s 
participation in the study.  
Patients with any of the following cardiovascular conditions are excluded:  
a. Acute myocardial infarction within 6 months before starting study drug.  
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 12/28 
Version 1.0: October 21st, 2022 
 
b. Evidence of current uncontrolled cardiovascular conditions including cardiac arrhythmias, 
angina, pulmonary hypertension, or electrocardiographic evidence of acute ischemia or 
active conduction system abnormalities.  
c. Friderichia corrected QT interval (QTcF) >450 milliseconds (msec) (men) or >475 msec 
(women) on a 12-lead ECG during the screening period.  
d. Abnormalities on 12-lead ECG including, but not limited to, changes in rhythm and intervals 
that in the opinion of the investigator are considered to be clinically significant.  
24. Patients with history of hypersensitivity reactions to study drugs (nivolumab, cetuximab or 
paclitaxel) or any of their excipients.  
25. Symptomatic peripheral neuropathy of Grade ≥ 2 based on the CTCAE v5.0  
26. Pulmonary embolism, deep vein thrombosis, or other significant thromboembolic event ≤ 8 weeks 
prior to starting the study treatment.  
27. History of severe skin disorder that in the opinion of the investigator may interfere with study 
conduct.  
3.9. Total number of subjects 
Sample size has been calculated based on the primary objective of this clinical trial, to evaluate 2-year 
overall survival.  
Previous studies shown that the two-year OS in patients with recurrent or metastatic head and neck 
squamous cell carcinoma was about 16%. To accept the treatment efficacy, we will assume that the 2-
year OS with nivolumab in combination with weekly paclitaxel will be at least 26%. A sample size of 94 
evaluable patients achieves 80% power at a 0.05 significance level (alpha) to accept the efficacy of 
nivolumab in combination with weekly paclitaxel. An accrual time of 18 months and follow-up time of 24 
months (treatment and follow-up time) have been considered in the sample size calculation. Sample size 
was calculated for the experimental arm. 94 patients will be included in the experimental arm and 47 in 
the control arm. Total sample size is 141 patients. Patients will be randomized in a 2:1 ratio.  
Sample size has been calculated with one-sample survival method. The test statistic for survival 
probability is assumed to be based on the non-parametric estimate of the survival distribution. For median 
survival, a Brookmeyer-Crowley like test assumed*.  
A control group has been included to have a contemporary reference with a profile of patients equal to 
that of the experimental arm.  
* Brookmeyer R and Crowley, JJ. A confidence interval for the median survival time. Biometrics, 38, 29-
41, 1982. 
 
 
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 13/28 
Version 1.0: October 21st, 2022 
 
4. GENERAL CONSIDERATIONS 
The planned analysis specified in this document will be carried out after the database lock approved by the 
Sponsor. 
The statistical analysis will be performed using SPSS software. 
Data will be generally provided with one decimal. In those cases that a greater accuracy is required, as 
much decimals as needed will be provided. 
Adverse events will be codified using MedDRA dictionary (last version available). 
Continuous variables will be described by mean, median, standard deviation, minimum, maximum, Q1 and 
Q3. Categorical variables will be shown as distribution of frequencies and percentage. In case of missing 
data, to calculate percentages, missing values will not be considered for the analysis. In the frequency 
tables, missing data will not be included. The number of missing data will be detailed. No use of any method 
or imputation of data for the handling of missing data is foreseen. 
All results will be provided by treatment arm and global. 
5. STUDY POPULATIONS 
5.1. Definition of study populations to analyse 
The populations used for analysis will include the following: 
Intention-to-treat (ITT) efficacy population: consists of all patients who are randomized will analyse for 
efficacy endpoints. This will be the primary dataset for analysis of study conduct, study population and 
efficacy. 
Safety population: consists of all patients who received at least one dose of the study treatment and had 
at least one valid post baseline safety assessment. 
5.2. Study recruitment period 
 
The date of inclusion of the first and last subject in the study will be provided. 
 
 
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“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 14/28 
Version 1.0: October 21st, 2022 
 
5.3. Disposition of subjects 
 
Figure 1:  Disposition of subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discrepancies between the number of analysed patients and number of recruited patients into the database 
will be described. A list reporting the screening failures per patient and arm will be included. 
The frequency distribution and percentage of patients analysed will be provided by site. 
 
 
Screening failure 
(N= ) 
Assigned to NIVOTAX 
(N= ) 
Recruited patients  
(N= ) 
Assigned to ERBITAX 
(N= ) 
NIVOTAX 
(Treated patients N= ) 
ERBITAX 
(Treated patients N= ) 
NIVOTAX 
Treatment discontinuation (N= ) 
End of Paclitaxel treatment N= 
End of Monotherapy treatment N= 
 
NIVOTAX 
Treatment completed N=  
Treatment ongoing N=  
ERBITAX 
Treatment completed N=  
Treatment ongoing N=  
ERBITAX 
Treatment discontinuation (N= ) 
End of Paclitaxel treatment N= 
End of Monotherapy treatment N= 
 
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 15/28 
Version 1.0: October 21st, 2022 
 
5.4. Early withdrawal  
Number and percentage of patients who discontinued the study and their reasons will be described (End 
of treatment form from the clinical database information). 
A listing will be provided with the following information: Subject ID, arm, site, date, reason, relationship with 
the study drug, description, AE grade (if applicable), last time administered and comments (if applicable).  
5.5. Deaths 
Number and percentage of patients who died during the study and their reasons will be provided. Patients 
who have died due to adverse events or adverse reactions will be described in detail. 
6. SUBJECT DESCRIPTION 
6.1. Demographic and baseline description. General considerations 
The demographic and baseline description will be performed into the ITT population defined in section 5.1.  
6.2. Subject Characteristics 
The following variables will be described: 
a) Baseline characteristics: 
o 
Age (Continuous). 
o 
G8 score (only patients ≥ 70 years). 
o 
Gender (Male, Female). 
o 
Race (Caucasian, Black, Arab, Latin, Asian, Other and specify). 
o 
Weight (Kg) (Continuous). 
o 
Height (cm) (Continuous). 
o 
Serology: 
o 
HBsAg (Negative, Positive, or Not done and the reason) 
o 
HC Ab (Negative, Positive, or Not done and the reason) 
o 
HCV RNA (negative, positive, or not done and the reason) 
o 
Toxic habits:  
o 
Smoking history:  
 
Has the patient ever smoked? (Yes, No, Unknown); if yes: 
 
Average number of cigarettes smoked per day (Continuous). 
 
Number of years (Continuous) 
 
Does the patient currently smoke? (Yes, No, Unknown); if yes: 
 
Average number of cigarettes smoked per day (Continuous). 
o 
Alcohol consumption:  
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 16/28 
Version 1.0: October 21st, 2022 
 
 
Has the patient ever abused alcohol? (Yes, No, Unknown); if yes: 
 
Current, Former, or never. 
 
b) Cancer history: 
o 
Time from initial diagnosis (Continuous): defined as time elapsed between the initial diagnosis 
date and randomization date (months). 
o 
Time from initial diagnosis to metastatic diagnosis (Continuous): defined as time elapsed 
between the initial diagnosis date and the metastatic diagnosis date (months). 
o 
Time from metastatic diagnosis (Continuous): Defined as time elapsed between metastatic 
diagnosis date and randomization date (months). 
o 
Number and percentage of patients whose initial diagnosis was metastatic disease. 
o 
Stage will be described for initial diagnosis:  
 
Stage (0, I, II, III,  IVA, IVB, IVC)  
o 
Karnofsky* (Categorical; 0, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100).  
o 
Karfnosky will be classified as Karnofsky performance status (70% vs 80-100%) and will 
be described (Categorical).  
o 
The equivalence between Karnofsky and ECOG will be calculated, and the variable will be 
described, the following table describes the relation: 
Karnofsky Status 
Karnofsky 
Grade 
ECOG 
Grade 
ECOG Status 
Normal, no complaints  
100 
0 
Fully active, able to carry on all pre-disease 
performance without restriction  
Able to carry on normal activities. 
Minor signs or symptoms of 
disease  
90 
1 
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house 
work, office work  
Normal activity with effort  
80 
1 
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house 
work, office work  
Care for self. Unable to carry on 
normal activity or to do active work  
70 
2 
Ambulatory and capable of all selfcare but 
unable to carry out any work activities. Up 
and about more than 50% of waking hours  
Requires occasional assistance, 
but able to care for most of his 
needs  
60 
2 
Ambulatory and capable of all selfcare but 
unable to carry out any work activities. Up 
and about more than 50% of waking hours  
Requires considerable assistance 
and frequent medical care  
50 
3 
Capable of only limited selfcare, confined to 
bed or chair more than 50% of waking hours  
Disabled. Requires special care 
and assistance  
40 
3 
Capable of only limited selfcare, confined to 
bed or chair more than 50% of waking hours  
Severely disabled. Hospitalisation 
indicated though death non-
imminent  
30 
4 
Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair  
Very sick. Hospitalisation 
necessary. Active supportive 
treatment necessary  
20 
4 
Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair  
Moribund  
10 
4 
Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair  
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 17/28 
Version 1.0: October 21st, 2022 
 
Karnofsky Status 
Karnofsky 
Grade 
ECOG 
Grade 
ECOG Status 
Dead  
0 
5 
Dead  
  
o 
Tumor tissue sample collected prior to study treatment (Yes/No).  
o 
PD-L1 CPS (Continuous).  
o 
PD-L1 CPS will be classified as CPS score ≥1 / <1 and will be described (Categorical)*. 
o 
HNSCC type (Oral cavity, Oropharynx (related or not related HPV), Larynx, Hypopharynx). 
o 
Histology (squamous, other, if other specify). 
o 
Differentiation grade (G1, G2, G3, G4, GX, Not available) 
o 
Type of disease (loco-regional disease, loco-regional disease + M1, Metastatic disease). 
o 
Oropharyngeal cancer** (Yes, No). If affirmative, 
o 
Oropharyngeal cancer HPV – (p16 IHC/HPV DNA)  
o 
Oropharyngeal cancer HPV + (p16 IHC & HPV DNA). 
o 
Unable platinum treatment group***: Group 1 (Platinum-refractory); Group 2 (Platinum-sensitive 
but unable to receive cisplatin); Group 3 (Platinum-sensitive but cumulative cisplatin 
dose≥225mg/m²given for locally-advanced disease) (Categorical). 
 
Note*: Screening visit Karnofsky and PD-L1 variables will be analysed since the information collected on 
the randomization screen is not correct. 
Note**: The information of oropharyngeal and HPV+ and HPV- for the analysis will be provided by the study 
CRA (protocol deviations) since the information collected on the randomization screen is not correct. 
Definition (randomization screen information) ***: 
Group 1: Platinum resistant population: Patients who have experienced disease progression or relapse 
during or within 6 months of receiving platinum-based therapy administered as neoadjuvant, adjuvant 
therapy or as concomitant chemotherapy with radiotherapy and have received at least 200 mg/m2 of 
cisplatin.  
Group 2: Platinum sensitive but unable for cisplatin-based therapy according to one of these criteria:  
1. Karnofsky grade 70% or  
2. Impaired renal function, creatinine clearance >30 Ml/min and <80 Ml/min GFR could be 
assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation 
from serum or plasma creatinine, or  
3. Class III heart failure according to the New York Heart Association (see annex 9 of protocol 
v4.0), or  
4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or  
5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.  
 
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 18/28 
Version 1.0: October 21st, 2022 
 
If the patient meets more than one of the first three criteria, the patient cannot be included in the 
study. (Criteria 1, 2 and 3 cannot coincide in the same patient; criteria 4 and 5 can go alone or in 
combination with any other).  
Group 3: Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (a 
patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin 
≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the 
start of first line treatment for R/M disease is >6 months.  
c) Locations:  
 
The analysis of target and non-target baseline lesions will be performed together.  
It will be considered affected location when the patient presents at least one lesion in one organ or system, 
regardless of the number of lesions in the organ or system. It will be provided: 
 
The number and percentage of patients with each affected location (Categorical). 
 
The number and percentage of patients by number of affected locations (Categorical). 
 
7. TREATMENT ADMINISTRATION 
7.1. Treatment description. General considerations 
Treatment description will be performed for ITT efficacy population defined in section 5.1.  
It will be described the number of administrations received  by study drug in each study phase (combination 
and monotherapy) and considering both phases together. 
7.2. Combination treatment administration  
It will be described the number of patients who received the complete pattern of 12 administrations of 
combination treatment phase in each study drug by the number and percentage by treatment arm. 
7.2.1. NIVOTAX arm 
 
The following data will be described for nivolumab: 
 
Delay administration (Yes, No): If yes: 
o 
Number and percentage of patients by the no. of delayed doses (Categorical). 
o 
Reasons for dose delay (Categorical). 
o 
Total number of weeks with dose delay and percentage regarding total weeks with 
administration (Categorical). 
 
No administered treatment (Yes, No): If dose no administered: 
o 
Number and percentage of patients by the no. of no administered doses (Categorical). 
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 19/28 
Version 1.0: October 21st, 2022 
 
o 
Reasons for no administration (Categorical). 
o 
Total number of weeks no administered and percentage regarding total weeks with 
administration (Categorical). 
The following data will be described for paclitaxel: 
 
Dose reductions (Yes, No): If yes: 
o 
Number and percentage of patients by the no. of reductions (Categorical). 
o 
Reasons for dose reduction (Categorical). 
o 
Total number of weeks with dose reduction and percentage regarding total weeks with 
administration (Categorical). 
 
Delay administration (Yes, No): If yes: 
o 
Number and percentage of patients by the no. of delayed doses (Categorical). 
o 
Reasons for dose delay (Categorical). 
o 
Total number of weeks with dose delay and percentage regarding total weeks with 
administration (Categorical). 
 
No administered treatment (Yes, No): If dose no administered: 
o 
Number and percentage of patients by the no. of no administered doses (Categorical). 
o 
Reasons for no administration (Categorical). 
o 
Total number of weeks no administered and percentage regarding total weeks total 
weeks with administration (Categorical). 
The NIVOTAX treatment time will be defined as the elapsed time, in weeks, between the date of first 
administered week and the end of combination treatment date. The NIVOTAX treatment will be described 
as continuous variable. 
It will be described the number of administrations received by study drug separately and additionally the 
combination: nivolumab, paclitaxel and nivolumab + paclitaxel. 
7.2.1.1. 
NIVOTAX dose intensity 
Dose intensity will be defined as the total dose of nivolumab or paclitaxel (separately) received by the 
patient with respect to the NIVOTAX treatment time. 
The relative dose intensity will be defined as the total dose of nivolumab or paclitaxel received by the patient 
in relation to the theoretical total dose that patient should had received per protocol during Nivotax treatment 
time. 
The dose intensity and relative dose intensity will be described as continuous variables. 
 
 
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 20/28 
Version 1.0: October 21st, 2022 
 
7.2.2. ERBITAX arm 
 
The following data will be described for cetuximab: 
 
Dose reductions (Yes, No): If yes: 
o 
Number and percentage of patients by the no. of reductions (Categorical). 
o 
Reasons for dose reduction (Categorical). 
o 
Total number of weeks with dose reduction and regarding total weeks with 
administration (Categorical). 
 
Delay administration (Yes, No): If yes: 
o 
Number and percentage of patients by the no. of delayed doses (Categorical). 
o 
Reasons for dose delay (Categorical). 
o 
Total number of weeks with dose delay and percentage regarding total weeks with 
administration (Categorical). 
 
No administered treatment (Yes, No): If dose no administered: 
o 
Number and percentage of patients by the no. of no administered doses (Categorical). 
o 
Reasons for no administration (Categorical). 
o 
Total number of weeks no administered and percentage regarding total weeks with 
administration (Categorical). 
 
The following data will be described for paclitaxel: 
 
Dose reductions (Yes, No): If yes: 
o 
Number and percentage of patients by the no. of reductions (Categorical). 
o 
Reasons for dose reduction (Categorical). 
o 
Total number of weeks with dose reduction and percentage regarding total weeks with 
administration (Categorical). 
 
Delay administration (Yes, No): If yes: 
o 
Number and percentage of patients by the no. of delayed doses (Categorical). 
o 
Reasons for dose delay (Categorical). 
o 
Total number of weeks with dose delay and percentage regarding total weeks with 
administration (Categorical). 
 
No administered treatment (Yes, No): If dose no administered: 
o 
Number and percentage of patients by the no. no of administered dose (Categorical). 
o 
Reasons for no administration (Categorical). 
o 
Total number of weeks no administered and percentage regarding total weeks with 
administration (Categorical). 
 
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 21/28 
Version 1.0: October 21st, 2022 
 
The ERBITAX treatment time will be defined as the elapsed time, in weeks, between the date of first 
administered week and the end of combination treatment date. The ERBITAX treatment will be described 
as continuous variable. 
It will be described the number of administrations received by study drug separately and additionally the 
combination: cetuximab, paclitaxel and cetuximab + paclitaxel. 
7.2.2.1. 
ERBITAX dose intensity 
Dose intensity will be defined as the total dose of cetuximab, or paclitaxel (separately) received by the 
patient with respect to the Erbitax treatment time. 
The relative dose intensity will be defined as the total dose of cetuximab, or paclitaxel received by the 
patient in relation to the theoretical total dose that patient should had received per protocol during treatment 
time. 
The dose intensity and relative dose intensity will be described as continuous variables. 
7.2.3. End of paclitaxel treatment (combination treatment administration) 
Number and percentage of patients who discontinued paclitaxel treatment and their reasons will be 
described by treatment arm. 
A listing will be provided with the following information: subject ID, arm, site, date, reason, relationship with 
the study drug, description, AE grade (if applicable), last time administered and comments (if applicable).  
7.3. Monotherapy treatment administration  
The number and percentage of patients who continued study treatment will be provided by treatment arm. 
7.3.1. NIVOTAX arm 
The following data will be described for nivolumab: 
 
Delay administration (Yes, No): If yes: 
o 
Number and percentage of patients by the no. of delayed doses (Categorical). 
o 
Reasons for dose delay (Categorical). 
o 
Total number of administrations with dose delay and percentage regarding total 
administrations (Categorical). 
 
No administered treatment (Yes, No): If no administered: 
o 
Number and percentage of patients by the no. of no administered dose (Categorical). 
o 
Reasons for no administration (Categorical). 
o 
Total number of no administrations and percentage regarding total administrations 
(Categorical). 
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 22/28 
Version 1.0: October 21st, 2022 
 
The monotherapy Nivolumab treatment time will be defined as the elapsed time, in weeks, between the 
date of first monotherapy administration and the end of monotherapy treatment date (end of treatment 
form). The monotherapy nivolumab treatment will be described as continuous variable. 
It will be described the number of nivolumab administrations received during monotherapy phase. 
7.3.1.1. 
NIVOTAX dose intensity 
Dose intensity will be defined as the total dose of Nivolumab received by the patient with respect to the 
nivolumab monotherapy treatment time. 
The relative dose intensity will be defined as the total dose of Nivolumab received by the patient in relation 
to the theoretical total dose that patient should had received per protocol during treatment time.  
The dose intensity and relative dose intensity will be described as continuous variables. 
7.3.2. ERBITAX arm 
The following data will be described for cetuximab: 
 
Dose reductions (Yes, No): If yes: 
o 
Number and percentage of patients by the no. of reductions (Categorical). 
o 
Reasons for dose reduction (Categorical). 
o 
Total number of administrations with dose reduction and percentage regarding total 
administrations (Categorical). 
 
Delay administration (Yes, No): If yes: 
o 
Number and percentage of patients by the no. of delayed doses (Categorical). 
o 
Reasons for dose delay (Categorical). 
o 
Total number of administrations with dose delay and percentage regarding total 
administrations (Categorical). 
 
No administered treatment (Yes, No): If no administered: 
o 
Number and percentage of patients by the no. of no administered dose (Categorical). 
o 
Reasons for no administration (Categorical). 
o 
Total number of no administrations and percentage regarding total administrations 
(Categorical). 
The monotherapy cetuximab treatment time will be defined as the elapsed time, in weeks, between the 
date of first monotherapy administered week and the end of monotherapy treatment date (end of treatment 
form). The monotherapy cetuximab treatment will be described as continuous variable. 
It will be described the number of cetuximab administrations received during monotherapy phase. 
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 23/28 
Version 1.0: October 21st, 2022 
 
7.3.2.1. 
ERBITAX dose intensity 
Dose intensity will be defined as the total dose of cetuximab received by the patient with respect to the 
cetuximab monotherapy treatment time. 
The relative dose intensity will be defined as the total dose of cetuximab received by the patient in relation 
to the theoretical total dose that patient should had received per protocol during treatment time. 
The dose intensity and relative dose intensity will be described as continuous variables. 
 
7.4. Post-study anticancer treatments 
It will be described the number and percentage of patients who received post-study treatments by treatment 
arm.  
All post-study anticancer treatments will be classified in immunotherapies (alone or combination), 
cetuximab-based and chemotherapy-based. The description on classified post-study treatments will be 
provided by treatment arm. 
Additionally, the subgroup of patients who withdrawn study treatment due to progression (described in 
section 5.4 Early withdrawal) will be describe the post-study treatment by treatment arm. 
 
8. EFFICACY ASSESSMENT 
Efficacy assessment will be performed for ITT efficacy population defined in section 5.1. 
Time-to-event variables will be analyzed according to the Kaplan-Meier method. Kaplan-Meier survival 
curves, median, 95% CI, number of events and censored and number of patients at risk will be presented.  
ORR and DCR will be  provided by treatment arm using RECIST criteria v1.1. 
8.1. 
Primary endpoint 
 
Primary objective of this study is to assess the efficacy of nivolumab plus paclitaxel, in terms of two years 
Overall Survival (OS), for first-line treatment of recurrent or metastatic HNSCC in the platinum ineligible 
and platinum refractory settings.  
OS is defined as the time (in months) between the date of randomization and the date of death. For subjects 
without documentation of death, OS will be censored on the last date in which the subject was known to be 
alive.  
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 24/28 
Version 1.0: October 21st, 2022 
 
OS in each treatment arm will be estimated using KM method. Kaplan-Meier survival curves, median, 95% 
CI, number of events and censored and number of patients at risk will be presented. OS rates at 2 and 5 
years and 95%CI will be estimated for each treatment arm. 
OS in each treatment arm will be evaluated in the following groups: 
 
CPS score ≥1 vs <1.  
 
Oropharyngeal cancer HPV - (p16 IHC/HPV DNA) vs Oropharyngeal cancer HPV + (p16 IHC 
& HPV DNA). 
 
Karnofsky performance status (70% vs 80-100%). 
 
Group 1 vs Group 2 vs Group 3 (Unable platinum treatment group). 
 
Patients < 70 years vs ≥ 70 years. 
Cox regression models will be used to calculate the risk reduction. Hazard ratio (HR) with 95% CIs will be 
reported to evaluate the impact of treatment arm and stratification variables: CPS (≥1vs <1), HPV (positive 
vs negative) and Karnofsky PS (70% vs 80-100%). Individual and general Cox regression models will be 
calculated. 
8.2. 
Secondary endpoints 
Progression free survival (PFS): PFS will be defined as the time (in months) from randomization to the 
date of first documented disease progression, as assessed by the investigator using RECIST 1.1 criteria, 
or death due to any cause, whichever occurs first. Subjects who died without a reported progression will be 
considered to have progressed on the date of their death. Subjects who did not progress or die will be 
censored on the date of their last evaluable tumor assessment. Subjects who did not have any on study 
tumor assessments and did not die will be censored on the date they were randomized. Subjects who 
started any subsequent anti-cancer therapy without a prior reported progression will be censored at the last 
evaluable tumor assessment prior to/on initiation of the subsequent anti-cancer therapy.  
PFS in each treatment arm will be estimated using KM method. Kaplan-Meier survival curves, median, 95% 
CI, number of events and censored and number of patients at risk will be presented. PFS rates at 6 months 
and 2 years and 95%CI will be estimated for each treatment arm. 
PFS in each treatment arm will be evaluated in the following groups: 
 
CPS score ≥1 vs <1.  
 
Oropharyngeal cancer HPV - (p16 IHC/HPV DNA) vs Oropharyngeal cancer HPV + (p16 IHC 
& HPV DNA). 
 
Karnofsky performance status (70% vs 80-100%). 
 
Group 1 vs Group 2 vs Group 3 (Unable platinum treatment group). 
 
Patients < 70 years vs ≥ 70 years. 
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 25/28 
Version 1.0: October 21st, 2022 
 
Cox regression models will be used to calculate the risk reduction. Hazard ratio (HR) with 95% CIs will be 
reported to evaluate the impact of treatment arm and stratification variables: CPS (≥1vs <1), HPV (positive 
vs negative) and Karnofsky PS (70% vs 80-100%). Individual and general Cox regression models will be 
calculated. 
 
Overall Response Rate (ORR): ORR is defined as the number of subjects with a best overall response 
(BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized subjects 
for each treatment group. The BOR is defined as the best response designation, as determined investigator 
assessment, recorded between the date of randomization and the date of progression, as assessed by 
investigator per RECIST 1.1, or the date of subsequent anticancer therapy, whichever occurs first. For 
subjects without evidence of RECIST 1.1 progression or subsequent anticancer therapy, all available 
response designations will contribute to the BOR assessment. For subjects who continue treatment beyond 
progression, the BOR will be determined based on response designations up to the time of initial RECIST 
1.1 progression. 
 
Number and percentage of ORR will be provided by treatment arm, along with associated 95% confident 
interval. 
 
ORR in each treatment arm will be evaluated in the following groups: 
 
CPS score ≥1 vs <1.  
 
Oropharyngeal cancer HPV - (p16 IHC/HPV DNA) vs Oropharyngeal cancer HPV + (p16 IHC 
& HPV DNA). 
 
Karnofsky performance status (70% vs 80-100%). 
 
Group 1 vs Group 2 vs Group 3 (Unable platinum treatment group). 
 
Patients < 70 years vs ≥ 70 years. 
Disease control rate (DCR): DCR is defined as the number of subjects with a best overall response (BOR) 
of a complete response (CR), partial response (PR) or stable disease (SD) divided by the number of 
randomized subjects for each treatment group.  
Description of DCR will be provided by treatment arm, along with associated 95 % confident interval. 
Duration of Response (DoR): DoR is defined as the time between the date of first confirmed response to 
the date of the first documented tumor progression (per RECIST 1.1), or death due to any cause, whichever 
occurs first. Subjects who neither progress nor die will be censored on the date of their last evaluable tumor 
assessment. Subjects who started any subsequent anti-cancer therapy without a prior reported progression 
will be censored at the last evaluable tumor assessment prior to or on initiation of the subsequent anti-
cancer therapy. DoR will be evaluated for responders (confirmed CR or PR) only.  
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 26/28 
Version 1.0: October 21st, 2022 
 
DoR in each treatment arm will be estimated using KM method for all randomized subjects. Kaplan-Meier 
survival curves, median, 95% CI, number of events and censored and number of patients at risk will be 
presented. 
Rate of progressive disease (PD) at 6 months: Rate of PD is defined as the number of subjects with PD 
at 6 months divided by the number of randomized subjects for each treatment group.  
Description of rate of PD will be provided by treatment arm, along with associated 95% confident interval. 
 
9. SAFETY ASSESSMENT 
9.1. 
Safety assessment. General considerations 
The assessment will be performed for safety population defined in section 5.1. Adverse events will be 
evaluated according to NCI CTCAE vs 5.0 criteria. Adverse events will be coded by the latest available 
version of MedDRA dictionary. AEs will be evaluated with the MedDRA code by system organ class (SOC) 
and preferred term (PT). 
The analysis will be performed with the information completed into the adverse event eCRF section. 
The analysis of adverse events will be performed per patient, for that the maximum grade for each adverse 
event completed of each patient will be calculated. 
All safety sections detailed below (9.1.1 and 9.1.2) will be analyzed for the following subgroups separately: 
 
Combination treatment: 
o 
NIVOTAX  
o 
ERBITAX 
 
Monotherapy treatment: 
o 
NIVOTAX 
o 
ERBITAX 
 
Complete treatment (combination + monotherapy): 
o 
NIVOTAX 
o 
ERBITAX 
9.2. 
Adverse Events 
All adverse events evaluated will be described. The analysis of AEs will be described the following: 
 
The number and percentage of patients with at least one adverse event. 
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 27/28 
Version 1.0: October 21st, 2022 
 
 
The number and percentage of patients with each adverse event by grade, grades 3+4 and grades 
3+4+5 aggrupation. 
 
The number and percentage of patients who discontinued due to AEs. 
9.3. 
Adverse Reactions (toxicities) 
All adverse event indicated as related with any study treatment drug in the eCRF adverse event section will 
be considered. The analysis of toxicities will be provided: 
 
The number and percentage of patients with at least one toxicity. 
 
The number and percentage of patients with each toxicity by grade, grades 3+4 and grades 3+4+5 
aggrupation. 
These analyses will be performed separately for each study drug and according to section 9.1. 
9.4. 
Adverse Events of Special Interest (AESI) 
The AESIs were defined as Nivolumab Immune-mediated AEs (IMAE) and is only applicable in NIVOTAX 
arm defined in protocol section 11.3.6 Immune-mediated adverse events. the analysis of AESIs will be 
performed with the information collected into the Pharmacovigilance database. AESIs listing will be 
provided the following information: 
 
Site. 
 
Subject ID. 
 
AE description. 
 
Grade (1-5) NCI CTC AE v5.0. 
 
Start date. 
 
End date. 
 
Action taken 
Additionally, the analysis of AESIs will be provided: 
 
The number and percentage of patients with at least one AESI. 
 
The number and percentage of patients with each AESI by grade, grades 3+4 and grades 3+4+5 
aggrupation. 
 
 
 
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


“Phase II multicenter randomized trial to assess the efficacy 
and safety of first line nivolumab in combination with paclitaxel 
in subjects with R/M HNSCC unable for cisplatin-based 
chemotherapy (NIVOTAX)” 
 
 
NIVOTAX Study 
APICES Project No.: TTC277007 
STP-703-E1 Statistical Analysis Plan Rev02.3 
 
                                     Page 28/28 
Version 1.0: October 21st, 2022 
 
9.5. 
Serious Adverse Events  
Serious adverse events listing will be provided the following information: 
 
Site. 
 
Subject ID. 
 
Arm. 
 
SOC (System Organ Class). 
 
PT (Preferred Term). 
 
AE description. 
 
Grade (1-5) NCI CTC AE v5.0. 
 
Seriousness criteria. 
 
Resolution. 
 
Relation. 
 
Serious adverse events analysis includes the following: 
 
The number and percentage of patients with at least one serious adverse event by arm. 
 
The number and percentage of patients with each serious adverse event by grade and arm. 
 
 
 
 
DocuSign Envelope ID: C471B839-966E-4B95-B049-62A32C47B15E


Certificado de finalización
Identificador del sobre: C471B839966E4B95B04962A32C47B15E
Estado: Completado
Asunto: Complete with DocuSign: TTC277007(NIVOTAX)_StatisticalAnalysisPlan_VF1.0_20221021.docx
Sobre de origen: 
Páginas del documento: 28
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Susana Vara
Firma guiada: Activado
Sello del identificador del sobre: Activado
Zona horaria: (UTC+01:00) Bruselas, Copenhague, Madrid, París
APICES SOLUCIONES, S.L.
Av Antonio Lopez 16 - 1°A
PINTO, Madrid  28320
susana.vara@apices.es
Dirección IP: 83.33.49.201   
Seguimiento de registro
Estado: Original
             14 de noviembre de 2022 | 13:16
Titular: Susana Vara
             susana.vara@apices.es
Ubicación: DocuSign
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Santiago Martín
santiago.martin@apices.es
DM
APICES
Nivel de seguridad: Correo electrónico, 
Autenticación de cuenta (ninguna)
Adopción de firma: Estilo preseleccionado
Utilizando dirección IP: 46.25.253.163
Enviado: 14 de noviembre de 2022 | 13:19
Visto: 14 de noviembre de 2022 | 13:20 
Firmado: 14 de noviembre de 2022 | 13:20
Información sobre confidencialidad de registros y firmas electrónicos: 
      No ofrecido a través de DocuSign
Laura Fuentes
laura.fuentes@apices.es
PROJECT MANAGER
APICES
Nivel de seguridad: Correo electrónico, 
Autenticación de cuenta (ninguna)
Adopción de firma: Estilo preseleccionado
Utilizando dirección IP: 77.211.4.234
Enviado: 14 de noviembre de 2022 | 13:21
Visto: 14 de noviembre de 2022 | 13:22 
Firmado: 14 de noviembre de 2022 | 13:22
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      No ofrecido a través de DocuSign
Marisa Durán
mduran@ttccgrupo.com
TTCC
Nivel de seguridad: Correo electrónico, 
Autenticación de cuenta (ninguna)
Adopción de firma: Estilo preseleccionado
Utilizando dirección IP: 2.138.93.30
Enviado: 14 de noviembre de 2022 | 13:22
Reenviado: 15 de noviembre de 2022 | 09:27
Visto: 15 de noviembre de 2022 | 09:28 
Firmado: 15 de noviembre de 2022 | 09:28
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      No ofrecido a través de DocuSign
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