Vaccination Against cOvid In CancEr
Phase: NA
Conditions: Cancer
Sponsor: University Medical Center Groningen

NL76095.042.20 / VOICE 
 
 
 
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Vaccination against cOvid In CancEr 
(December 2021) 
 
 
 
 
 
 
 
 
 
 
 

NL76095.042.20 / VOICE 
 
 
 
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PROTOCOL TITLE: VOICE Vaccination against cOvid In CancEr 
 
Protocol ID 
Will be submitted to ClinicalTrials.gov. 
Short title 
VOICE 
Version 
6.0 
Date 
27 December 2021 
Project leader 
 
E.G.E. de Vries, MD, PhD, medical oncologist          
Department of Medical Oncology 
University Medical Center Groningen 
E-mail: e.g.e.de.vries@umcg.nl 
Principal 
investigator(s) 
(in 
Dutch: 
hoofdonderzoeker/ 
uitvoerder) 
A.A.M. van der Veldt, MD, PhD, medical oncologist        
Departments of Medical Oncology and Radiology & 
Nuclear Medicine  
Erasmus MC-Cancer Institute, Rotterdam 
E-mail: a.vanderveldt@erasmusmc.nl 
 
J.B.A.G. Haanen, MD, PhD, medical oncologist          
Department of Medical Oncology,  
Netherlands Cancer Institute – Antoni van 
Leeuwenhoek Hospital, Amsterdam 
E-mail: j.haanen@nki.nl 
 
S.F. Oosting, MD, PhD, medical oncologist          
Department of Medical Oncology 
University Medical Center Groningen 
E-mail: s.oosting@umcg.nl 
Writing committee / Investigators 
VOICE Consortium 
UMCG, Groningen 
D. van Baarle, PhD, immunologist                   
Department of Medical Microbiology and Infection 
Prevention                                                                       
E-mail: d.van.baarle@umcg.nl 
 
 

NL76095.042.20 / VOICE 
 
 
 
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M. Jalving, MD, PhD, medical oncologist         
Department of Medical Oncology                                    
E-mail: m.jalving@umcg.nl 
 
R.S.N. Fehrmann, MD, PhD, medical oncologist    
Department of Medical Oncology                                    
E-mail: r.s.n.fehrmann@umcg.nl 
 
T.J.N. Hiltermann, MD, PhD, pulmonologist   
Department of Pulmonary Diseases                               
E-Mail: t.j.n.hiltermann@umcg.nl 
 
Erasmus MC, Rotterdam                                              
C. Geurts van Kessel, PhD, clinical virologist 
Department of Viroscience                                            
E-mail: c.geurtsvankessel@erasmusmc.nl 
 
M.P.G. Koopmans, PhD, virologist                   
Department of Viroscience                                              
E-mail: m.koopmans@erasmusmc.nl 
 
A.C. Dingemans, MD, PhD, pulmonologist 
Department of Respiratory Medicine                              
E-mail: a.dingemans@erasmusmc.nl 
 
NKI-AvL, Amsterdam 
P. Kvistborg, PhD, scientist                              
Department of Molecular Oncology and Immunology 
E-mail: p.kvistborg@nki.nl 
 

NL76095.042.20 / VOICE 
 
 
 
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C.U. Blank, MD, PhD, medical oncologist       
Department of Medical Oncology                                   
E-mail: c.blank@nki.nl 
 
E.F. Smit, MD, PhD, pulmonologist                  
Department of Thoracic Oncology                                 
E-mail: e.smit@nki.nl 
 
RIVM National Institute for Public Health and the 
Environment 
 
C.A.C.M. van Els, PhD, vaccinologist                             
E-mail: cecile.van.els@rivm.nl 
 
N.Y. Rots, PhD, scientific advisor                                    
E-mail: nynke.rots@rivm.nl 
 
Sponsor 
(in 
Dutch: 
verrichter/opdrachtgever) 
University Medical Center Groningen 
Hanzeplein 1 
9713 GB Groningen 
The Netherlands 
Subsidizing party 
ZonMW 
Independent expert 
G.A. Huls, MD PhD                                         
Department of Hematology                                 
University Medical Center Groningen                              
E-mail: g.huls@umcg.nl 
Laboratory sites  
Fiona van der Klis, Center for Infectious Disease 
Control, RIVM 
Debbie van Baarle, 
Medical Microbiology and 
Infection Prevention, UMCG 
Corine Geurts van Kessel, Department Viroscience, 
Erasmus MC 

NL76095.042.20 / VOICE 
 
 
 
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Pia Kvistborg, Department of Molecular Oncology and 
Immunology, NKI-AvL 
D. van den Broek PhD, Head Clinical Laboratory, NKI-
AVL. E-mail: d.vd.broek@nki.nl 

NL76095.042.20 / VOICE 
 
 
 
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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
J.A. Gietema, MD, PhD 
 
 
 
Project leader: 
E.G.E. de Vries, MD, PhD 
 
 
 
 
 

NL76095.042.20 / VOICE 
 
 
 
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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................13 
2. 
OBJECTIVES ................................................................................................................18 
3. 
STUDY DESIGN ...........................................................................................................19 
4. 
STUDY POPULATION ..................................................................................................20 
4.1 
Population (base) ...................................................................................................20 
4.2 
Inclusion criteria .....................................................................................................20 
4.3 
Exclusion criteria ....................................................................................................21 
4.4 
Sample size calculation ..........................................................................................22 
5. 
TREATMENT OF SUBJECTS .......................................................................................23 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................24 
7. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................24 
8. 
METHODS ....................................................................................................................24 
8.1 
Study parameters/endpoints ...................................................................................24 
8.1.1 
Main study parameter/endpoint .......................................................................24 
8.1.2 
Secondary study parameters/endpoints ..........................................................24 
8.1.3 
Exploratory study parameters ..........................................................................25 
8.2 
Randomization, blinding and treatment allocation ..................................................25 
8.3 
Study procedures ...................................................................................................25 
8.4 
Withdrawal of individual subjects ............................................................................27 
8.4.1 
Specific criteria for withdrawal (if applicable) ...................................................27 
8.5 
Replacement of individual subjects after withdrawal ...............................................28 
8.6 
Follow-up of subjects withdrawn from treatment .....................................................28 
8.7 
Premature termination of the study .........................................................................28 
9. 
SAFETY REPORTING ..................................................................................................28 
9.1 
Temporary halt for reasons of subject safety ..........................................................28 
9.2 
AEs, AESIs and SUSARs .......................................................................................28 
9.2.1 
Adverse events (AEs) ......................................................................................28 
9.2.2 
Serious Adverse events (AEs) .........................................................................28 
9.2.3 
Adverse events of special interest (AESIs) ......................................................29 
9.2.4 
Immune related adverse events (irAEs)...........................................................30 
9.2.5 
Suspected unexpected serious adverse reactions (SUSARs) .........................30 
9.3 
Annual safety report ...............................................................................................31 
9.4 
Follow-up of AEs ....................................................................................................32 
10. 
STATISTICAL ANALYSIS ..........................................................................................32 
10.1 
Primary study parameter ........................................................................................32 
10.2 
Secondary study parameters ..................................................................................33 
10.3 
Other study parameters ..........................................................................................34 
10.4 
Interim analysis (if applicable) ................................................................................35 
11. 
ETHICAL CONSIDERATIONS ...................................................................................36 
11.1 
Regulation statement .............................................................................................36 
11.2 
Recruitment and consent........................................................................................36 

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11.3 
Objection by minors or incapacitated subjects ........................................................37 
11.4 
Benefits and risks assessment, group relatedness .................................................37 
11.5 
Incentives (if applicable) .........................................................................................38 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................38 
12.1 
Handling and storage of data and documents ........................................................38 
12.2 
Monitoring and Quality Assurance ..........................................................................39 
12.3 
Amendments ..........................................................................................................39 
12.4 
Annual progress report ...........................................................................................40 
12.5 
Temporary halt and (prematurely) end of study report ............................................40 
12.6 
Public disclosure and publication policy ..................................................................40 
13. 
STRUCTURED RISK ANALYSIS...............................................................................40 
14. 
REFERENCES ..........................................................................................................42 
 
Appendix 1: Toxicity grading scale for solicited systemic and local adverse events .............. 46 
 
Appendix 2: Adverse events of special interest..................................................................... 47 
 
Appendix 3: ECOG performance status ................................................................................ 48 
 
Appendix 4: Summary of product characteristics  ................................................................. 49 

 
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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALAT 
Alanine aminotransferase 
ASAT 
Aspartate aminotransferase 
CBG 
College ter Beoordeling van Geneesmiddelen 
CBS 
Centraal Bureau voor de Statistiek 
CI 
Confidence Interval 
COVID-19 Coronavirus Disease 2019 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board 
ECOG PS Eastern Cooperative Oncology Group Performance Status 
EMA 
European Medicines Agency 
EU 
European Union 
GBA 
Gemeentelijke Basis Administratie 
GCP 
Good Clinical Practice 
GMC 
Geometric Mean Concentration 
IC 
Informed Consent 
ICI 
Immune Checkpoint Inhibitor 
IKNL 
Integraal Kankercentrum Nederland 
IFN-ɣ 
Interferon-gamma 
irAE 
immune related Adverse Event 
IST 
Investigator Sponsored Trial 
METC  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
MIA 
Multiplex Immunoassay 
NIBSC 
National Institute for Biological Standards and Control 
PBMC 
Peripheral Blood Mononuclear Cells 
PD1 
Programmed Death 1 (immune checkpoint) 
PD-L1 
Programmed Death-ligand 1 (immune checkpoint) 
PIF 
Participant Information Form 
(S)AE 
(Serious) Adverse Event  
SARS-
CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SPC 
Summary of Product Characteristics; in Dutch: officiële productinformatie 

 
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IB1-tekst 
Sponsor 
The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A 
party that provides funding for a study but does not commission it is not 
regarded as the sponsor, but referred to as a subsidising party. 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
WHO 
World Health Organization 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

 
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SUMMARY 
 
Rationale: Patients with cancer have an increased risk of adverse outcome of COVID-19, 
which is determined by their underlying disease and/or cancer treatment. Therefore, 
vaccination of cancer patients against COVID-19 is recommended. However, phase III 
studies do not provide robust information on efficacy and safety in this vulnerable population. 
In patients with cancer, the disease itself, but also immunotherapy and chemotherapy, may 
have a significant impact on the ability to develop an effective immune response to COVID-
19 vaccination, and could even increase the risk of adverse events. 
 
Objective: To assess immune response and adverse events after administration of one 
approved vaccine against COVID-19 in patients with cancer treated with immunotherapy 
and/or chemotherapy. 
 
Study design: This is a prospective multicenter, multicohort study. 
 
Study population: Four cohorts will receive vaccination against COVID-19:  
A. Individuals without cancer (N=246, i.e., partners of patients in cohort B, C, and D) 
B. Patients with cancer treated with immunotherapy (N=135) 
C. Patients with cancer treated with chemotherapy (N=246) 
D. Patients with cancer treated with chemo-immunotherapy (N=246) 
Main inclusion criteria: 
- age of 18 years or older 
- life expectancy > 12 months 
- ability to provide informed consent 
- last immunotherapy cycle within 3 months of vaccination (cohort B and D) 
- last chemotherapy cycle within 4 weeks of vaccination (cohort C and D) 
Main exclusion criteria: 
- confirmed SARS-CoV-2 infection (current or previous)  
- women who are pregnant or breastfeeding 
- active hematologic malignancy     
- immune deficiency not related to cancer or cancer treatment   
- systemic treatment with immune suppressive medication, including chronic steroid use of 
>10 mg prednisone or equivalent 
 

 
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Intervention: Participants will be vaccinated against COVID-19 with an approved vaccine. 
Blood will be drawn at different time points by venipuncture and mucosal lining fluid will be 
collected at 2 time points.  
 
Main study parameters/endpoints: The primary endpoint is the antibody based immune 
response on day 28 after the second vaccination. Participants will be classified as 
responders or non-responders. The definition of response is seroconversion defined as 
presence of SARS-CoV-2 spike S1-specific IgG antibodies in individuals without measurable 
anti-S antibodies at baseline.  Participants who are seropositive at baseline will not be 
included in the analysis of the primary endpoint. The percentage of responders of each 
patient cohort will be compared with the percentage responders in the control group. Safety 
is a secondary endpoint which will be reported in terms of percentage of solicited local and 
systemic adverse events (AEs) graded according to severity. Other secondary endpoints 
include longevity at 6 months and levels of SARS-CoV-2 specific T cell responses. 
 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: Participants will have to visit the hospital at 6 time points, and 
participants who receive a third vaccination will have 2 additional hospital visits. The vaccine 
will be administered two times according to the standard of care, with the option of a third 
vaccination for participants without an adequate response after 2 vaccinations. Blood will be 
drawn (~373 ml in total for participants receiving 2 vaccinations, and ~539 ml in participants 
receiving 3 vaccinations) prior to the vaccinations and at day 28 and 6 months, 11 months 
and 18 months after the second vaccination. Nasal mucosal lining fluid samples will be 
collected at baseline and day 28 after the second vaccination in a subgroup of patients. 
Blood sampling will give minor discomfort, mucosal lining fluid collection is a non-invasive 
procedure. Vaccination can cause AEs including fatigue, chills, headache, myalgia, and pain 
at the injection site. For seven days after each vaccination, participants will be asked to 
record local and systemic reactions using a questionnaire. At baseline and at 3, 6, 9,12, 15 
and 18 months after the second vaccination, patients will be asked to complete 
questionnaires about potential subsequent testing for SARS-CoV-2, diagnosis of COVID-19, 
and severity of COVID-19.  
 
This study will collect information on immune response and adverse events after vaccination 
against COVID-19 in a vulnerable patient cohort. It will also explore immune response and 
safety of a third vaccination in participants without an adequate antibody response after the 
second vaccination. Understanding the ability or disability to mount a protective immune 
response after vaccination will help to counsel patients during the pandemic and support 

 
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decisions on whom to vaccinate and to identify patients who require other measures to 
protect them from COVID-19. Participants will be informed about their antibody titer in a letter 
that includes an explanation about what this means to them. This will be done after antibody 
measurements have been completed for day 28 after second vaccination, and again after 
completion of measurements for 6 months and 28 days after third vaccination, and 11 
months and 18 months after the second vaccination. 
 
1. INTRODUCTION AND RATIONALE 
 
1.1 Impact of COVID-19 pandemic on oncological care 
The SARS-CoV-2 pandemic is having a huge impact on societies all around the globe. As of 
December 8, 2020, over 65 million people have been diagnosed with Coronavirus induced 
disease (COVID-19), resulting in over 1,5 million deaths with numbers still increasing [1,2]. 
Over the past 6 months, regular health care, including cancer care [3,4], has been scaled 
down because hospitals were flooded with patients with COVID-19. In addition, hospital visits 
for anticancer therapies may put patients at even more risk of getting infected with SARS-
CoV-2 [5,6]. As the COVID-19 pandemic overwhelmed healthcare systems worldwide, non-
evidence-based decisions had to be made about the treatment of patients with cancer. 
Consequently, oncological treatment was frequently adjusted during the COVID-19 
pandemic, even in regions with relatively low COVID-19 incidence [3]. These treatment 
adjustments were made according to COVID-19 guidelines of (inter)national oncological 
societies, which were primarily based on expert opinions [7-10]. The limited capacity to 
deliver cancer care, the lockdown isolating patients at home, and their fear of entering 
hospitals, has led to suboptimal cancer care. In addition, there was a 30% underdiagnosis 
and delayed diagnosis of cancer in the Netherlands [11,12]. This most likely will result in 
higher cancer-specific mortality rates in the years to come. 
 
1.2 Outcome of COVID-19 in patients with cancer 
Patients with cancer have a higher risk for a dismal outcome of COVID-19 [13-15]. 
Therefore, international registries have been initiated to identify the clinical characteristics of 
cancer patients with severe COVID-19 [5,6, 16-25]. The worse outcome of COVID-19 in 
patients with cancer is determined by their underlying disease and/or cancer treatment. In 
particular, lung cancer and hematological malignancies are independent risk factors for a 
fatal outcome of COVID-19 [4]. In addition, chemotherapy and chemo-immunotherapy have 
been identified as risk factors for mortality of COVID-19 in patients with cancer [26,27].  
 
1.3 COVID-19 vaccination  

 
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Several vaccines are currently in development and the RNA vaccines by BioNTech/Pfizer 
and Moderna [28-31], were granted conditional marketing authorization by EMA. Vaccination 
of the Dutch population has started in January 2021. For the VOICE study the  mRNA-1273 
SARS-CoV-2 vaccine from Moderna will be used. In the randomized phase III study with 
mRNA-1273, 30,420 volunteers received two intramuscular injections of the vaccine (100 ug) 
or placebo 28 days apart [32]. None of the  participants was treated with chemotherapy 
and/or immunotherapy for cancer at the time of vaccination. In the placebo group 185 
participants developed symptomatic COVID-19 versus 11 participants who received the 
vaccine, resulting in  94.1% vaccine efficacy (95% CI, 89.3 to 96.8%; P<0.001). Severe 
COVID-19 only occurred in the placebo group: in 30 participants including one fatality. 
Solicited AEs at the injection site were common in the vaccine group (84.2% after the first 
injection and 88.6% after the second injection) but mainly low grade and of short duration. 
Solicited systemic AEs in this group were reported by 54.9% of the participants after the first 
dose and by 79.4% after the second dose, and mainly consisted of headache, fatigue, 
myalgia and chills. The rate of unsolicited AEs and SAEs up to 28 days after vaccination was 
similar in both arms. Hypersensitivity reactions occurred in 1.5% in the vaccine group and 
1.1% in the placebo group. 
 
1.4 COVID-19 vaccination in patients with cancer 
Patients with cancer have an increased risk for an adverse outcome of COVID-19 [13-15]. As 
a consequence, many patients strictly adhere to self-isolation, resulting in loneliness and loss 
of quality of life. Therefore, vaccination needs to be prioritized for these vulnerable patients. 
In addition, effective COVID-19 vaccination is of extreme importance to protect patients with 
cancer to continue care and cure. An immune response to vaccination would not only protect 
them from life-threatening COVID-19 but also allow close contact with their loved ones. 
Therefore, patients and patient organizations have already claimed prioritization of 
vaccination against COVID-19 for patients with cancer. 
For proper protection against COVID-19 by vaccination, specific immune responses need to 
be induced. SARS-CoV-2 specific immune cells are essential to combat the virus. B cells are 
important for antibody responses to neutralize the virus, while CD8 positive T cells can 
specifically recognize and eradicate virus-infected cells. In addition, CD4 positive T cells are 
required for providing necessary help to B cells and CD8 positive T cells. Cancer 
immunotherapy activates T cells against cancer cells by blocking the interaction between 
Programmed Death 1 (PD1) and its ligand (PD-L1) [33]. How this treatment impacts immune 
responses to vaccination is unknown. Chemotherapy causes bone marrow suppression and 
reduces the number of immune cells in the blood circulation, which may hamper the 
induction of protective immune responses after vaccination as suggested in studies on 

 
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influenza vaccination [34]. However, it is striking how little information is available on safety 
and efficacy of vaccination in cancer patients. As compared to the healthy population, 
patients with cancer treated with immunotherapy and/or chemotherapy may be more prone 
to adverse events of vaccination. Immunotherapy could potentially result in an augmented 
immune response to vaccination resulting in fever, chills, and other immune-related adverse 
events. Chemotherapy is known for significant fatigue, which impacts performance status 
and increases vulnerability. As a result, immunotherapy and chemotherapy may have a 
significant impact on the effectiveness but also on the safety of COVID-19 vaccination. In 
several countries including Belgium and France, immunocompromised patients are now 
offered a third vaccination. An advice from the Dutch Health Council about additional 
vaccination of immunocompromised patients in the Netherlands is expected soon. To protect 
patients with cancer from COVID-19, clinical trials are urgently needed to evaluate whether 
they develop an effective, safe, and durable immune response during immunotherapy and/or 
chemotherapy. 
 
1.5 Current trial 
The one central question is whether patients with cancer and especially those requiring 
systemic treatment, can develop protective immunity against COVID-19 upon vaccination. 
This question needs to be answered urgently and would help the medical oncology 
community to decide whether optimal cancer care can be delivered safely to vaccinated 
patients with cancer. In the VOICE trial, this important question will be addressed in a 
longitudinal cohort in which patients with solid cancers requiring systemic therapy will be 
vaccinated with the available COVID-19 vaccine according to the Dutch vaccination program. 
Patients with hematologic malignancies are not included in this study because it is known 
from influenza vaccination studies that those patients are frequently not able to build an 
effective immune response [35]. This means that protection of patients with a hematologic 
malignancy may require a different protective strategy such as treatment with SARS-CoV-2 
specific antibodies.  
In the VOICE study, the ability to mount antibody responses, will be measured in three 
cohorts of patients treated with chemotherapy, immunotherapy, or chemo-immunotherapy. 
Their immune response to COVID-19 vaccination will be compared to the immune response 
of participants without cancer and vaccinated with the same vaccine. Next to measuring 
antibody responses and their kinetics over time, also an in-depth analysis of T cell immunity, 
side effects of vaccination, SARS-CoV-2 infection rate, and severity of COVID-19 will be 
assessed. The VOICE trial will address a high unmet medical need, i.e., vastly gathering 
information on vaccine safety and effectiveness in one of the most vulnerable populations 
and could serve as a model for studies in other fragile populations. Understanding the ability 

 
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or disability to mount a protective immune response to a COVID-19 vaccine will help to 
counsel patients with cancer during this pandemic. Moreover, it will support decisions how to 
administer the best cancer care safely.  
 
1.6 First results VOICE trial 
Between February 17th and March 12th, 2021, 791 participants were enrolled in the current 
trial. For the primary endpoint at 28 days after the second vaccination, 743 participants were 
evaluable (per-protocol population): 240 individuals without cancer and 131 patients 
receiving immunotherapy, 229 patients receiving chemotherapy, and 143 patients receiving 
chemo-immunotherapy. SARS-CoV-2-binding antibody response (>10 binding antibody units 
(BAU)/mL) was found in 100%, 99.3%, 97.4%, and 100% of the participants in cohorts A, B, 
C, and D, respectively.  
Given the importance for clinical decisions, we defined, based on neutralizing capacity, a cut-
off level at 300 BAU/mL to discriminate between suboptimal and adequate responders. 
Twenty eight days after the second vaccination, 99.6% (A), 93.1% (B), 83.8% (C), and 88.8% 
(D) had an adequate response. Spike-specific T cell responses were detected in almost half 
of the suboptimal and non-responders. No new safety signals were observed [36]. 
1.7 Third vaccination 
Although most patients with solid tumors develop an adequate SARS-CoV-2-binding 
antibody response after vaccination, 6.9%, 16.2%, and 11.2% of patients treated with 
immunotherapy, chemotherapy, and chemo-immunotherapy, respectively, are still suboptimal 
or non-responders. As most of them show an increase in antibody concentration after the 
second vaccination, an additional third vaccination might turn them into adequate 
responders. In the extension of the VOICE trial, we will investigate whether non and 
suboptimal responders might benefit from a third vaccination. We will study whether an 
additional mRNA-1273 administration can improve the antibody response of participants in 
the VOICE trial who had a low antibody response on day 28 following two mRNA-1273 
vaccinations. In addition safety, neutralizing antibodies and SARS-CoV-2 Spike-specific 
interferon-gamma T cell response will be studied.  
 
1.8 Current vaccination strategy in the Netherlands 
Since October 2021, all patients with cancer who received chemotherapy and/or 
immunotherapy during or within 3 months before their first vaccination received an invitation 
for a third vaccination with an mRNA vaccine as part of their primary vaccination. This 
applies to all patients in the VOICE trial who did not receive a third vaccination within the 
study. Furthermore, everyone is entitled to receive a booster vaccination with an mRNA 
vaccine at least 3 months after completion of the primary vaccination, whether that consisted 

 
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of 2 or 3 vaccinations. This means that the majority of the study participants will have had 
extra vaccinations at different time points by January 2022. Therefore, we will implement 2 
cross sectional measurements at 11 and 18 months after the second vaccination (in 
February and September 2022) and record the date and type of those extra vaccinations 
retrospectively. This will provide insight in the immune status against COVID-19 of cancer 
patients in the Netherlands compared to a cohort without cancer in 2022. 
 

 
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2. OBJECTIVES 
 
 
Primary Objective:  
 
To assess the antibody based immune response after vaccination against COVID-19 
in patients with cancer treated with immunotherapy and/or chemotherapy as 
compared to controls 
 
Secondary Objectives:  
 
To assess adverse events (AEs) after vaccination against COVID-19 in patients with 
cancer treated with immunotherapy and/or chemotherapy 
 
To assess durability of the antibody response in patients with cancer treated with 
immunotherapy and/or chemotherapy 
 
To analyze the SARS-CoV-2 specific T cell response after vaccination in patients with 
cancer treated with immunotherapy and/or chemotherapy 
 
Exploratory Objectives: 
 
To perform in-depth analysis of cellular immune responses in patients with cancer 
treated with immunotherapy and/or chemotherapy 
 
To identify baseline (immune) parameters associated with vaccination response in 
patients with cancer treated with immunotherapy and/or chemotherapy 
 
To assess the neutralizing capacity of antibodies against SARS-CoV-2 after 
vaccination in patients with cancer treated with immunotherapy and/or chemotherapy 
 
To analyze induction of mucosal antibodies against SARS-CoV-2 in mucosal lining 
fluid samples. To describe the incidence of SARS-CoV-2 infection, outcome of 
COVID-19 during 12 months after vaccination in patients with cancer treated with 
immunotherapy and/or chemotherapy 
 
To analyze SARS-CoV-2-binding antibody concentration after a third vaccination in 
participants without an adequate antibody response after two vaccinations 
 
To analyze safety of a third vaccination 
 
 
 
 

 
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3. STUDY DESIGN 
 
This is a prospective multicenter cohort study, designed to evaluate the immune response 
and safety after vaccination against COVID-19 in three cohorts with cancer patients and one 
cohort of participants without cancer (see Fig.1). The patient cohorts are defined by type of 
cancer treatment. Immunotherapy, chemotherapy and chemo-immunotherapy were chosen 
because these treatment regimens may affect the efficacy and safety of vaccination against 
COVID-19 in different ways.  
 
Figure 1. Trial design 
 
 
 
 
 
To reflect the real-world population of patients with cancer treated with immunotherapy 
and/or chemotherapy, this trial is designed as inclusive as possible. Exclusion criteria are 
minimal and serve to exclude patients who are not evaluable, or in whom vaccination is 
considered not safe or not effective. A cohort of volunteers without a cancer diagnosis is 
included for comparison. Because age is an important predictor of the ability to mount an 
effective immune response to vaccination [37], partners of patients are enrolled in cohort A. 
We will take care that from all patient cohorts partners are approached, until cohort A is 
complete. We anticipate that accrual of cohort A will be completed earlier than the patient 
cohorts. 
All participants will receive two vaccinations against COVID-19 according to standard of care. 
Participants with an inadequate antibody response will be offered a third vaccination. To 
assess immune responses after vaccination, blood samples will be collected at baseline (i.e. 

 
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prior to first vaccination), at the day of the second (and if applicable the third) vaccination and 
at day 28 after the second and third vaccination and 6, 11 and 18 months after the second 
vaccination by venipuncture. To evaluate hematology, with or without liver and kidney 
function, additional blood samples will be collected at baseline, at the day of the second and 
third vaccination, and at day 28 after the second and third vaccination and 6, 11 and 18 
months after the second vaccination. Nasal mucosal lining fluid will be collected at baseline 
and at day 28 after the second vaccination according to a non-invasive sampling method. 
 
To evaluate vaccination related AEs, patients will be asked to collect solicited local and 
systemic AEs for 7 days after each vaccination using a questionnaire. Similarly serious AEs 
(SAEs) will be collected for 7 days after each vaccination. Most patients who receive 
systemic cancer treatment experience multiple AEs that are cancer treatment related, or 
disease related. As vaccination related AEs are mainly expected within the first week after 
vaccination, it is not useful to collect all AEs for a prolonged period. Instead, all newly 
occurring immune related AEs (irAEs) are collected for the immunotherapy and chemo-
immunotherapy cohorts (B and D) up to 28 days after the second and if applicable the third 
vaccination. irAEs are toxicities from immune checkpoint inhibitors and do not include 
infusion reactions [38]. Furthermore, adverse events of special interest (AESIs) will be 
collected for the duration of the study in the patient cohorts.  
Information on incidence of SARS-CoV-2 infection, outcome of COVID-19 during 18 months 
after the second vaccination will be collected using questionnaires. For the study participants 
who give separate consent, information on positive corona tests during the study will also be 
collected from the RIVM.   
Although this study is not powered to detect differences in protection against COVID-19 
between patients and controls, information on incidence of SARS-CoV-2 infection, outcome 
of COVID-19 will be collected up to 18 months after the second vaccination for descriptive 
purposes. 
 
 
4. STUDY POPULATION 
4.1 Population (base)  
4.2 Inclusion criteria 
To be eligible to participate in this study, a subject must meet all of the following criteria: 
 
Age of 18 years or older 
 
Life expectancy > 12 months 
 
Ability to provide informed consent 

 
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Additional criteria for cohort A: 
 
Partner of a participating patient 
 
Additional criteria for cohort B: 
 
Histological diagnosis of a solid malignancy 
 
Treatment with monotherapy immune checkpoint inhibitor (ICI) against 
Programmed Death 1 (PD1) or its ligand PD-L1 (in curative or non-curative 
setting) 
 
Last ICI administration within 3 months of vaccination 
 
Additional criteria for cohort C: 
 
Histological diagnosis of a solid malignancy 
 
Treatment 
with 
cytotoxic 
chemotherapy 
(monotherapy 
and 
combination 
chemotherapy is allowed, as well as a combination with radiotherapy, in curative 
or non-curative setting) 
 
Last chemotherapy administration within 4 weeks of vaccination 
 
Additional criteria for cohort D: 
 
Histological diagnosis of a solid malignancy 
 
Treatment with a PD1 or PD-L1 antibody in combination with cytotoxic 
chemotherapy (in curative or non-curative setting) 
 
Last chemotherapy administration within 4 weeks of vaccination 
 
Last ICI administration within 3 months of vaccination 
 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
 
Confirmed SARS-CoV-2 infection (current or previous) 
 
Women who are pregnant or breastfeeding 
 
Active hematologic malignancy     
 
Any immune deficiency not related to cancer or cancer treatment (e.g. inherited 
immune deficiency or known infection with Human Immunodeficiency Virus) 
 
Systemic treatment with corticosteroids (> 10 mg daily prednisone equivalent) or 
other immunosuppressive medication within 14 days of vaccination. Inhaled or 
topical steroids, and adrenal replacement steroids (> 10 mg daily prednisone 
equivalent) are permitted. In addition, standard of care with short course steroids 
to prevent nausea and allergic reactions from chemotherapy or iodinated CT 
contrast is allowed. 
 

 
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Additional criteria for cohort A: 
 
Current or previous diagnosis of a solid malignancy, unless treated with curative 
intent >5 years before enrolment and without signs of recurrence during proper 
follow-up 
 
Previous history of a hematologic malignancy 
 
Additional criteria for cohort B: 
 
Treatment with cytotoxic chemotherapy within 4 weeks of vaccination 
 
Additional criteria for cohort C: 
 
Treatment with an ICI within 3 months of vaccination 
 
 
4.4 Sample size calculation 
The primary endpoint is the antibody based immune response on day 28 after the second 
vaccination in patients receiving cancer treatment as compared to individuals without 
cancer. Participants are classified as responders or non-responders to vaccination against 
COVID-19. In patients treated with immunotherapy, we assume that the immune response 
rate is similar to that in individuals without cancer. In patients treated with chemotherapy 
or chemo-immunotherapy, we expect a lower immune response rate. As the percentage 
of responders is still unknown for vaccination against COVID-19, especially when a lower 
rate of immune response is expected, a power calculation for different scenarios has been 
performed, thereby comparing cohorts B, C, and D separately with cohort A.  
 
Patients receiving immunotherapy (cohort B) vs. individuals without cancer (cohort A) 
We assume that 90% of the individuals without cancer  will be responders and that this 
will be similar in patients receiving immunotherapy. If there is truly no difference (90% 
responders in both groups), then 112 individuals without cancer and 112 patients are 
required to be 80% sure that the upper limit of a one-sided 95% confidence interval will 
exclude a difference in favor of the individuals without cancer of more than 10%. 
 
Patients receiving chemotherapy (cohort C) or chemo-immunotherapy (cohort D) vs. 
individuals without cancer (cohort A) 
For patients receiving chemotherapy or chemo-immunotherapy, we expect a lower 
percentage of responders compared to the group without cancer based on influenza 
vaccination trials [29].  However, the percentage of responders is still unknown for 
vaccination against COVID-19. Therefore, we performed a power calculation for two 
different scenarios, 1) anticipated true response rate in the groups receiving 

 
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chemotherapy and chemo-immunotherapy of 60% and 2) anticipated true response rate in 
the groups receiving chemotherapy and chemo-immunotherapy of 40%.  
Scenario 1: If there is a true difference in favor of the group without cancer of 30% (90% 
vs. 60%), then 205 individuals without cancer and 205 patients in cohort C and D are 
required to be 80% sure that the upper limit of a one-sided 95% confidence interval will 
exclude a difference in favor of the group without cancer of more than 40%. 
Scenario 2: If there is a true difference in favor of the group without cancer of 50% (90% 
vs. 40%), then 205 individuals without cancer and 205 patients in cohort C and D are 
required to be 80% sure that the upper limit of a one-sided 95% confidence interval will 
exclude a difference in favor of the group without cancer of more than 50%. 
In summary, these power calculations indicate that for the cohort C vs. cohort A 
comparison and for the cohort D vs. A comparison we need a total of 205 individuals 
without cancer , 205 patients treated with chemotherapy and 205 patients treated with 
chemo-immunotherapy. With these numbers we have enough power to assess non-
inferiority in both scenarios with an alpha of 0.05 and 80% power. 
 
 
Correction for drop-out 
We expect that a proportion of the participants will already have SARS-CoV-2 antibodies 
at baseline and will not be evaluable for the primary endpoint. In addition, we anticipate 
that there will be a drop-out of participants at later time points. Reasons for drop-out may 
include death or poor performance status as a result of progressive malignancy and/or 
cancer treatment related AEs. Therefore, we will correct for non-evaluable patients by 
increasing each cohort with 20%. This means that 246 participants will be recruited in 
cohorts A, C and D, and 135 participants will be enrolled in cohort B. In total, 873 
participants (627 patients and 246 individuals without cancer) will be included. 
 
 
5. TREATMENT OF SUBJECTS 
Vaccination will be performed according to the standard of care. The name of the vaccine, 
batch number and date and time of administration will be recorded. This study investigates 
the immune response and AEs in a vulnerable population of patients who receive cancer 
treatment. If subjects had not participated in this study, they would have received the same 
vaccine or another registered vaccine against COVID-19 according to standard of care via 
their general practitioner without additional testing.  
 
 

 
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6. INVESTIGATIONAL PRODUCT  
The product information of the approved mRNA-1273 SARS-CoV-2 vaccine administered to 
participants in this study is provided in Appendix 4. 
 
 
7. NON-INVESTIGATIONAL PRODUCT 
Not applicable 
 
 
8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
The primary endpoint is the antibody based immune response to vaccination against 
COVID-19 on day 28 after the second vaccination in patients receiving cancer 
treatment as compared to individuals without cancer. Participants will be classified 
as responders or non-responders. The definition of response is seroconversion 
defined as presence of SARS-CoV-2 spike S1-specific IgG antibodies in individuals 
without measurable anti-S antibodies at baseline. Participants who are seropositive 
at baseline will not be included in the analysis of the primary endpoint (see 
paragraph 10.1).  The percentage of responders of each patient cohort will be 
compared with the percentage responders in the group without cancer. 
8.1.2 Secondary study parameters/endpoints  
 
Safety assessment through: 
o Incidence and severity of solicited AEs during 7 days after each 
vaccination (see Appendix 1) 
o Incidence and nature of SAEs during 7 days after each vaccination 
o Incidence and nature of newly occurring irAEs [38] grade ≥ 3 in cohort B 
and D up to 28 days after the last vaccination graded according to the 
Common 
Terminology 
Criteria 
for 
Adverse 
Events 
version 
5.0 
(CTCAEv5.0) 
o Incidence, nature and severity of AESIs (see Appendix 2) graded 
according to CTCAEv5.0  
 
In depth assessment of immune response through: 

 
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o Measurement of SARS-CoV2 specific antibodies before the second 
vaccination to analyze initial response, and at 6 and 11 and 18 months 
after the second vaccination to measure longevity 
o Measurement of SARS-CoV2 specific antibodies at day 28 after the third 
vaccination if applicable 
o Assessment of SARS-CoV2 specific T cells response at 28 days after the 
second and third vaccination and at 6, 11 and 18  months after the second 
vaccination using a high throughput Interferon ɣ ELIspot 
8.1.3 Exploratory study parameters 
 
In-depth flow-cytometric analyses for functional and phenotypical characterization 
of SARS-CoV-2 specific cellular immune responses will be performed followed by 
assessment of proliferative capacity, cytokine production and phenotypical 
markers in a subset of patients 
 
To determine baseline (immune) parameters associated with immune response to 
COVID-19 vaccination  
 
To assess the induction of SARS-CoV-2-specific antibodies in mucosal lining fluid  
 
Neutralizing capacity of antibodies to test functionality.  
 
Information on incidence of SARS-CoV-2 infection, outcome of COVID-19 will be 
collected and reported during 18 months after the second vaccination. To this 
end, questionnaires will be used. Information on positive corona tests during the 
study will also be collected from the RIVM.  
 
 To analyze SARS-CoV-2-binding antibody concentration after a third vaccination 
in participants without an adequate antibody response after two vaccinations on 
day 28 after the third vaccination. 
 
To analyze safety of a third vaccination as indicated under 8.1.2 
 
To assess SARS-CoV2 specific T cell response at 28 days after the third 
vaccination 
 
8.2 Randomization, blinding and treatment allocation 
Not applicable. 
 
8.3 Study procedures 
This study is executed as a low-risk intervention trial, for which no labeling is 
required according to Annex 13. However, the vaccine release and drug 
accountability will be done according to  GCP.  
 
 

 
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Table 1: Flow chart/time and events schedule 
 
Procedure 
Screeninga 
(within 28 
days) 
Vacc 
1 
Vacc 
2 
Day 
28 
vacc
2b  
(± 3) 
Day 
90 
(± 7) 
Day 
180 
(± 7) 
Vacc 
3m 
Day 
28 
vacc
3 
(± 3) 
Day 
270 
(±7) 
Day  
330 
(± 14) 
Day 
540 (± 
21) 
Informed consent 
x 
 
 
 
 
 
x 
 
 
 
 
Inclusion/exclusion 
criteria 
x 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
x 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
Smoking history 
x 
 
 
 
 
 
 
 
 
 
 
ECOG PSb 
x 
 
 
 
 
 
 
 
 
 
 
Height/weight 
x 
 
 
 
 
 
x 
 
 
 
 
Vital signsc 
x 
x 
x 
 
 
 
x 
 
 
 
 
Blood testsd 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
Nasal 
MLF 
collectione 
 
x 
 
x 
 
 
 
 
 
 
 
Sollicited adverse 
eventsf 
x 
x 
x 
x 
 
 
x 
 
 
 
 
SAEsg 
 
x 
x 
x 
 
 
x 
 
 
 
 
irAEsh 
x 
x 
x 
x 
 
 
x 
x 
 
 
 
AESIsi 
 
 
Will be reported for the entire duration of the study 
Vaccine 
administrationj 
 
x 
x 
 
 
 
x 
 
 
 
 
COVID-19 
questionnairek 
x 
 
 
 
x 
x 
x 
 
x 
x 
x 
Survival status 
 
 
 
 
 
x 
 
 
 
x 
x 
 
a Screening should be performed within 28 days prior to the first vaccination but can 
be done on the same day as the first vaccination. 
b ECOG performance status: see appendix 3. 
c Vital signs: blood pressure, heart rate, temperature. 
d See Table 2. 
e MLF = mucosal lining fluid, will be collected using a synthetic absorptive matrix [39] 
f Participants will complete a questionnaire for solicited systemic and local AEs on a 
daily basis from each vaccination until 7 days after each vaccination, see Appendix 1. 
g SAEs that occur within 7 days of each vaccination will be reported 
h Newly developed irAEs [38] grade ≥ 3 need to be reported for cohort B and D up to 
28 days after the second vaccination and from the third vaccination to 28 days 
thereafter. 

 
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i AESIs (see Appendix 2) will be reported by the treating physicians up to 18 months 
after vaccination for cohorts B-D. 
j The name of the vaccine, batch number and date and time of administration will be 
recorded. 
k Participants will complete a questionnaire for diagnosis of SARS-CoV-2 infection, 
severity and outcome of COVID-19.  
l Only participants with an inadequate antibody response (≤300 BAU/mL) on day 28 
after the second vaccination. 
 
Table 2: Blood tests 
 
 
Vacc1a Vacc2a Day 
28 
Vacc2 
Day 
180 
 
Vacc3ad 
Day 
28 
vacc3 
 
Day 
330 
Day 
540 
SARS-Cov-2 
antibodies 
x 
x 
x 
x 
x 
x 
x 
x 
PBMC isolation 
for 
in 
depth 
cellular 
immune 
response 
x 
 
x 
x 
x 
x 
x 
x 
Routine 
hematologyb 
x 
x 
x 
x 
x 
x 
x 
x 
Routine 
chemistryc 
x 
x 
x 
 
x 
x 
 
 
 
      PBMC = peripheral blood mononuclear cells 
a Blood has to be drawn before vaccination 
b Hemoglobin, red blood cell count, platelet count, white blood cell count, white blood 
cell differential 
c glucose, creatinine, aspartate aminotransferase (ASAT), alanine aminotransferase 
(ALAT), albumin, lactate dehydrogenase (LDH), C-reactive protein (CRP). 
d Only participants with an inadequate antibody response (≤300BAU/mL) on day 28 
after the second vaccination. 
 
8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without 
any consequences. The investigator can decide to withdraw a subject from the study 
for urgent medical reasons. 
8.4.1 Specific criteria for withdrawal (if applicable) 
  Not applicable 
 

 
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8.5 Replacement of individual subjects after withdrawal 
Not applicable  
 
8.6 Follow-up of subjects withdrawn from treatment 
Participants who receive at least one dose of the vaccine will be monitored for AEs, 
SAEs, AESIs and irAEs according to the protocol (up to day 7 after each vaccination 
for cohorts A and C and up to day 28 after the last vaccination for cohorts B and D). 
If the subject does not withdraw consent, also blood samples will be drawn 
according to the protocol. 
 
8.7 Premature termination of the study 
Not applicable since vaccination is standard of care.  
 
 
9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardize subject 
health or safety. The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed. 
  
 
9.2 AEs, AESIs and SUSARs 
9.2.1 Adverse events (AEs) 
AEs are defined as any undesirable experience occurring to a subject during the 
study, whether or not considered related to COVID-19 vaccination. In this study, 
solicited AEs will be reported by all participants on a daily basis for 7 days after each 
vaccination.  
 
9.2.2 
Serious Adverse events (AEs) 
 
 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 

 
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- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs that occur within 7 days of administration of the 
vaccine to the PI without undue delay after obtaining knowledge of the events. 
 
 
The coordinating investigator, the PI or delegated trial personnel will report the SAEs 
through the web portal ToetsingOnline to the accredited METC that approved the 
protocol, within 7 days of first knowledge for SAEs that result in death or are life 
threatening followed by a period of maximum of 8 days to complete the initial 
preliminary report. All other SAEs will be reported within a period of maximum 15 
days after the sponsor has first knowledge of the serious adverse events.  
 
9.2.3  Adverse events of special interest (AESIs) 
Adverse events of special interest (AESIs) and serious adverse events (SAEs) 
frequently occur in patients with cancer who receive systemic therapy as a result of 
the cancer treatment or the underlying disease. Therefore, AESIs will be collected in 
this study (see Appendix 2). Treating physicians from patients in cohorts B, C and D 
will report AESIs to the PI. The coordinating investigator, the PI or delegated trial 
personnel will report the AESIs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 15 days after first knowledge of 
the AESIs.  
Since the vaccine is a registered agent, and the number of controls in this study is 
very small compared to the registration trials, AESIs from the control group will not 
meaningfully add to the existing safety data. Therefore, subjects in the control group 
will be asked to report potential side effects of vaccination according to the national 
guidelines for the general population to the Dutch pharmacovigilance center Lareb. 
 
  

 
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Death of any cause is considered an AESI, because life expectancy of at least 12 
months is required for inclusion. We will report deaths and collect information on 
cause of death. In order to be as complete as possible, informed consent is asked for 
coupling of data with the Gemeentelijke Basis Administratie (GBA) and  Centraal 
bureaus voor Statistiek (CBS), also from individuals without cancer. However, this is 
optional and participants who do not consent to coupling of data with CBS and GBA 
can participate in the study. 
9.2.4 Immune related adverse events (irAEs) 
irAEs are toxicities from immune checkpoint inhibitors and do not include infusion 
reactions [38]. For patients in cohorts B and D treated with immunotherapy, all irAEs 
[38] that occur between the first vaccination and 28 days after the last vaccination will 
be collected and graded according to CTCAEv5.0. irAEs of grade ≥3 are required to 
be reported to the PI immediately (i.e. no more than 24 hours after learning of the 
event). The coordinating investigator, the PI or delegated trial personnel will report 
grade ≥3 irAEs through the web portal ToetsingOnline to the accredited METc that 
approved the protocol, within 15 days of first knowledge of the irAEs that result in 
death or are life-threatening. All other irAEs will be reported within a period of 
maximum 15 days.  
9.2.5 Suspected unexpected serious adverse reactions (SUSARs) 
Adverse reactions are all untoward and unintended responses to an investigational 
product related to any dose administered. 
 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. the event must be serious: 
 - results in death; 
- is life-threatening (at the time of the event); 
- requires hospitalization or prolongation of existing inpatients’ hospitalization; 
- results in persistent or significant disability or incapacity; 
- is a congenital anomaly or birth defect; or 
- any other important medical event that did not result in any of the outcomes 
listed above due to medical or surgical intervention but could have been based 
upon appropriate judgement by the investigator. 
2. there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of 
the administered dose; 

 
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3. the adverse reaction must be unexpected, that is to say, the nature and severity 
of the adverse reaction are not in agreement with the product information as 
recorded in the Summary of Product Characteristics (SPC).  
 
 
The sponsor will report expedited the following SUSARs through the web portal 
ToetsingOnline to the METC: 
 SUSARs that have arisen in the clinical trial that was assessed by the METC; 
 SUSARs that have arisen in other clinical trials of the same sponsor and with the 
same medicinal product, and that could have consequences for the safety of the 
subjects involved in the clinical trial that was assessed by the METC. 
The remaining SUSARs are recorded in an overview list (line-listing) that will be 
submitted once every half year to the METC. This line-listing provides an overview 
of all SUSARs from the vaccine, accompanied by a brief report highlighting the main 
points of concern.  
The expedited reporting of SUSARs through the web portal Eudravigilance or 
ToetsingOnline is sufficient as notification to the competent authority. 
 
The expedited reporting will occur not later than 15 days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life-threatening cases, the term will 
be maximal 7 days for a preliminary report with another 8 days for completion of the 
report.  
 
9.3 Annual safety report 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year 
throughout the clinical trial, a safety report to the accredited METC and competent 
authority. 
This safety report consists of: 
 a list of all suspected (unexpected or expected) serious adverse reactions, along with 
an aggregated summary table of all reported serious adverse reactions, ordered by 
organ system, per study; 
 a report concerning the safety of the subjects, consisting of a complete safety analysis 
and an evaluation of the balance between the efficacy and the harmfulness of the 
medicine under investigation. 
 

 
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9.4 Follow-up of AEs 
All solicited AEs, SAEs, AESIs and irAEs will be followed until they have abated, or until a 
stable situation has been reached. Depending on the event, follow up may require 
additional tests or medical procedures as indicated, and/or referral to the general 
physician or a medical specialist. 
 
 
10. STATISTICAL ANALYSIS 
A description of the participant population will be included in a statistical output report, 
including subgroups of gender, tumor type, treatment, and treatment intent (curative versus 
non-curative).  
Participants who are seropositive to SARS-CoV-2 at baseline and participants who have not 
received at least one dose of the vaccine will be excluded from the immune response 
analyses, including the primary analysis. All subjects who received at least one 
administration of the vaccine will be included in the analyses of AEs, SAEs and AESIs, as 
well as irAEs for cohorts B and D. 
 
For description of the results of this study, appropriate descriptive statistics will be used, 
including estimates of variance. For comparisons between patient cohorts and controls, the 
most robust appropriate statistical tests will be applied, after checking that all assumptions 
for a specific test are met. We will be fully transparent about the analyses (including scripts 
for analyses) and will report the testing results of the assumptions. In addition, we will 
present all individual data points of the primary and secondary study parameters. 
 
10.1 Primary study parameter 
The primary study parameter is the antibody based immune response to vaccination 
against COVID-19 on day 28 after the second vaccination in cancer patients as compared 
to individuals without cancer. SARS-CoV-2 S-specific serum IgG antibody concentrations 
will be measured at the RIVM using a validated fluorescent bead-based multiplex-
immunoassay [40]. Geometric mean concentrations (GMCs) and 95% confidence 
intervals (CIs) will be calculated for the SARS-CoV-2 S-protein-specific IgG antibodies at 
baseline and day 28 after vaccination for each cohort. Participants will be classified as 
responders or non-responders. The definition of response is seroconversion defined as 
presence of SARS-CoV-2 spike S1-specific IgG antibodies with a threshold for 
seropositivity based on Receiver Operator Curve (ROC) analysis and set at 1.04 AU/mL 
[41]; in individuals without measurable anti-S antibodies at baseline. Concentrations have 
been interpolated from a reference consisting of pooled sera using a 5-parameter logistic 

 
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fit that was calibrated against the NIBSC/WHO COVID-19 reference serum 20/136 and 
expressed as international binding antibody units per ml (BAU/mL).The value of 1.04 
AU/mL corresponds to 10 BAU/mL. Participants who are seropositive at baseline will not 
be included in the analysis of the primary endpoint. The percentage of responders and 
corresponding 95% CI for each cohort will be calculated. The percentage of responders 
of each patient cohort will be compared with the percentage responders in the group 
without cancer, using a modified standard fixed‐delta test [42]. 
 
10.2 Secondary study parameters  
 
Incidence and severity of solicited AEs during 7 days after each vaccination is a 
key secondary endpoint (see Appendix 1). Frequencies and absolute numbers of 
mild, moderate and severe solicited AEs per cohort will be listed for the first, 
second and third vaccination separately.  
 
The numbers, nature and severity of SAEs graded according CTCAEv5.0 will be 
listed per cohort. 
 
Incidence and nature of newly occurring irAEs grade ≥ 3 in cohorts B and D up to 
28 days after the second vaccination is the second safety endpoint. irAEs will be 
graded according CTCAEv5.0. Frequencies and absolute numbers of all newly 
occurring irAEs grade ≥ 3 that occur between the first vaccination and 28 days 
after the second vaccination in cohorts B and D will be listed.  
 
Incidence, nature and severity of AESIs comprise the third safety endpoint. AESIs 
will be graded according CTCAEv5.0. Absolute numbers and frequencies of all 
AESIs will be listed per cohort and subdivided by severity.  
 
Levels of SARS-CoV-2 S-specific IgG antibodies at 28 days after the second 
vaccination will be compared between each patient cohort and the non-cancer 
cohort using ANOVA or Kruskal–Wallis one-way analysis of variance, and Welch t-
tests or Mann-Whitney U tests, depending on the distribution of the data.    
 
Levels of SARS-CoV-2 S-specific IgG antibodies before the second vaccination 
and at 6, 11 and 18months after the second vaccination will be measured to 
assess early antibody response and longevity. GMCs and 95% CIs will be 
calculated. The absolute numbers and percentages of responders will be reported 
for each cohort for each time point. Antibody levels before the second vaccination 
and at 6, 11 and 18 months will be compared between each patient cohort and the  
non-cancer cohort using ANOVA or Kruskal–Wallis one-way analysis of variance, 
and Welch t-tests or Mann-Whitney U tests, depending on the distribution of the 
data. 

 
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 
SARS-CoV-2 specific T cell response will be measured at baseline, and at 28 days 
after the second and third vaccination, and 6, 11 and 18 months after the second 
vaccination and expressed as the number of IFN-ɣ producing SARS-CoV2 specific 
T cells/million PBMC. To assess the contribution of CD8+ T cells in this response, 
we will assess the number of IFN-ɣ producing T cells after blocking with an MHC 
class I antibody. This will be expressed as the number of IFN-ɣ producing CD4+ T 
cells/ million PBMCs. Subtraction of the number of responding CD4+ T cells from 
the total number of responding T cells will lead to the number of IFN-γ producing 
CD8+ T cells/ million PBMCs. Results will be compared between each patient 
cohort and the cohort of individuals without cancer using ANOVA or Kruskal–
Wallis one-way analysis of variance, and Welch t-tests or Mann-Whitney U tests, 
depending on the distribution of the data. 
 
10.3 Other study parameters 
 
Dynamics of SARS-CoV-2 specific antibody concentrations will be analyzed, e.g. 
by calculating geometric mean fold-rise between baseline and post-baseline time 
points and antibody decay after day 28.  
 
In-depth flow-cytometric analyses for functional and phenotypical characterization 
of SARS-CoV-2 specific cellular responses will be performed by assigning 
proliferative capacity, cytokine production and phenotypical markers (>25 markers 
in parallel) in a subset of patients. These descriptive study parameters will not be 
statistically compared between cohorts. 
 
Baseline (immune) parameters will be related to vaccination response using 
univariate analysis.  
 
As a functional readout, the neutralizing capacity SARS-CoV-2 antibodies will be 
measured at baseline, 28 days and 6 , 11 and 18 months after the second 
vaccination. Titers will be expressed as GMCs with 95% CIs for each cohort, for 
each time point. 
 
To assess induction of a mucosal antibody response, mucosal lining fluid samples 
will 
be 
collected 
for 
measurement 
of 
SARS-CoV-2-specific 
antibody 
concentrations with multiplex immunoassay at baseline and at 28 days after the 
second vaccination. Additional analyses e.g. neutralizing capacity of mucosal 
antibodies can be performed. 
 
Mucosal SARS-CoV-2-specific antibody response will be correlated with serum 
SARS-CoV-2-specific antibody response. 

 
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 
Information on incidence of SARS-CoV-2 infection, outcome of COVID-19 during 
18 months after the second vaccination will be collected. The number of 
participants tested, the number of SARS-CoV-2 tests and test results will be 
reported. For participants with a positive test, information about severity will be 
presented including hospital admissions, use of oxygen, intensive care admission 
and mechanical ventilation. 
 
Levels of SARS-CoV-2 S-specific IgG antibodies before the third vaccination, and 
at day 28 after the third vaccination will be measured to assess antibody response 
in participants with an inadequate response to two mRNA-1273 vaccinations. 
 
Safety of a third mRNA-1273 vaccination in participants with an inadequate 
response to two mRNA-1273 vaccinations as mentioned under 10.2. 
 
10.4 Interim analysis (if applicable) 
Not applicable. 

 
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11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
The protocol has been written, and the study will be conducted according to the ICH 
Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at 
https://www.ema.europa.eu/documents/scientific-guideline/ich-e6-r1-guideline-good-
clinicalpractice_en.pdf). The study will be in agreement with the principles of the 
Declaration of Helsinki (64, October 2013, Fortaleza, Brazil, available on the World 
Medical Association web site (http://www.wma.net) and with Dutch law, in accordance 
with the Medical Research Involving Human Subjects Act (WMO, available at 
https://wetten.overheid.nl/BWBR0009408/2020-01-01). 
 
11.2 Recruitment and consent 
Vaccination of elderly has started in Q1 2021 in the Netherlands. In order to be able to 
launch this study at the time the vaccine is available, potential participants will be 
identified early at oncology clinics in the participating institutes and informed about: 
 
the aims of the study 
 
the potential risks of participation  
 
the procedures and the possible hazards to which participants will be exposed  
 
the obligation to register date of vaccination and type of vaccine in a national 
database 
 
otherwise strict confidentiality of any patient data 
 
medical records possibly being reviewed for trial purposes by authorized 
individuals other than their treating physician 
A pre-screening Participant Information Form (PIF) will be offered. After signing pre-
screening informed consent (IC), baseline information will be collected and eligibility for 
the study will be estimated. A list of potentially eligible individuals will be created who can 
be contacted immediately when the vaccine is available. Potential participants will then 
receive the study PIF. Both the pre-screening PIF and the study PIF will be submitted to 
the METC along with the study protocol, there are separate versions for cancer patients 
(cohort B-D) and individuals without cancer (cohort A). A statement of approval should be 
provided before commencement of the study. Potential participants will be asked for IC by 
one of the investigators (a medical doctor or specialized nurse). Each subject will be given 
the opportunity to ask questions and will be informed about the right to withdraw from the 
study at any time without prejudice. Participants without an adequate antibody response 
after two vaccinations will be informed about the option to receive a third vaccination, a 
separate IC must be obtained. The formal written IC for this trial must be obtained before 

 
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initiation of any study-specific procedures. Subjects must be given adequate opportunity 
to read the information and enquire about details of the study before consent is given. The 
IC procedure is done according to the ICH guidelines on Good Clinical Practice. This 
implies that the written informed consent form will be signed and personally dated by the 
participant. The informed consent statement will be signed and dated by the investigator 
afterwards and the subject will receive a copy. Subjects are free to decide whether or not 
to participate in this trial. Non-participation will not have any consequences concerning 
their treatment. If the patient does not want to participate in the trial, it will be enough if 
he/she informs one of the investigators about the decision. The decision will be 
documented in the (electronic) patient dossier. 
 
11.3 Objection by minors or incapacitated subjects 
Not applicable.   
 
11.4 Benefits and risks assessment, group relatedness 
Patients with cancer are hit harder by the COVID-19 pandemic than healthy individuals. 
As they have a higher risk of adverse outcome of COVID-19, many patients strictly adhere 
to self-isolation, resulting in loneliness and loss of quality of life. An immune response to 
vaccination would not only protect them from life-threatening COVID-19 but also allow 
close contact with their loved ones. Participation in this study gives early access to 
vaccination against COVID-19. For the control group, participation in the trial helps to 
protect their partners with cancer from getting COVID-19, and gives them early access to 
the vaccine. This study will generate highly valuable information on the ability to mount an 
effective immune response during cancer treatment that can guide management of cancer 
patients during the pandemic worldwide. 
Participants without an adequate antibody response will be offered a third vaccination. 
Most participants in the VOICE study showed an increase in SARS-CoV-2-binding 
antibody concentration following a second vaccination, a third vaccination will therefore 
likely further increase the antibody response. Patients with cancer could therefore benefit 
from better protection induced by a third vaccination. A third vaccination with another 
mRNA vaccine (BNT162b2, Pfizer-BioNTech) in 101 solid organ transplant recipients 
showed that from the 59 patients who did not have SARS-CoV-2 specific antibodies 
before the 3rd vaccination, 44% was seropositive 28 days after the third vaccination. 
Patients who were already seropositive before the third vaccination showed a significant 
increase in antibody concentration. No serious adverse events were reported after the 
administration of the third dose, and no acute rejection episodes occurred [43]. The FDA 

 
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on August 12th authorized additional mRNA-1273 and BNT162b2 vaccine doses for 
immunocompromised individuals, administered at least 28 days after the two-dose 
regimen of the same vaccine [44]. Recently, Moderna requested a general FDA approval 
for a third dose of mRNA-1273, based on a study in 344 volunteers [45]. Currently both 
mRNA-1273 and BNT162b2 are used for third vaccinations in immunocompromised 
patients and for boosters in the Netherlands. 
Participation in this study requires 6 hospital visits at which blood will be drawn by 
venipuncture and 2 non-invasive collections of nasal mucosal lining fluid are performed. 
Maximum 3 additional hospital visits are required for participants who will receive a third 
vaccination. Participants have to fill in a questionnaire at baseline, and at 3, 6, 9, 12, 15 
and 18 months after the last vaccination. Participants will be informed about their antibody 
titer in a letter that includes an explanation about what this means to them. This will be 
done after antibody measurements have been completed for day 28 after vaccination, and 
again after 6, 11 and 18 months after the second vaccination. Participants who receive 3 
vaccinations will also receive their antibody concentration on day 28 after the third 
vaccination. Potentially eligible subjects who decide not to participate in the study will 
have access to the general Dutch vaccination program, which now includes a third 
vaccination as part of the primary vaccination  in immunocompromised patients and a 
booster for everybody at a minimum of 3 months after completion of the primary 
vaccination.  
 
11.5 Incentives (if applicable) 
For each day of subject related study procedures, the subjects will receive compensation 
for travelling expenses (€ 0.19/km) and parking. 
 
 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
Study subjects will receive a code. The key to the code (number linked to patient) is 
safeguarded by the investigator. The study code assigned to the patients will be used in 
the collection of all the study results by IKNL (Integraal Kankercentrum Nederland).  
An overview of all data and data-analysis is made according to this code, so that the final 
results cannot be traced back to the patients by another person than the investigators 
involved in the study (in compliance with the Dutch Personal Data Protection Act). For the 
study participants who give separate consent, information on positive COVID-19 tests 

 
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during the study will also be collected from the RIVM. Data will be stored for a maximum 
period of 15 years after the study is finished. 
 
12.2 Monitoring and Quality Assurance  
On-site and centralized monitoring will take place according to the NFU (Nederlandse 
Federatie 
van 
Universitaire 
Medisch 
Centra)-guideline 
“Kwaliteitsborging 
van 
mensgebonden onderzoek 2019” by the appointed monitor. This study is classified as 
negligible risk because vaccination is standard of care. Monitoring will take place to 
assure the quality and validity of the research data. The monitor will perform source data 
verification on the research data by comparing the data entered into the CRF with the 
available source documentation and other available documents. Source documents are 
defined as the patient’s hospital medical records, clinician notes, laboratory print outs, 
digital and hard copies of imaging, memos, electronic data etc. 
The monitor will verify the following items: Informed consent forms (presence, dates, 
signatures); Informed consent process, Investigator Files (presence of all documents), in-
/exclusion criteria (using source documents); AESIs/irAEs/SAEs (number, missed, 
reporting procedures); study product (administration). After each control the monitor will 
send a written report to the sponsor (including a summary; quality assessment; summary 
of findings, deviations and shortcomings; possible solutions to warrant compliance with 
the protocol; final conclusion). 
 
12.3 Amendments  
A ‘substantial amendment’ is defined as an amendment to the terms of the METC 
application, or to the protocol or any other supporting documentation, that is likely to 
affect to a significant degree: 
- the safety or physical or mental integrity of the subjects of the trial; 
- the scientific value of the trial; 
- the conduct or management of the trial; or 
- the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. 
 
Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor.  
 

 
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12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the trial, SAEs/ serious adverse reactions, other problems, and amendments.  
 
12.5 Temporary halt and (prematurely) end of study report 
The sponsor will notify the accredited METC and the competent authority of the end of 
the study within a period of 90 days. The end of the study is defined as 18 months after 
the second vaccination of the last patient. 
 
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action. 
 
In case the study is ended prematurely, the sponsor will notify the accredited METC and 
the competent authority within 15 days, including the reasons for the premature 
termination. 
 
Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC and the Competent Authority. 
 
12.6 Public disclosure and publication policy 
This study is registered in a public trial registry (ClinicalTrials.gov), identifier 
NCT04715438. 
The results of the study will be disclosed unreservedly and are submitted to a peer 
reviewed scientific journal. Data will be presented at the European Society for Medical 
Oncoloy (ESMO) annual conference presidential symposium on September 20th, 2021. 
 
 
13. STRUCTURED RISK ANALYSIS  
 
Patients will be vaccinated against COVID-19 according to the standard of care in the 
Netherlands. It is anticipated that a third vaccination will become standard of care for 
immunocompromized patients in the Netherlands by Autumn 2021, as is already the case in 
several other countries. The vaccine is approved for use by EMA and CBG. A full synthesis 

 
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of the risk of vaccination with mRNA-1273 SARS-CoV-2 vaccine   can be found in the SPC. 
The burden for the subject is described in section 11.4.  
Patients who receive cancer treatment might have a higher risk of AEs related to vaccination, 
therefore safety is a secondary endpoint and will be assessed by collection of solicited AEs, 
SAEs, AESIs and irAEs. 
 
 
 
 
 

 
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43. Kamar N, Abravanel F, Marion O, et al. Three doses of an mRNA Covid-19 vaccine in 
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Appendix 1: Toxicity grading scale for solicited systemic and local adverse events. 
 
Mild 
Moderate 
Severe 
Arthralgia  
No interference  
with activity  
Some interference  
with activity  
Significant;  
prevents daily  
activity  
Fatigue  
No interference  
with activity  
Some interference  
with activity  
Significant;  
prevents daily  
activity  
Fever  
38.0°C – 38.4°C  
38.5°C – 38.9°C  
39.0°C - 40°C  
Chills  
No interference  
with activity  
Some interference  
with activity  
Significant;  
prevents daily  
activity  
Headache  
No interference with  
activity  
Repeated 
use 
of 
non-  
narcotic pain  
reliever > 24 hours 
or  
some interference  
with activity  
Significant; any  
use of narcotic  
pain reliever or  
prevents daily  
activity  
Myalgia  
No interference  
with activity  
Some interference  
with activity  
Significant;  
prevents daily  
activity  
Nausea  
No interference  
with activity or 1 – 2  
episodes/24 hours  
Some interference  
with activity or > 2  
episodes/24 hours  
Prevents daily  
activity, requires  
outpatient IV  
hydration  
Size (diameter) of 
erythema/redness  
2.5 – 5 cm  
5.1 – 10 cm  
> 10 cm  
Size (diameter) of 
induration/swelling  
2.5 – 5 cm  
5.1 – 10 cm  
> 10 cm  
Pain 
(at 
injection 
site)  
Does not interfere  
with activity  
Repeated 
use 
of 
non-narcotic 
pain 
reliever > 24 hours 
or 
interferes 
with 
activity  
Any use of narcotic 
pain 
reliever 
or 
prevents daily  
activity  
 

 
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Appendix 2: Adverse events of special interest 
 
Body 
system/ 
Classification 
AESI  
Auto-immune diseases 
Guillain-Barre Syndrome (GBS) 
 
Acute disseminated encephalomyelitis (ADEM) 
 
Narcolepsy 
 
Acute aseptic arthritis 
 
Type I Diabetes 
Cardiovascular system 
Acute cardiovascular injury including: Microangiopathy, Heart 
failure, Stress cardiomyopathy, Myocarditis 
Circulatory system 
Single Organ Cutaneous Vasculitis 
Nerves 
and 
central 
nervous 
System 
Generalized convulsion 
Meningoencephalitis 
Transverse myelitis 
Respiratory system 
Acute respiratory distress syndrome 
Skin 
and 
mucous 
membrane, 
bone and joints system 
Erythema multiforme 
Other system 
Anaphylaxis 
 
Death (any causes) 
Other 
Any AE that is considered of special interest in relation to 
vaccination by the treating physician 
 
 
 
 

 
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Appendix 3: ECOG performance status 
 
ECOG performance status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair 
5 
Dead 
 
 
 

 
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Appendix 4: Summary of product characteristics 
 
 
https://www.ema.europa.eu/en/documents/product-information/spikevax-previously-covid-19-
vaccine-moderna-epar-product-information_en.pdf