Version number: 6.0, 27 December 2021 36 of 49 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 Su bjects 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, pote ntial participants will be identified early at oncology clinics in the participating institutes and informed about :  the aims of the study  the p otential risks of participation  the procedures and the possible hazards to which participants will be e xposed  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 ph ysician A pre-screening Participant Information Form (PIF) will be offered. After signing pre- screen ing informed consent (IC), baseline information will be collected and eligibility for the study will be estimated. A list of potential ly eligible individual s will be created who can be contacted immediately when the vaccine is available . Potential participants will t hen receive the study PIF . Both the pre -screening PIF and the study PIF will be submitted to the MET C 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 do ctor 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 Version number: 6.0, 27 December 2021 37 of 49 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 conseq uences 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 pat ients 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 wil l 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 offer ed 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 can cer 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 eve nts were reported after the administration of the third dose, and no acute rejection episodes occurred [43]. The FDA Version number: 6.0, 27 December 2021 38 of 49 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 month s 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, a nd 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 th e 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 Dutc h Personal Data Protection Act). For the study participants who give separate consent, information on positive COVID -19 tests Version number: 6.0, 27 December 2021 39 of 49 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 fin ished. 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 201 9” 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 re search 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 c opies 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); AE SIs/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 shor tcomings; 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 ME TC 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 ME TC and to the competent authority . Non-substantial amendments will not be notified to the accredited ME TC and the competent authority , but will be recorded and filed by the sponsor. Version number: 6.0, 27 December 2021 40 of 49 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) e nd 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, includi ng 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 an d the Competent Authority. 12.6 Public disclosure and public ation 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 b e vaccinated against COVID -19 according to the standard of care in the Netherlands . It is antic ipated 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 Version number: 6.0, 27 December 2021 41 of 49 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 h ave 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. Version number: 6.0, 27 December 2021 42 of 49 14.