Liquid biopsy-based minimal residual disease monitoring for early risk stratification and decision-making in advanced non-small cell lung cancer - DEDICATION co-hort

The Project Data EGAC50000000832 was generated in Liquid biopsy-based minimal residual disease monitoring Project that included two real-world cohorts of 26 and 81 adults with histologically- or cytologically confirmed advanced NSCLC who started treatment with ICIs as part of (i) routine care at the Radboudumc, Nijmegen, The Netherlands, between May 2018 and April 2023 (BTO cohort), or the (ii) DEDICATION-1 study between November 2020 and December 2023 (DEDICATION-1 cohort), respectively. DEDICATION-1(/NVALT-30) is an ongoing Dutch open-label, randomized, controlled, multi-center study that aims to investigate the non-inferiority of a reduced pembrolizumab dose compared to its standard-of-care dose in advanced NSCLC patients eligible for first-line treatment with ICIs. Details regarding the trial design and study protocol have previously been published and can be found on clinicaltrials.gov (NCT04909684). The Liquid biopsy-based minimal residual disease monitoring Project aimed to (i) expand a next-generation sequencing (NGS) data analysis pipeline with an algorithm that automatically classifies serial cfDNA samples in terms of presence or absence of ctDNA, (ii) explore the potential value of ctDNA-based MRD monitoring with this algorithm for risk stratification and decision-making, and (iii) explore whether simultaneous STM monitoring could improve risk stratification and decision-making. Access to Project Data will be granted to qualified researchers for approved use and will be governed by the provisions laid out in the associated informed consent of individual data subjects for each cohort and/or of the associated ethics committee approval of the associated cohort, the Data Access Procedure set forth below and the terms of the Data Access Agreement attached hereto. A qualified researcher refers to a senior investigator who is employed or legitimately affiliated with an academic, non-profit or government institution and who has a track record in the field. Access to Project Data is available by application to the Liquid biopsy-based minimal residual disease monitoring Data Access Committee. Researchers granted access to Project Data must feedback the results of their research to this committee, after publication in accordance with the Liquid biopsy-based minimal residual disease monitoring publication policy set forth in the Data Access Agreement. Access is conditional upon availability of data and on signed agreement by the researcher(s) and the responsible employing institution to abide by the policies and conditions related to publication, data ownership, data return, intellectual property rights, data disposal, ethical approval, confidentiality and commercialization referred herein. Data Available The follow Project Data are available: CfDNA samples For the BTO cohort, peripheral blood was collected before start of and during treatment in EDTA K2E tubes (Becton Dickinson Vacutainer) and processed within maximally 4 hours after collection. Plasma was separated by centrifugation at 1600g for 10 minutes at room temperature, transferred to 5 mL polypropylene centrifugation tubes, centrifuged at 16,000g for 10 minutes at 4 °C to remove cellular debris, and stored at -80 °C. After plasma sample selection, the selected plasma samples were thawed at room temperature and Phosphate Buffered Saline (PBS) was added to reach a required volume between 8.2-8.5 mL. The selected plasma samples were then again stored at -80 °C before isolation and genomic analysis were performed. Additionally, whole blood was collected at baseline in EDTA K2E tubes (Becton Dickinson Vacutainer) and stored at room temperature before white blood cell (WBC) isolation and genomic analysis were performed. For the DEDICATION-1 cohort, peripheral blood was collected in Cell-Free DNA Collection Tubes® (Roche) before start of treatment and at 3, 6, 12, and 24 weeks after treatment start, and at end-of-study treatment as defined by the DEDICATION-1/NVALT-30 study protocol. For patients recruited at the Radboudumc, samples were processed within maximally 4 hours after collection. For patients recruited at external treatment sites, samples were first shipped to the Radboudumc and preferably processed within 24 hours after collection, taking into account the Cell-Free DNA Collection Tubes® (Roche) sample stability of 7 days. At the Radboudumc, plasma was first separated by centrifugation at 1600g for 10 minutes at room temperature, transferred to 5 mL cryogenic tubes, and stored at -80 °C. Buffy coat was collected after the initial centrifugation for (preferably) baseline samples and stored in the original collection tube at -80 °C. After plasma sample selection, the selected plasma samples were thawed at room temperature, pipetted into 5 mL polypropylene conical tubes, and centrifuged at 16,000g for 10 minutes at 4 °C to remove cellular debris. The supernatant was then pipetted into 10 mL conical tubes and PBS was added to reach a required volume between 8.2-8.5 mL. The selected plasma samples were again stored at -80 °C before isolation and genomic analysis were performed. DNA isolation, library preparation, and targeted sequencing For plasma samples, DNA was isolated from 8 mL plasma using the QIAsymphony DSP Circulating DNA kit (Qiagen) according to the manufacturer’s instructions and DNA was diluted in 60 μL low-TE buffer. The concentration and quality of purified plasma DNA was determined using a Tapestation (Agilent Cell-free DNA kit). A volume of 35 μL with a median concentration of 0.9 ng/μL (IQR: 0.6-1.6) (BTO cohort) and 1.7 ng/μL (IQR: 0.8-3.2) (DEDICATION-1 cohort) was used for library preparation and targeted sequencing. For buffy coat samples, DNA was isolated using the Chemagic DNA Blood 4K kit (PerkinElmer) according to the manufacturer’s instructions. WBC concentrations were measured using a Fluoreye (Hamilton) and DNA was mechanically fragmented on a Covaris (160 sec, 10 cycles, PIP 280, 25 DF, CPB 50, AIP 70). A median of 150 ng sheared gDNA was used for library preparation and targeted sequencing. For whole blood samples, gDNA isolation was performed within maximally 1 week after collection using the Chemagic STAR nucleic acid extraction robot (Hamilton) according to the manufacturer’s instructions. Targeted sequencing of all samples was carried out using an in-house developed and validated NGS panel (NEN-EN-ISO 15189+C11:2015), covering clinically relevant regions of 45 genes for different oncological indications (including NSCLC). Technical details have previously been described by Hofste et al. and Tolmeijer et al. Data Access Committee Applications for access to Project Data must be made to the Liquid biopsy-based minimal residual disease Data Access Committee (DAC), which consists of Alessandra Buma, Franziska Bervoets-Metge, Marjolijn Ligtenberg and Michel van den Heuvel. Data Access Procedure 1. Application for Access The handling of applications, the issue of Project Data and any associated operations, administration and audits will be performed by the Radboudumc on behalf of the Consortium. Applications for Access to Project Data must be submitted using the online EGA data request procedure and using the form in Appendix 1. The information disclosed in the application will be treated as confidential and will only be disclosed to the persons evaluating the application. All incoming applications will be documented, including any conjunct agreements with the applicants. Unless explicitly consented for by the applicant, this information will not be used for purposes other than evaluation of the application. The research topic of the applications which have been granted will be published on the website of the Project. Applications which have not been granted will not be published. In cases where an application contains classified plans, know-how or trade secrets, the applicant may request the conclusion of a separate confidentiality agreement. 2. Multiple applications Applicants agree to use the Project Data for the approved purpose and project described in the application; use of the data for a new purpose or project will require a new application and approval. The DAC will consider applications that include named collaborators, but each Institution must sign a separate Data Access Agreement. In the event an applicant wishes to share the data with additional collaborators not previously approved, these additional collaborators must make a separate application for access to the Project Data. In the event two or more applications overlap, the DAC may propose the respective applicants to align their applications. 3. Assessment criteria Applications which seek to reserve Project Data for unspecified research goals will not be taken into consideration. Applications for access to Project Data must be Specific, Measurable, Attainable, Resourced and Timely (SMART). Specifically, the Liquid biopsy-based minimal residual disease DAC will assess each application to determine whether: i. it has been submitted by a qualified researcher or researchers, who is employed by or legitimately affiliated with a recognised research institution that can provide institutional responsibility for appropriate research governance; ii. its proposed use of the Project Data is in accordance with and meets the objectives of the Liquid biopsy-based minimal residual disease Project and the objectives of the associated cohorts and collections; iii. its proposed use of the Project Data constitutes research in the context of the individual sample donor consent process, and is likely to be understood as such by the individual sample donors; iv. it would breach any of the ethical permissions or restrictions in the consent forms for any component cohort; v. all required ethico-legal approvals, restrictions and commitments for the proposed use of the Project Data have been obtained and adhered to; vi. the proposed research has any adverse potential impact, specifically whether the proposed research could affect minorities; vii. the nature of the funding of the application and the applicant; viii. the research proposal has been peer-reviewed, and, if not, whether the proposal satisfies applicable scientific standards; ix. the requested data are, quantitatively and qualitatively, suitable and not excessive for the applicant’s proposed research; x. there are any similar applications pending or granted; xi. the proposed use of the Project Data has the potential to produce information that will enable identification of the individual sample donors. xii. In the event the applicant(s)’ proposed use of Project Data involves use of his/their your own data the applicant has warranted that he has obtained all required ethico-legal approvals, restrictions and commitments, without limitation his data subject consent and approval of his pertinent medical ethical review board, for his proposed use of his data in combination with the Project Data, as appropriate. 4. Access decision The DAC will decide on an application within a reasonable period of time after it has received all pertinent information. If the DAC grants an application, additional agreements may be made regarding authorships along the lines set forth in the Publication Policy attached to the Data Access Agreement. Rejections of applications will be motivated. Mode of Access to Data; restrictions and authentication The DEDICATION-1 Consortium will make the pseudonymised Project Data available through the European Genome Phenome Archive (EGA), hosted at the European Bioinformatics Institute. Issue of Project Data may be subject to restrictions pursuant to data subject’s or ethics committee’s consent. The issue of Project Data and the Data Access Agreement will be administered by Radboudumc. Data Access Conditions Access to Project Data is conditional on prior receipt by the Consortium of the Data Access Agreement attached as Appendix 2 hereto, signed and dated by the applicant(s) and the responsible employing Institution(s). Authors who use Project Data must: 1. Acknowledge the DEDICATION-1 Consortium using the following wording: "This study makes use of data generated by the DEDICATION-1 Consortium. Funding for the project was provided by Stichting Treatmeds and Health-Holland to the DEDICATION-1 consortium.“ 2. Acknowledge, by reference, the DEDICATION-1 where the samples and Project Data have been derived from. 3. Cite the relevant primary Liquid biopsy-based minimal residual disease publication: Application Form for Access to Liquid biopsy-based minimal residual disease Data PLEASE SUBMIT COMPLETED, SIGNED AND DATED FORM BY EMAIL TO: alessandra.buma@radboudumc.nl 1. Name and position of the Applicant(s), including employment or affiliation with any organization Please ensure that a full postal and email address is included for each applicant. 2. Title of the study In less than 30 words. 3. Research Question Please describe the study in no more than 750 words. Include: a. outline of the study design; b. an indication of the methodologies to be used; c. proposed use of the Project Data; d. preceding peer-reviews of the study (if any present); e. specific details of what you plan to do with the Project Data; f. timeline; g. key references.   4. Consent and Approvals Does your proposed use of Project Data involve use of your own data? Yes […..] No […..] If Yes, with signing this document you confirm the following: ‘I confirm that I have obtained all approvals required by the rules and regulations of my jurisdiction, including my institution’s institutional rules, and the consent of my data subjects, for my use of my own data in combination with the Project Data in the study.’ 5. Resources, Feasibility & Expertise Please confirm that you have secured funding for your proposed use of the Project Data and that you will carry out your research within a reasonable period of time after the granting of this application: by ticking the following box: Yes, we will □. Please describe your experience and expertise, and that of your collaborators, and how this will be applied to the proposed study (in 250 words). Please provide a list of recent publications (max. 10). Appendix 2 Data Access Agreement This agreement governs the terms on which access will be granted to the Project Data generated by the Liquid biopsy-based minimal residual disease Project. In signing this agreement, You are agreeing to be bound by the terms and conditions of access set out in this agreement. For the sake of clarity, the terms of access set out in this agreement apply both to the User and the User’s Institution (as defined below). User Institution and User are referred to within the agreement as “You” and “Your” and shall be construed accordingly. Definitions: “Consortium” refers to the DEDICATION-1 Consortium. “Project” refers to the Liquid biopsy-based minimal residual disease project. “Project Data” refers to the human genomic data generated by the Project. “Data Subject” refers to the person whose sample has been used to generate Project Data. “User” refers to a researcher who has successfully applied for access to Project Data. “Publications” refers to, without limitation, articles published in print journals, electronic journals, reviews, books, posters and other written and verbal presentations of research. “User Institution” refers to the organization with which the User is employed, affiliated or enrolled. Terms and Conditions: In signing this Agreement: 1. You agree to use Project Data only for the advancement of scientific and medical research. 2. You agree not to use, and not to allow use of, Project Data or any part thereof for the creation of products or services for sale or for any commercial purpose, whether sale by You or by third parties. 3. You acknowledge that the Project Data You receive is pseudonymised and that the Consortium will under no circumstances provide You with any means to identify any Data Subject. You agree not to use Project Data to identify or contact individual Data Subjects. You agree to preserve, at all times, the confidentiality of information and Project Data. In particular, You undertake not to use, or attempt to use Project Data to compromise or otherwise infringe the confidentiality of information on Data Subjects and their right to privacy. 4. You agree to disclose Project Data only to those of Your employees who strictly need access to it for the purpose of your approved study (Authorized Recipients), and who are bound by a duty of confidentiality which is at least as strict as provided for in this agreement. 5. You agree to ensure that any Authorized Recipient who has access to Project Data is advised of the confidentiality of Project Data. Upon request by the Consortium, you agree to furnish the Consortium the names of all Authorized Recipients who have gained access to Project Data. You agree that You are responsible for all breaches of confidentiality and of the terms of this agreement by your Authorized Recipients. 6. You agree to store Project Data on a computer with adequate security controls that prevent unauthorized access to or loss of Project Data and to maintain appropriate control over the Project Data. You represent and warrant that You have in place, and You agree that You will keep having in place, state of the art technical and organizational security measures preventing unauthorized access and loss of Project Data or other forms of unlawful processing of Project Data, including without limitation, physical security measures, access controls, security and privacy technologies, security checks in relation to personnel, security incident response management and audit arrangements. You agree to notify forthwith the administrator of the Project, Radboudumc, of any violations of the foregoing. 7. You represent and warrant that you have obtained and adhered to all required ethico-legal approvals, restrictions and commitments, without limitation data subject consent and approval of the pertinent medical ethical review board, for Your proposed use of Your data in combination with the Project Data. 8. In the event the Project Data is issued to You subject to any Data Subject’s restrictions, you hereby assume the obligation to abide by these restrictions as Your own obligation towards the Data Subject. You agree that Data Subjects can enforce such restrictions as well as any pertinent provisions of this agreement as third-party beneficiaries and, in the event they choose to do so, that You will not object to Data Subjects being represented by an association or other bodies if they so wish. You agree that a Data Subject who has suffered damage(s) as a result of any violation by You of pertinent provisions in this Agreement or of applicable legislation, is entitled to receive compensation from You for the damage(s) suffered. You agree that, in the event of such a violation, the Data Subject may bring an action before a court within the Data Subject’s jurisdiction against You. 9. You agree not to attempt to link Project Data to other information or archive data available for the data sets provided to You under this agreement, even if access to that data has been formally granted to you, or it is freely available without restriction, without the required consents and approvals. You agree to retain control over Project Data, and NOT TO DISTRIBUTE (individual-level or aggregated) Project Data provided under this agreement, in any form, to any entity or individual. 10. You agree not to transfer, share or disclose Project Data, in whole or in part, to or with anybody else, whether or not he or she is affiliated with Your institution, unless he or she is a named and approved collaborator under the Liquid biopsy-based minimal residual disease Data Access Procedure. 11. You agree to use Project Data for the purpose and project described in your application (nr.____________________), as approved by the Liquid biopsy-based minimal residual disease Data Access Committee; use of the data for a new purpose or project or by another researcher will require a new application and approval. Substantive modification of the original application requires submission of an amendment to the original application. 12. You agree to, when analyses result in newly estimated variables at an individual level (e.g. haplotypes), submit these new variables for archiving with the Consortium. This should be done no later than that the related paper will be submitted for publication. 13. You accept that Project Data will be reissued from time to time, with suitable versioning. If the reissue is at the request of sample donors and/or subject to other ethical scrutiny, You will destroy earlier versions of the Project Data. 14. You agree to destroy the Project Data after the resulting paper has been published. To meet journals’ requirements for availability of Project Data for reviewers to see and readers to use, you agree to refer to the availability of the Project Data as deposited with EGA, under the terms hereof. You agree that the availability of the data resulting from your study of the Project Data for reviewers to see and readers to use is subject to this Access Policy, Procedure and this Data Access Agreement. 15. You agree to acknowledge in any work based in whole or in part on Project Data, the published paper from which the Project Data derives, the version of the data, and the role of the Consortium and the relevant primary collectors and their funders, as per the wording provided in the paragraph “Data Access Conditions”. 16. You accept that the Consortium, the original Project Data generators and the funders of the Project Data: a) bear no legal responsibility whatsoever for the accuracy, completeness or comprehensiveness of the Project Data; and b) accept no liability for direct, indirect, consequential or incidental, damages or losses arising from any use of Project Data by anyone, including without limitation any clinical use and any commercial use thereof, or arising from the unavailability of, or break in access to, the Project Data for whatever reason. 17. You understand and acknowledge that Project Data are protected by copyright, database right and other intellectual property and proprietary rights, and that duplication, sale, licensing or any other form of disposing or distribution or making available, of all or part of the Project Data on any media is not permitted. 18. You acknowledge that the Project Data are made available to you under this agreement on the title of unassignable, non exclusive “loan”. You recognise that nothing in this agreement shall operate to transfer to You any rights, including but not limited to intellectual property rights and database rights, in or relating to Project Data. 19. You accept that this agreement will terminate immediately upon any breach of this agreement by You and You will be required to destroy any Project Data held. 20. You accept that it may be necessary for the Consortium or its appointed agent to alter the terms of this agreement from time to time in order to address new concerns. In this event, the Consortium or its appointed agent will contact You to inform You of any changes and You agree that Your continued use of Project Data shall be dependent on the parties entering into a new version of the agreement. 21. You agree that You will submit a report to the Consortium Data Access Committee, if requested, on completion of your study of the Project Data. Such report will include the data resulting from your study of the Project Data. The Consortium Data Access Committee agrees to treat the report and all information, data, results, and conclusions contained within such report as confidential information. 22. You accept that Project Data may be protected by and subject to national and international laws and that You are responsible for ensuring compliance with any such applicable law. The Consortium Data Access Committee reserves the right to request and inspect Your data security and management documentation to ensure the adequacy of data protection measures in countries that have no national laws comparable to that which pertain in the European Economic Area (EEA). 23. This agreement shall be construed, interpreted and governed by the laws of the Netherlands. Signed by: ……………………………………………………………. ………………………………….……………………………………. Name of Applicant: Legal representative of Applicant’s Institution: Affiliation of Applicant with Institution: Name of Applicant’s Institution: ……………………………………………………………. ……………………………………………………………………….. Place:………………………………………………….. Place:……………………………………………………………… Date:…………………………………………………… Date:……………………………..……………………………….. Stamp or Seal of Applicant’s Institution: ………………………………………………………………………..