New Strategies to Detect Cancers in Carriers of Mutations in RB1 (NIRBTEST)

New Strategies to Detect Cancers in Carriers of Mutations in RB1: Blood Tests Based on Tumor-educated Platelets, or Extracellular Vesicles.

Rationale: Individuals with a cancer predisposition due to a mutation in the paradigm tumor suppressor gene RB1, have a high risk to develop the childhood cancer retinoblastoma (Rb). Biopsies are not possible in Rb, before treatment selection. Heritable Rb patients have also a high risk to develop other types of second primary, either childhood or adult, malignancies (SPMs), notably sarcomas and melanomas. Remarkably, SPMs are now the leading cause of death in heritable-Rb-survivors. Unfortunately, there are no well-developed regular surveillance protocols for SPMs in Rb survivors available right now. Recently, new non-invasive cancer test have been developed, based on either RNA-sequencing data from platelets (ThromboSeq), or on extracellular membrane vesicles (EVs) derived from tumor cells present in blood.

Objective:

• Determine the non-cancerous baseline in adult RB1-mutation carriers (heritable-Rb-survivors).
• Contribute to the biobanking of blood and cancerous tissues from RB1-mutation carriers with SPMs.
• The development of blood-based tests, either platelet or EV-based, for the detection of (the type of) tumors in RB1-mutation carriers.

Study design: Cross-sectional multicenter trial.

Study population:

• 40 Rb patients (children),
• 40 controls (children),
• 153 Rb survivors (adults),
• 153 controls (adults),
• 10 Rb survivors with SPM (children/adults).

Main study parameters/endpoints:

• Determine the non-cancerous baseline in adult RB1-mutation carriers (heritable-Rb-survivors).
• Contribute to the biobanking of blood and cancerous tissues from RB1-mutation carriers with SPMs.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

Two blood samples totalling 10ml blood will be collected for every participant. Additionally, a short questionnaire has to be filled in concerning their and their family's cancer history. Blood draws will be done, when participants are already present in the hospital for other appointments, and thus no extra visits are required. For all children, blood will be collected through an already present IV, and so no extra venepuncture is required. Children have to be included because Rb is a tumor only present in this patient group.

Study Overview

• Status: Completed
• Conditions: Retinoblastoma; Secondary Primary Malignancies After Retinoblastoma
• Intervention / Treatment: Other: blood draw

• Study Type: Observational
• Enrollment (Actual): 378

Contacts and Locations

Study Locations

• France
  • Paris, France
    • Institute Curie
• Germany
  • Essen, Germany
    • University Hospital Essen (UHE)
• Netherlands
  • Amsterdam, Netherlands
    • Amsterdam UMC, location VUmc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 99 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Control samples for the Rb survivor group (adult) are already available at the VUMC for the platelet study; unselected volunteers from an anti-cancer campaign. Control samples (adult) for the EV study will be collected in a blooddrive at the Essen site.

Pediatric patients. For the pediatric Rb patients, blood draw is part of standard care (3mth-4y). The control blood samples of healthy children (12) will be drawn from healthy children, where the blood draw is already part of otherwise planned care (e.g. patients which are completely healthy besides having an unrelated problem for which surgery is required). Controls will be age-matched as much as possible.

Description

Inclusion Criteria:

Adult (16 years and older):

• Group 1: germline mutation RB1.
• Group 2 (control): no germline mutation RB1.

Pediatric (until 6 years of age):

• Group 1: somatic or germline mutation RB1 and retinoblastoma.
• Group 2 (control): no mutation RB1.

Exclusion Criteria:

Adult (16 years and older):

• Group 1: concomitant heritable (inherited) disorder other than caused by monoallelic mutation of RB1.
• Group 2 (control): cancer or already known cancer predisposition syndrome.

Pediatric (until 6 years of age):

• Group 1: concomitant heritable (inherited) disorder other than caused by monoallelic mutation of RB1.
• Group 2: cancer or already known cancer predisposition syndrome.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

5

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Retinoblastoma patients (children); Children that are currently diagnosed with a retinoblastoma. Blood will be collected and a short questionnaire has to be filled by the parent or legal guardian. Samples will be taken together with standard care blood draw, so no extra venepuncture is required.	Other: blood draw; Control samples for the Rb survivor group (adult) are already available at the VUMC for the platelet study; unselected volunteers from an anti-cancer campaign. Control samples (adult) for the EV study will be collected in a blooddrive at the Essen site. Pediatric patients. For the pediatric Rb patients, blood draw is part of standard care (3mth-4y). The control blood samples of healthy children (12) will be drawn from healthy children, where the blood draw is already part of otherwise planned care (e.g. patients which are completely healthy besides having an unrelated problem for which surgery is required). Controls will be age-matched as much as possible.
Controls (children); Children with an unrelated problem/condition for which surgery is needed Blood will be collected and a short questionnaire has to be filled by the parent or legal guardian. Samples will be taken during standard care blood draw, so no extra venepuncture is required.	Other: blood draw; Control samples for the Rb survivor group (adult) are already available at the VUMC for the platelet study; unselected volunteers from an anti-cancer campaign. Control samples (adult) for the EV study will be collected in a blooddrive at the Essen site. Pediatric patients. For the pediatric Rb patients, blood draw is part of standard care (3mth-4y). The control blood samples of healthy children (12) will be drawn from healthy children, where the blood draw is already part of otherwise planned care (e.g. patients which are completely healthy besides having an unrelated problem for which surgery is required). Controls will be age-matched as much as possible.
Retinoblastoma survivors (adults); Adults that carry a RB1 germline mutation and were diagnosed and treated for retinoblastoma in the past. Blood will be collected and a short questionnaire has to be filled.	Other: blood draw; Control samples for the Rb survivor group (adult) are already available at the VUMC for the platelet study; unselected volunteers from an anti-cancer campaign. Control samples (adult) for the EV study will be collected in a blooddrive at the Essen site. Pediatric patients. For the pediatric Rb patients, blood draw is part of standard care (3mth-4y). The control blood samples of healthy children (12) will be drawn from healthy children, where the blood draw is already part of otherwise planned care (e.g. patients which are completely healthy besides having an unrelated problem for which surgery is required). Controls will be age-matched as much as possible.
Controls (adults); Healthy adult controls Blood will be collected and a short questionnaire has to be filled.	Other: blood draw; Control samples for the Rb survivor group (adult) are already available at the VUMC for the platelet study; unselected volunteers from an anti-cancer campaign. Control samples (adult) for the EV study will be collected in a blooddrive at the Essen site. Pediatric patients. For the pediatric Rb patients, blood draw is part of standard care (3mth-4y). The control blood samples of healthy children (12) will be drawn from healthy children, where the blood draw is already part of otherwise planned care (e.g. patients which are completely healthy besides having an unrelated problem for which surgery is required). Controls will be age-matched as much as possible.
Retinoblastoma survivors with Secondary primary malignancies; Adults that carry a RB1 germline mutation, were treated for retinoblastoma in the past, and are currently diagnosed with a secondary primary malignancy. Blood will be collected and a short questionnaire has to be filled. Tumor tissue will be collected during surgery.	Other: blood draw; Control samples for the Rb survivor group (adult) are already available at the VUMC for the platelet study; unselected volunteers from an anti-cancer campaign. Control samples (adult) for the EV study will be collected in a blooddrive at the Essen site. Pediatric patients. For the pediatric Rb patients, blood draw is part of standard care (3mth-4y). The control blood samples of healthy children (12) will be drawn from healthy children, where the blood draw is already part of otherwise planned care (e.g. patients which are completely healthy besides having an unrelated problem for which surgery is required). Controls will be age-matched as much as possible.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
RNA expression on platelets and allelic DNA balance of EVs in the blood of adult RB1 mutation carriers (Rb-survivors) and retinoblastoma patients (children).	blood analyses at time of inclusion to determine baseline	blood will be taken at study inclusion, patients will be followed throughout the study, max 3 years and 9 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
RNA expression on platelets, allelic DNA balance of EVs in blood and genomic analysis on tumor tissue of RB1-mutation carriers diagnosed with a second primary malignancy.	Comparison of blood at time of inclusion and blood at time of SPM diagnosis versus tumor tissue (if available)	blood will be taken at study inclusion, patients will be followed throughout the study, max 3 years and 9 months. In case of second primary tumor a second sample will be taken.

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Collaborators: University Hospital, Essen; Institut Curie; Ligue contre le cancer, France
• Investigators: Principal Investigator: Armida Fabius, VUMC

Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2018
• Primary Completion (Actual): March 31, 2023
• Study Completion (Actual): March 31, 2023

Study Registration Dates

• First Submitted: November 7, 2019
• First Submitted That Met QC Criteria: November 12, 2019
• First Posted (Actual): November 15, 2019

Study Record Updates

• Last Update Posted (Actual): July 25, 2023
• Last Update Submitted That Met QC Criteria: July 24, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: cancer; Retinoblastoma; blood test; liquid biopsy; SPM; RB1; Secondary primary malignancies
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Eye Diseases; Retinal Diseases; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Eye Diseases, Hereditary; Eye Neoplasms; Retinal Neoplasms; Neoplasms; Retinoblastoma
• Other Study ID Numbers: 129; NL8013 (Registry Identifier: Nederlands Trial Register)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No