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

• ClinicalTrials.gov Identifier: NCT04164134
• Recruitment Status: Completed
• First Posted: November 15, 2019
• Last Update Posted: July 25, 2023
• Sponsor: Amsterdam UMC, location VUmc
• Collaborators: University Hospital, Essen; Institut Curie; Ligue contre le cancer, France
• Information provided by (Responsible Party): Armida W. M. Fabius, Amsterdam UMC, location VUmc

Tracking Information

• First Submitted Date: November 7, 2019
• First Posted Date: November 15, 2019
• Last Update Posted Date: July 25, 2023
• Actual Study Start Date: December 13, 2018
• Actual Primary Completion Date: March 31, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 12, 2019)

RNA expression on platelets and allelic DNA balance of EVs in the blood of adult RB1 mutation carriers (Rb-survivors) and retinoblastoma patients (children). [ Time Frame: blood will be taken at study inclusion, patients will be followed throughout the study, max 3 years and 9 months. ]

blood analyses at time of inclusion to determine baseline

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 12, 2019)

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. [ Time Frame: 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. ]

Comparison of blood at time of inclusion and blood at time of SPM diagnosis versus tumor tissue (if available)

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Observational
• Study Design: Observational Model: Case-Control; Time Perspective: Cross-Sectional
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

Serum, white blood cells, platelets, tissue

• 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.

Condition

• Retinoblastoma
• Secondary Primary Malignancies After Retinoblastoma

Intervention

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.

Study Groups/Cohorts

• 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.
  Intervention: Other: blood draw
• 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.
  Intervention: Other: blood draw
• 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.

  Intervention: Other: blood draw
• Controls (adults)
  Healthy adult controls Blood will be collected and a short questionnaire has to be filled.
  Intervention: Other: blood draw
• 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.

  Intervention: Other: blood draw

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 24, 2023): 378
• Original Estimated Enrollment (submitted: November 12, 2019): 396
• Actual Study Completion Date: March 31, 2023
• Actual Primary Completion Date: March 31, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 0 Years to 99 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, Germany, Netherlands

Administrative Information

• NCT Number: NCT04164134
• Other Study ID Numbers: 129; NL8013 ( Registry Identifier: Nederlands Trial Register )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Armida W. M. Fabius, Amsterdam UMC, location VUmc
• Original Responsible Party: Same as current
• Current Study Sponsor: Amsterdam UMC, location VUmc
• Original Study Sponsor: Same as current

Collaborators

• University Hospital, Essen
• Institut Curie
• Ligue contre le cancer, France

Investigators

• Principal Investigator: Armida Fabius; VUMC

• PRS Account: Amsterdam UMC, location VUmc
• Verification Date: July 2023