LIBERTY: Liquid Biopsy to Diagnose and Monitor CNS Involvement in High-risk B Cell Non-Hodgkin Lymphoma (SAKK 38/23)

March 13, 2024 updated by: Swiss Group for Clinical Cancer Research

LIBERTY: Liquid Biopsy to Diagnose and Monitor Central Nervous System (CNS) Involvement in High-risk B Cell Non-Hodgkin Lymphoma

Prevention and treatment of CNS relapse remains a great unmet clinical need in the management of aggressive B-NHL. Hence, investigating novel diagnostic tests is of paramount importance to improve risk-stratification of lymphoma patients at diagnosis, as is the evaluation of novel therapeutic approaches that may prevent and / or treat CNS recurrence. Based on the highlighted evidence, the investigators hypothesize that ctDNA detected within the CSF could potentially improve the detection rate of CNS involvement and consequently improve patients' stratification and better discriminate those in need of consolidative CNS prophylaxis on a molecular basis. Similarly, the investigators postulate that CSF ctDNA could be used as a monitoring tool to assess treatment response and guide therapeutic management.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Non-Hodgkin B-cell lymphoma (B-NHL) are cancers that arise from a subtype of white blood cells (lymphocyte) and typically involve the lymphatic system; they represent 4% of all cancers [SEER database, access 2022]. Despite booming novel antineoplastic agent development, a significant number of aggressive B-NHL patients continue to succumb to their disease, experiencing rapidly progressive disease or early relapse. Central nervous system or CNS (brain, spinal cord and cerebrospinal fluid (CSF)) involvement in aggressive B-NHL is a rare (2-5%) but it is a devastating event, with a life expectancy ranging between 2 and 5 months [PMID: 30125215]. Circulating tumor DNA (ctDNA) represents fragmented DNA that originates from tumors cells, carrying specific cancer-associated mutations that can be detected in the blood or other fluids subsumed under "liquid biopsies".

The role of ctDNA gained momentum with the advent of high throughput sequencing technologies, becoming increasingly relevant for clinical practice. In lymphoma, detecting and monitoring ctDNA has been shown to be feasible and of high prognostic relevance regarding response and relapse. As such, ctDNA is emerging as a promising biomarker that can provide valuable diagnostic and prognostic information [PMID: 30125215, PMID: 29449275]. Identification of patients suffering from aggressive B-NHL at high risk of CNS relapse remains extremely challenging and currently mainly relies on a clinical score (CNS-IPI) [PMID: 27382100]. The detection of asymptomatic CNS is limited to conventional techniques and is not standardized [PMID: 22927246]. In patients with biopsy-proven CNS lymphoma, ctDNA can be detected in CSF (CSF ctDNA) in approximately 95% of cases. Furthermore, CSF ctDNA is predictive of CNS relapse in a small series of neurologically asymptomatic patients with aggressive B-NHL [PMID: 36542815, PMID: 32079701, PMID: 34551072]. Prevention and treatment of CNS involvement remains a great unmet clinical need. The discovery of novel and robust biomarkers is of paramount importance for early detection and risk-adapted therapeutic strategies for CNS involvement. The investigators hypothesize that CSF ctDNA is superior to current standard diagnostic procedures (e.g., flowcytometry or cytology) to detect CNS involvement in high-risk patients.

Furthermore, in patients with positive CSF ctDNA, the investigators also postulate that the concept of monitoring minimal residual disease (MRD, small amount of ctDNA that persists in patients that have no signs of active disease on standard imaging techniques) will provide additional information on patient prognosis.

This is a multicenter prospective diagnostic study to compare the performance of experimental diagnostic test (ctDNA) versus conventional cytology (CC) and flow cytometry (FC). Each high-risk B-NHL participant will proceed through standard work-up to evaluate potential CNS involvement including a neurological physical examination, a brain MRI and a diagnostic lumbar puncture. Each participant's CSF will be assessed by the two diagnostic tests (CSF ctDNA and conventional test (CC/FC)); the gold standard being proven CNS lymphoma involvement.

Study Type

Interventional

Enrollment (Estimated)

64

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Sabrina Chiquet
  • Phone Number: +41 31 389 91 91
  • Email: trials@sakk.ch

Study Locations

  • Switzerland
      • Aarau, Switzerland, 5001
        • Not yet recruiting
        • Kantonspital Aarau
        • Contact:
        • Principal Investigator:
          • Marc Heizmann, MD
      • Basel, Switzerland, 4056
        • Recruiting
        • Universitätsspital Basel
        • Contact:
        • Principal Investigator:
          • Benjamin Kasenda, MD
      • Bellinzona, Switzerland, 6500
        • Not yet recruiting
        • Istituto Oncologico della Svizzera Italiana (IOSI)
        • Contact:
        • Principal Investigator:
          • Maria Pirosa, MD
      • Bern, Switzerland, 3010
        • Recruiting
        • Inselspital Bern - Universitätsklinik für Medizinische Onkologie
        • Principal Investigator:
          • Urban Novak, MD
        • Contact:
      • Chur, Switzerland, 7000
        • Recruiting
        • Kantonsspital Graubunden
        • Principal Investigator:
          • Ulrich Mey, Prof
        • Contact:
      • Fribourg, Switzerland, 1708
        • Recruiting
        • Hôpital Fribourgeois - Hôpital Cantonal
        • Principal Investigator:
          • Gaëlle Rhyner Agocs, MD
        • Contact:
      • Geneva, Switzerland, 1205
        • Recruiting
        • Hopitaux Universitaire de Genève (HUG)
        • Principal Investigator:
          • Noémie Lang, MD
        • Contact:
      • Lausanne, Switzerland, 1011
        • Not yet recruiting
        • CHUV - Départment d'oncologie
        • Contact:
        • Principal Investigator:
          • Amandine Segot, MD
      • Liestal, Switzerland, 4410
        • Recruiting
        • Kantonsspital Baselland
        • Contact:
        • Principal Investigator:
          • Michèle Voegeli, MD
      • Sion, Switzerland, 1951
        • Recruiting
        • Hôpital du Valais, Hôpital de Sion
        • Contact:
        • Principal Investigator:
          • Grégoire Berthod, MD
      • St. Gallen, Switzerland, 9007
        • Recruiting
        • Kantonsspital St. Gallen
        • Principal Investigator:
          • Felicitas Hitz, MD
        • Contact:
      • Zurich, Switzerland, 8032
        • Recruiting
        • Klinik für Hämatologie und Onkologie Hirslanden Zürich
        • Contact:
        • Principal Investigator:
          • Christoph Renner, Prof
      • Zürich, Switzerland, 8063
        • Recruiting
        • Stadtspital Triemli Zürich
        • Principal Investigator:
          • Adrian Schmidt, MD
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Informed consent as documented by signature before registration and prior to any trial specific procedures, according to Swiss law and ICH E6 regulations Swiss law and ICH GCP E6(R2) regulations before registration.
  • Histologically and/or cytologically confirmed newly diagnosed lymphomas including the following:

  • Diffuse large B-cell lymphoma (DLBCL) with at least one of the following characteristics:

    • CNS IPI > 4
    • Non-GC/ABC subtype with IPI > 3
    • Testicular involvement
    • Breast involvement
    • Kidney involvement
    • Adrenal involvement
    • Paranasal sinus / orbit involvement
    • Involvement of ≥ 3 extranodal sites
    • HIV-positive
    • Radiological or histological CNS involvement
  • High-grade B-cell lymphoma with MYC translocation with BCL2 and / or BCL6 (HGBL)
  • Burkitt lymphoma
  • Mantle cell lymphoma (blastoid variant or Ki67 >30% or TP53 mutated)
  • Primary CNS lymphoma

Note:

  • Aggressive transformation from indolent lymphomas (pretreated or not) are allowed

  • Patients enrolled in other clinical trials may be included

    • Patients must be willing to undergo a lumbar puncture at screening
    • Age ≥ 18 years

Exclusion Criteria:

  • Subtypes of Non-Hodgkin lymphoma (NHL) not fulfilling above mentioned criteria (e.g., indolent lymphoma, T-cell lymphoma)
  • Relapsing B-NHL
  • Low/intermediate-risk DLBCL (CNS-IPI < 4) AND no CNS involvement on imaging
  • Any prior lymphoma-directed therapy before registration, with the exception of a maximum of 48 hours steroids prior to lumbar puncture procedure and therapies received for indolent lymphomas prior to transformation
  • Any active advanced or metastatic cancer
  • Any clinical contraindication to lumbar puncture procedure as per local guidelines
  • Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned diagnostic procedure.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: experimental diagnostic test
Lumbar punction at diagnosis. CSF and blood samples will be assessed by the two diagnostic tests (CSF ctDNA and conventional test (CC/FC))
Diagnostic test: ctDNA detection
ctDNA detection on CSF and blood

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Sensitivity
Time Frame: at baseline

Sensitivity of liquid biopsy (ctDNA) measured within CSF in its performance to detect CNS involvement in newly diagnosed high-risk B-NHL in comparison to standard conventional diagnostic approaches (CC / FC). For the evaluation of the primary endpoint, only patients with confirmed CNS involvement at baseline (real positives) will be analyzed. CNS involvement at baseline is defined as having at least one of the following conditions:

  • Positive brain or spine MRI
  • Neurological symptoms of lymphoma manifestations (including ophthalmic symptoms)
  • Histologically confirmed CNS involvement
at baseline

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Specificity
Time Frame: at baseline

Specificity of liquid biopsy (ctDNA) measured within CSF in its performance to detect CNS involvement in newly diagnosed high-risk B-NHL in comparison to standard conventional diagnostic approaches (CC / FC). For the evaluation of specificity, only patients without CNS involvement at baseline (real negatives) will be analyzed. Absence of CNS involvement at baseline is defined as having none of the following conditions:

  • Positive brain or spine MRI
  • Neurological symptoms of lymphoma manifestations (including ophthalmic symptoms)
  • Histologically confirmed CNS involvement
at baseline
Time to lymphoma manifestation in the CNS
Time Frame: from the date of registration until the date of assessment of neurological symptoms or death due to lymphoma, assessed up to 1 year after registration

Time to lymphoma manifestation in the CNS, defined as time from diagnosis to one of the following events, whatever occurs first:

  • Clinical neurological symptoms likely related to lymphoma manifestations
  • Brain or spine MRI changes compatible with lymphoma involvement
  • Histologically confirmed CNS involvement
  • Confirmed involvement of the eye (positive CC / FC)
  • Death due to lymphoma Patients without lymphoma manifestation in the CNS will be censored at their last tumor assessment by CNS imaging showing non-progression
from the date of registration until the date of assessment of neurological symptoms or death due to lymphoma, assessed up to 1 year after registration
Progression-free survival (PFS)
Time Frame: from the date of registration until the date of progression or relapse as per Lugano and / or IPCG criteria, or death whatever occurs first, assessed up to 1 year after registration
PFS is defined as the time from diagnosis to lymphoma progression or relapse as per Lugano and / or IPCG criteria, or death whatever occurs first. Patients not having an event at the time of the analysis will be censored at the date of their last tumor assessment showing non-progression.
from the date of registration until the date of progression or relapse as per Lugano and / or IPCG criteria, or death whatever occurs first, assessed up to 1 year after registration
Event-free survival (EFS)
Time Frame: from the date of registration until the date of progression or relapse as per Lugano and / or IPCG criteria, treatment stop without achieving a complete response or death whatever occurs first, assessed up to 1 year after registration
EFS is defined as the time from diagnosis to lymphoma progression or relapse as per Lugano and / or IPCG criteria, treatment stop without achieving a complete response or death whatever occurs first. Patients not having an event at the time of analysis will be censored at the date of their last tumor assessment showing non-progression. This endpoint will be calculated separately for each treatment line.
from the date of registration until the date of progression or relapse as per Lugano and / or IPCG criteria, treatment stop without achieving a complete response or death whatever occurs first, assessed up to 1 year after registration
Overall survival (OS)
Time Frame: from the date of registration until the date of death, assessed up to 1 year after registration
OS will be calculated from diagnosis until death from any cause. Patients not experiencing an event will be censored at the last date they were known to be alive.
from the date of registration until the date of death, assessed up to 1 year after registration
Overall response rate (ORR)
Time Frame: At the date of tumor assessment according to the Lugano criteria, assessed up to 1 year after registration

Overall response rate (ORR) is defined as either PR or CR according to the Lugano criteria. Patients with no tumor assessment will be considered:

  • non-ORR, if they have no following tumor assessment within the trial (patient died, refused or was lost to follow-up) or if they have non-ORR at the following tumor assessment after the end of therapy.
  • ORR, if they have ORR at the following tumor assessment after end of therapy. This endpoint will be calculated separately for each treatment line.
At the date of tumor assessment according to the Lugano criteria, assessed up to 1 year after registration
Duration of response (DOR)
Time Frame: from the date of first response CR until the date of lymphoma progression, relapse or death, whatever occurs first, assessed up to 1 years after registration
DOR is evaluated in all patients who achieved a CR after the end of the intended treatment. DOR is defined as time from first complete response until lymphoma progression, relapse or death, whatever occurs first. Response and progression are evaluated according to Lugano criteria. Patients not having an event at the time of analysis will be censored at the date of their last tumor assessment showing non-progression.
from the date of first response CR until the date of lymphoma progression, relapse or death, whatever occurs first, assessed up to 1 years after registration
Time to minimal residual disease (MRD) negativity
Time Frame: from the date of first documented MRD positivity (CSF ctDNA detected positive) to the date of first documented MRD negativity, assessed up to 1 years after registration
Time from first documented MRD positivity (CSF ctDNA detected positive) to first documented MRD negativity. Patients not reaching MRD negativity will be censored at the last time they were known to be MRD positive. Evaluated only in patients with documented MRD positivity at any time.
from the date of first documented MRD positivity (CSF ctDNA detected positive) to the date of first documented MRD negativity, assessed up to 1 years after registration

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Swiss Group for Clinical Cancer Research

Investigators

  • Study Chair: Noémie Lang, MD, Hôpitaux Universitaires Genève

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 12, 2024

Primary Completion (Estimated)

December 1, 2026

Study Completion (Estimated)

December 1, 2026

Study Registration Dates

First Submitted

October 12, 2023

First Submitted That Met QC Criteria

October 18, 2023

First Posted (Actual)

October 19, 2023

Study Record Updates

Last Update Posted (Actual)

March 15, 2024

Last Update Submitted That Met QC Criteria

March 13, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SAKK 38/23

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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