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ctDNA and Metabolites in CSF as Early Biomarkers of Secondary CNS Involvement in Diffuse Large B-cell Lymphoma (CNSctDNA)

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ClinicalTrials.gov Identifier: NCT04112238
Recruitment Status : Recruiting
First Posted : October 2, 2019
Last Update Posted : October 4, 2019
Sponsor:
Collaborator:
Weill Medical College of Cornell University
Information provided by (Responsible Party):
Lars Møller Pedersen, Herlev Hospital

Brief Summary:
The study is a prospective clinical study which investigates the use of new diagnostic methods to localize aggressive lymphoma involving the central nervous system(CNS). By measuring cell-free tumor DNA and metabolomics in cerebrospinal fluid and blood in patients with systemic Diffuse Large B-cell Lymphoma the investigators aim to improve the diagnostic certainty of an impending relapse of lymphoma in CNS.

Condition or disease
Diffuse Large B Cell Lymphoma Central Nervous System Metastasis

Detailed Description:

Diffuse Large B-cell Lymphoma is a malignant, aggressive cancer representing 40% of Non-Hodgkin Lymphomas globally. The risk of relapse after primary treatment is approximately 30% of which up to 10 % occurs in the central nervous system (CNS). The prognosis after CNS relapse is severely discouraging with an overall survival of 3-6 months. Currently CNS relapse is diagnosed by either flow cytometry performed on cerebrospinal fluid or a stereotactic biopsy based on tumor localization by an MRI scan. Both diagnostic methods however require a certain tumor mass in order avoid false negative test results.

The purpose of this study is to learn whether tumor-derived cell-free circulating DNA (cfDNA) and/or metabolite profiles from diffuse large B-cell lymphoma (DLBCL) cells can be identified in the cerebrospinal fluid (CSF), before the malignant cells themselves are detectable in CSF. Thus the investigators aim to investigate the diagnostic potential of cfDNA and/or metabolites measured in blood and cerebrospinal fluid. The study is based on the following four hypotheses:

Hypothesis 1: Measurement of cfDNA and/or metabolites in CSF are more sensitive methods of detecting DLBCL involvement in CNS compared to conventional diagnostics.

Hypothesis 2: Quantitative cfDNA/metabolomics in CSF has independent prognostic value in DLBCL.

Hypothesis 3: cfDNA and/or metabolite profile in CSF detected at primary diagnosis predicts relapse of DLBCL in the CNS also when CNS-IPI is taken into account.

Hypothesis 4: Particular aberrations of cfDNA and/or metabolite profiles detected in blood (plasma) may, in some cases, be associated with CNS involvement in DLBCL patients and/or predict CNS relapse.

The study is composed of a pilot study including 5 patients with verified either primary or secondary CNS lymphoma followed by two studies: One including 40 patients with de novo DLBCL and one including 30 patients in a relapse setting. The patients will have to consent to having a lumbar puncture performed and blood samples taken before treatment initiation. After treatment a second set of lumbar puncture and blood samples will be requested.

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Study Type : Observational [Patient Registry]
Estimated Enrollment : 75 participants
Observational Model: Case-Only
Time Perspective: Prospective
Target Follow-Up Duration: 2 Years
Official Title: Circulating Cell-free Tumor DNA and Metabolites in Cerebrospinal Fluid as Early Biomarkers of Secondary CNS Involvement in Diffuse Large B-cell Lymphoma
Actual Study Start Date : August 29, 2019
Estimated Primary Completion Date : June 2023
Estimated Study Completion Date : June 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma




Primary Outcome Measures :
  1. CSF tumor cfDNA and metabolite detectability and cytological/flow cytometric confirmation of CNS lymphoma at the time of diagnosis and relapse [ Time Frame: Two years ]

Secondary Outcome Measures :
  1. Progression free survival, PFS (time between inclusion and progression or relapse or beginning of a new treatment) [ Time Frame: Two years ]
  2. Overall survival, OS (time between inclusion and death) [ Time Frame: Two years ]
  3. Comparison of tumor cfDNA and metabolite levels and composition in CSF with levels in plasma at the time of diagnosis and relapse [ Time Frame: Two years ]
  4. For patients with both a pre- and a post-treatment CSF sample: correlation of cfDNA/metabolite levels pre-treatment to post-treatment with OS and risk of relapse. [ Time Frame: Two years ]
  5. Correlation of tumor cfDNA and metabolite levels and composition in CSF and patient survival at the time of diagnosis and relapse [ Time Frame: Two years ]
  6. Correlation of tumor cfDNA and/or metabolite identification in CSF of patients prior to diagnosis of CNS lymphoma at the time of diagnosis and relapse versus the appearance of later CNS lymphoma involvement [ Time Frame: Two years ]
  7. Comparison of the clonal similarity between tumor DNA in the blood and the CSF at relapse versus tumor DNA in the primary tumor (by NGS panel sequencing) [ Time Frame: Two years ]
  8. Comparison of CSF cytokines, other biomarkers and tumor DNA and metabolic profile in the prediction of CNS lymphoma disease [ Time Frame: Two years ]
  9. Comparison of mutational profile in diagnostic biopsy and/or cfDNA in peripheral blood with cfDNA in CSF and comparison of metabolic profiles in blood versus CSF in patients with and without development of CNS relapse. [ Time Frame: Two years ]
  10. YKL-40 in CSF as biomarker of CNS lymphoma [ Time Frame: Two years ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
See above
Criteria

Pilot Study:

Inclusion criteria:

  1. Verified or suspected primary CNS lymphoma or verified or suspected DLBCL relapsed in the CNS
  2. Treatment of the relapse not initiated (except pretreatment with corticosteroids)
  3. Age ≥ 18 years
  4. Patient must consent to genetic and metabolomic analysis of their cancer
  5. Written informed consent

Exclusion criteria:

  1. Evidence of a CNS mass creating mass‐effect or midline shift such that lumbar puncture is contraindicated
  2. Other contraindications to lumbar puncture according to local guidelines
  3. Other previous or current hematological malignancy
  4. Prior treatment for CNS disease (except CNS prophylaxis in first line lymphoma treatment)
  5. Known CNS autoimmune or inflammatory disease
  6. Known HIV infection
  7. Patient is currently receiving treatment for DLBCL

Study 1

Inclusion criteria:

  1. Previously diagnosed histologically documented DLBCL
  2. Verified relapsed DLBCL
  3. ≥ 1 prior DLBCL treatments
  4. Treatment of the relapse not initiated (except pretreatment with corticosteroids)
  5. Being able to undergo standard assessment ( eg, Fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG-PET), MRI of the neuroaxis and bone marrow biopsy)
  6. Tumor biopsy and/or bone-marrow biopsy used for diagnosis available
  7. Age ≥ 18 years
  8. ECOG performance status of 0, 1 or 2
  9. Life expectancy ≥ 12 weeks
  10. Patient must consent to permit genetic and metabolomic analysis of their cancer
  11. Patient must consent to permit access to records in order to ascertain progression or relapse of their cancer
  12. Written informed consent

Exclusion criteria:

  1. Evidence of a CNS mass creating mass‐effect or midline shift such that lumbar puncture is contraindicated
  2. Other contraindications to lumbar puncture according to local guidelines
  3. Other previous or current hematological malignancy
  4. Previous or current primary CNS malignancy including know DLBCL relapse to the CNS
  5. Prior treatment for CNS disease (except CNS prophylaxis in first line lymphoma treatment)
  6. Known CNS autoimmune or inflammatory disease
  7. Known HIV infection
  8. Patient is currently receiving treatment for DLBCL (except pretreatment with corticosteroids)

Study 2

Inclusion criteria:

  1. A newly diagnosed and histologically verified DLBCL
  2. No prior DLBCL treatments
  3. Anti-lymphoma treatment not initiated (except pretreatment with corticosteroids)
  4. CNS-IPI >/= 3
  5. Being able to undergo standard assessment ( eg, Fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG-PET), MRI of the neuroaxis and bone marrow biopsy)
  6. Tumor biopsy and/or bone-marrow biopsy used for diagnosis available
  7. Age ≥ 18 years
  8. ECOG performance status of 0, 1 or 2
  9. Life expectancy >/= 12 weeks
  10. Patient must consent to permit genetic analysis of their cancer
  11. Patient must consent to permit access to records in order to ascertain progression or relapse of their cancer
  12. Written informed consent

Exclusion criteria:

  1. Evidence of a CNS mass creating mass‐effect or midline shift such that lumbar puncture is contraindicated
  2. Other contraindications to lumbar puncture according to local guidelines
  3. Other previous or current hematological malignancy
  4. Previous or current primary CNS malignancy including primary CNS lymphoma
  5. Prior treatment for CNS disease
  6. Known CNS autoimmune or inflammatory disease
  7. Known HIV infection
  8. Patient is currently receiving treatment for DLBCL (except pretreatment with corticosteroids)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04112238


Contacts
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Contact: Anne Elisabeth Reuben Tolley, MD +4538686877 anne.elisabeth.reuben.tolley@regionh.dk
Contact: Lars Møller Pedersen, MD, PhD +4538686527 lars.moeller.pedersen.1.@regionh.dk

Locations
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Denmark
Herlev Hopital Recruiting
Herlev, Capital Region, Denmark, 2730
Contact: Anne Elisabeth Reuben Tolley, MD    +4538686877    anne.elisabeth.reuben.tolley@regionh.dk   
Contact: Lars Møller Pedersen, MD, PhD    +4568686527    lars.moeller.pedersen.01@regionh.dk   
Sponsors and Collaborators
Herlev Hospital
Weill Medical College of Cornell University
Investigators
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Principal Investigator: Anne Elisabeth Reuben Tolley, MD Herlev Hospital

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Responsible Party: Lars Møller Pedersen, Senior consultant, Herlev Hospital
ClinicalTrials.gov Identifier: NCT04112238    
Other Study ID Numbers: CNSctDNA
First Posted: October 2, 2019    Key Record Dates
Last Update Posted: October 4, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin