ctDNA-Guided Therapy for Non-Hodgkin's Lymphoma

Overseen By Research Nurse Navigator

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Hua-Jay J Cherng, MD

Disqualifiers: Pregnancy, CNS involvement, Richter transformation, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 6

Duration: 4 months

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The trial aims to determine if measuring circulating tumor DNA (ctDNA) in real-time during standard treatment for diffuse large B-cell lymphoma (DLBCL) can guide therapy decisions. Participants will receive standard immunochemotherapy for DLBCL, with blood samples taken to check ctDNA levels using Phased Variant Enrichment and Detection Sequencing (PhasED-seq). If ctDNA is undetectable mid-treatment and a scan shows no disease, participants may switch to a less intense treatment. This trial is suitable for those newly diagnosed with CD20+ DLBCL, who have not received prior treatment and are ready for outpatient care. As an unphased trial, this study offers a unique opportunity to contribute to innovative research that could personalize future DLBCL treatments.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that participants should not be on other anti-lymphoma therapies beyond R-CHOP or R-pola-CHP. It's best to discuss your current medications with the trial team to get a clear answer.

What prior data suggests that the PhasED-seq assay is safe for guiding treatment in DLBCL?

Research has shown that the PhasED-seq test, used in this trial, is designed to detect specific DNA changes in blood samples. Although the FDA has not yet approved this test, it remains safe as it involves only a blood test.

The trial does not introduce any new drugs. Participants will receive standard chemotherapy, which has been proven safe for treating diffuse large B-cell lymphoma (DLBCL). The test aims to assist in deciding treatment options, such as whether to adjust chemotherapy based on the results.

In summary, safety concerns are minimal because the test does not involve new medication. Participants will follow standard treatment methods that are well-known and widely used. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the ctDNA-Guided Therapy for Non-Hodgkin's Lymphoma because it uses a cutting-edge technique called Phased Variant Enrichment and Detection Sequencing (PhasED-seq). This approach allows doctors to monitor cancer's genetic material in the blood in real-time, providing insights into how well a patient is responding to treatment. Unlike traditional methods that rely solely on imaging and symptoms, this technique can detect minimal residual disease down to a molecular level. This precise monitoring can help tailor treatments more effectively, potentially reducing the need for aggressive chemotherapy if ctDNA is undetectable, leading to fewer side effects and improved quality of life for patients.

What evidence suggests that the PhasED-seq assay is effective for guiding treatment in Non-Hodgkin's Lymphoma?

Research has shown that the PhasED-seq test can significantly improve the detection of cancer DNA in the blood of patients with lymphoma. One study found that PhasED-seq identified cancer DNA in 25% more participants than older methods. This helps identify patients at a higher risk of cancer recurrence. This technology also enables doctors to monitor how well the cancer responds to treatment. In this trial, all participants will receive standard immunochemotherapy for the first four cycles, with blood samples collected for real-time ctDNA sequencing using the PhasED-seq assay. Participants in Group 1, who have undetectable ctDNA and a complete response on their PET/CT scan, will receive de-escalated treatment for cycles 5 and 6. Meanwhile, participants in Group 2, with detectable ctDNA or not in complete response, will continue standard care. Early results suggest that using PhasED-seq could help doctors adjust treatments, potentially leading to better outcomes for patients with diffuse large B-cell lymphoma (DLBCL). ^{5 6 7 8 9}

Who Is on the Research Team?

Hua-Jay J Cherng, MD

Principal Investigator

Columbia University

Are You a Good Fit for This Trial?

This trial is for individuals with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Participants will have their circulating tumor DNA (ctDNA) measured during standard chemotherapy to see if a shorter course of treatment can be just as effective.

Inclusion Criteria

Subject/legal representative willing and able to provide written informed consent

Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for duration of study participation

My organ and heart functions are good enough for standard cancer treatment.

Exclusion Criteria

My doctor thinks standard treatments won't work well for my condition.

My lymphoma has spread to my brain or spinal cord.

Simultaneous participation in other treatment clinical protocol

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive standard immunochemotherapy treatment for 4 cycles, with real-time ctDNA sequencing to guide potential de-escalation

4 months

4 cycles of treatment with blood sample collection

De-escalated Treatment

Participants with undetectable ctDNA and complete remission receive rituximab alone for cycles 5 and 6

2 months

2 cycles of rituximab treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Phased Variant Enrichment and Detection Sequencing (PhasED-seq)

Trial Overview

The study tests the use of PhasED-seq, an investigational assay not yet FDA-approved, to guide therapy. It aims to determine if patients with undetectable ctDNA midway through treatment can safely receive less chemotherapy than usual.

How Is the Trial Designed?

Group I: Group 2 Experimental Treatment 2 Interventions

All participants on this study will receive standard immunochemotherapy treatment for the first 4 cycles. Blood samples will be collected for real-time ctDNA sequencing with the PhasED-seq assay. Participants with detectable ctDNA, not in in a CR on PET/CT, and/or whose ctDNA sequencing was unsuccessful for any reason will continue standard of care for the remainder of treatment (cycle 5 and 6).

Group II: Group 1 Experimental Treatment 2 Interventions

All participants on this study will receive standard immunochemotherapy treatment for the first 4 cycles. Blood samples will be collected for real-time ctDNA sequencing with the PhasED-seq assay. Participants with undetectable ctDNA from the first day of cycle 4 and in a complete response (CR) on their PET/CT scan will get de-escalated treatment for cycle 5 and cycle 6 (rituximab alone without chemotherapy)

Who Is Running the Clinical Trial?

Hua-Jay J Cherng, MD

Lead Sponsor

Trials

1

Recruited

40+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Foresight Diagnostics

Collaborator

Trials

1

Recruited

40+

Conquer Cancer Foundation

Collaborator

Trials

22

Recruited

4,000+

Published Research Related to This Trial

Cell-free DNA (cfDNA) testing is a promising noninvasive method for detecting classical Hodgkin lymphoma (cHL), offering advantages like ease of blood sample collection, quick results, and consistency with tumor DNA analysis.

cfDNA levels correlate with important clinical features and can be used to evaluate treatment responses and monitor minimal residual disease, making it a valuable tool alongside traditional imaging methods like PET.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cell-Free DNA for the Management of Classical Hodgkin Lymphoma. Camus, V., Jardin, F.[2021]

The optimized pan-cancer target-enrichment panel for 51 oncogenes and tumor suppressors demonstrated high analytical sensitivity and precision, achieving a concordance correlation coefficient of 0.99 in variant detection across multiple sequencing runs.

In clinical assessments of 128 FFPE samples, the panel showed 78% sensitivity and 100% positive predictive value for known mutations, which improved to 87% sensitivity with the use of an orthogonal sequencing technology, emphasizing the importance of sample quality control in reducing false results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of an integrated clinical workflow for targeted next-generation sequencing of low-quality tumor DNA using a 51-gene enrichment panel. Choudhary, A., Mambo, E., Sanford, T., et al.[2019]

Circulating tumor DNA (ctDNA) offers a highly sensitive method for monitoring non-Hodgkin's lymphoma, detecting disease activity at a sensitivity level of one tumor cell per million, which can help in assessing tumor bulk and response to treatment.

ctDNA analysis can identify patients at high risk of treatment failure and detect disease progression months before traditional imaging methods, aiding in personalized treatment strategies through the identification of specific tumor mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liquid biopsy in non-Hodgkin's lymphoma. Melani, C., Wilson, WH., Roschewski, M.[2019]

Circulating tumor DNA (ctDNA) detection in blood offers a highly sensitive method for monitoring therapy effectiveness in non-Hodgkin lymphoma, potentially surpassing traditional imaging techniques like CT and PET scans, which have limitations such as radiation exposure and lack of tumor specificity.

ctDNA can serve as a 'liquid biopsy' to identify molecular changes and treatment-resistant clones, providing valuable insights for tailoring precision therapy in patients with both curable and incurable lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular Monitoring of Cell-Free Circulating Tumor DNA in Non-Hodgkin Lymphoma. Melani, C., Roschewski, M.[2018]

The Enrich Rare Mutation Sequencing (ER-Seq) technique significantly enhances the detection of circulating tumor DNA (ctDNA) by identifying a single mutation among 10 million wild-type nucleotides, improving the reliability of genetic analysis in clinical oncology.

ER-Seq covers over 95% of tumor-related driver mutations across 12 tumor types, making it a cost-effective and efficient method for accumulating genetic data and studying disease heterogeneity, with a typical processing time of just 1-2 days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Detection of Rare Mutations in CtDNA Using Next Generation Sequencing. Lv, X., Zhao, M., Yi, Y., et al.[2019]

The study developed an efficient workflow using the Vortex label-free CTC enrichment platform to isolate circulating tumor cells (CTCs) from blood, which is crucial for monitoring tumor genetics without the need for invasive tissue biopsies.

Using optimized whole genome amplification (WGA) methods, particularly REPLI-g, allowed for accurate detection of somatic mutations in CTCs from metastatic colorectal cancer patients, demonstrating the potential for real-time genetic monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Workflow optimization of whole genome amplification and targeted panel sequencing for CTC mutation detection. Liu, HE., Triboulet, M., Zia, A., et al.[2020]

Monitoring circulating tumor DNA (ctDNA) using next-generation sequencing can detect recurrent lymphoma earlier than traditional imaging scans, allowing for timely intervention.

ctDNA analysis can provide insights into tumor heterogeneity and resistance mechanisms, which can help tailor precision treatments for patients, highlighting the need for standardized collection and processing methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dynamic monitoring of circulating tumor DNA in non-Hodgkin lymphoma. Roschewski, M., Staudt, LM., Wilson, WH.[2021]

The SEQC2 project developed a targeted next-generation sequencing (NGS) method that improves the detection of actionable mutations in circulating tumor DNA (ctDNA), enhancing precision medicine.

By using synthetic internal standards for each mutation target, this method significantly increases sensitivity, allowing for the detection of true-positive mutations that were previously undetectable due to low variant allele fractions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advancing NGS quality control to enable measurement of actionable mutations in circulating tumor DNA. Willey, JC., Morrison, TB., Austermiller, B., et al.[2023]

Circulating tumor DNA (ctDNA) profiling offers a noninvasive method for monitoring B-cell lymphoma, providing real-time insights into the tumor's genetic makeup and allowing for better disease management compared to traditional tissue biopsies.

ctDNA assessment can enhance lymphoma subtype classification, treatment response evaluation, and monitoring of residual disease, making it a promising tool for personalized treatment strategies and potential use in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating tumor DNA in B-cell lymphoma: technical advances, clinical applications, and perspectives for translational research. Lauer, EM., Mutter, J., Scherer, F.[2023]

A new targeted resequencing platform using next-generation sequencing (NGS) has been developed to identify hotspot mutations in lymphoma patients, allowing for sensitive detection of genetic mutations even from limited samples.

This method enhances the ability to assess mutation clone sizes and could lead to more personalized, genotype-specific treatment strategies for lymphoma, addressing the challenges posed by genetic heterogeneity in cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Next-generation sequencing of cancer consensus genes in lymphoma. Hüllein, J., Jethwa, A., Stolz, T., et al.[2019]

PhasED-seq is a new method that significantly improves the sensitivity of detecting circulating tumor-derived DNA (ctDNA), allowing for detection in the parts per million range, which is better than previous methods.

In a study of 213 participants with B cell lymphomas, PhasED-seq identified ctDNA in 25% of patients who were considered ctDNA undetectable by other methods, indicating a potential for worse outcomes and highlighting its importance in monitoring minimal residual disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA. Kurtz, DM., Soo, J., Co Ting Keh, L., et al.[2022]

Formalin-fixed, paraffin-embedded (FFPE) samples can lead to sequencing artifacts, particularly strand-split artifact reads (SSARs), which complicate next generation sequencing (NGS) analysis due to damage to nucleic acids.

An effective method to reduce SSARs and other sequencing errors involves using S1 nuclease to remove problematic single-stranded fragments, which also improves the accuracy of variant detection in NGS data.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sources of erroneous sequences and artifact chimeric reads in next generation sequencing of genomic DNA from formalin-fixed paraffin-embedded samples. Haile, S., Corbett, RD., Bilobram, S., et al.[2020]

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Foresight Diagnostics and Roche Enter Licensing ...

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