Dynamics of MSI and Genomic Profile of Colorectal Cancer In the Course of Immune Checkpoint Inhibitor Therapy (BLOOMSI)

May 13, 2024 updated by: OncoAtlas LLC

A Multi-center Observational Clinical Trial Evaluating the Dynamics of Microsatellite Instability and Genomic Profile of Colorectal Cancer in the Course of Treatment With Immune Checkpoint Inhibitors

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Microsatellite instability or mismatch repair deficiency occurs in 20% of CRC, and is predominantly found in non-metastatic tumors. The success of the CheckMate 142 and KEYNOTE-177 clinical trials has shifted the treatment paradigm of the MSI/dMMR CRC, which has led to the adoption of immune checkpoint inhibitors (ICI) by international treatment standards. However, despite the encouraging effects of ICI, up to 30% of patients are resistant to treatment and exhibit rapid disease progression shortly after starting ICI. On the other hand, around 30% of patients treated with ICI demonstrate prolonged responses to the treatment with a duration of response of over 40 months. Furthermore, for ~10% of patients, treatment with ICI results in pseudo-progression - a phenomenon of a short-term increase followed by the decrease of the tumor volume.

Currently, the mechanisms and biomarkers associated with the response or resistance to ICI in MSI-positive CRC are largely unknown. Select studies suggest that BRAF mutations (specifically, BRAF p.V600E) might negatively affect the patients' progression-free survival following ICI, however, these data are premature.

The primary hypothesis is that the clonal heterogeneity and the evolution of MSI status of MSI-positive CRC will play a role in the development of ICI treatment resistance. The primary objective of the study is to investigate the dynamics of MSI status in serial liquid biopsy samples from patients with MSI-positive tumors receiving ICI.

Study Overview

Status

Recruiting

Conditions

Detailed Description

This is a multicenter observational trial designed to evaluate the dynamics of microsatellite instability and the genomic profiles of CRC during immune checkpoint inhibitor treatment.

Patients with MSI/dMMR-positive tumors who are candidates for the ICI treatment will be included in the study. MSI/dMMR positivity should be confirmed with polymerase chain reaction-based (PCR) assays, immunohistochemistry (IHC) or Next-generation sequencing (NGS). Treatment with any ICI will be allowed. Upon inclusion in the study, patients will be asked to provide the pre-treatment FFPE tumor and liquid biopsy (LB) samples along with LB samples on the 14th, 28th days of ICI, and at every control study. LB samples will be collected until treatment discontinuation.

The pre-treatment FFPE samples will be tested with an alternative routine method (PCR and/or IHC, depending on what method was used for initial testing), as well as with the Solo Atlas Pro NGS panel covering common cancer-related genes and short tandem repeats for MSI detection. All LB samples will be tested with the Solo Atlas Pro NGS panel. Dynamics of MSI and genomic profiles will be correlated with the treatment outcomes.

Disease response to study treatment will be evaluated by imaging methods. Response to treatment will be determined by RECIST v1.1.

Study Type

Observational

Enrollment (Estimated)

70

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

Study Locations

  • Russian Federation
      • Moscow, Russian Federation, 115478
        • Recruiting
        • N.N.Blokhin National Medical Research Center of Oncology
        • Contact:
          • Olesya Kuznetsova, MD
      • Moscow, Russian Federation, 142770
        • Recruiting
        • State Budgetary Institution of Healthcare of the City of Moscow "Moscow Multidisciplinary Clinical Center "Kommunarka" of the Department of Health of the City of Moscow
        • Contact:
          • Mikhail Fedyanin, MD, PhD

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

Sampling Method

Non-Probability Sample

Study Population

Patients with histologically confirmed colorectal cancer with microsatellite instability (MSI) or mismatch repair deficiency (dMMR)

Description

Inclusion Criteria:

  • Male/female participants must be at least 18 years of age on the day of signing informed consent and have a histologically confirmed diagnosis of colorectal cancer.
  • Verified MSI/dMMR positivity as measured by 5-loci PCR or 4-antibody IHC.
  • The patient is scheduled to start treatment with any of the immune checkpoint inhibitors 2-4 weeks after the inclusion in the study.
  • Have provided an archival tumor tissue sample obtained prior to the start of treatment with immune checkpoint inhibitor(s). Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.
  • Patient has to be able to provide serial blood samples during the course of treatment, as well as on every follow-up tumor scan.
  • The participant (or legally acceptable representative if applicable) provides written informed consent to participate in the trial.
  • Have measurable disease based on RECIST 1.1.
  • Have adequate organ function.

Exclusion Criteria:

  • Prior treatment with immune checkpoint inhibitors.
  • For female participants: pregnancy or planned pregnancy.
  • The unavailability of the tumor or serial liquid biopsy samples.

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Concordance of NGS and routine methods (PCR, IHC) for MSI analysis
Time Frame: Through study completion, an average of 3 years
Concordance will be calculated using Cohen's Kappa (κ)
Through study completion, an average of 3 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Concordance of MSI in tumor tissue and liquid biopsy (ctDNA)
Time Frame: Through study completion, an average of 3 years
Concordance will be calculated using Cohen's Kappa (κ)
Through study completion, an average of 3 years
Qualitative and quantitative status of MSI in serial liquid biopsy (ctDNA) samples
Time Frame: Through study completion, an average of 3 years
Liquid biopsy samples will be collected prior to the start of ICI, on the 14th and 28th days of therapy and at every follow-up tumor scan
Through study completion, an average of 3 years

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Correlation of biomarkers with the treatment outcomes
Time Frame: Through study completion, an average of 3 years
Dynamics of biomarkers in serial liquid biopsy samples will be correlated with treatment outcomes. Response to treatment will be determined by RECIST v1.1.
Through study completion, an average of 3 years
Evaluation of the ctDNA dynamics in the course of ICI in serial plasma samples
Time Frame: Through study completion, an average of 3 years
Dynamics of ctDNA in serial liquid biopsy samples will be correlated with treatment outcomes. Response to treatment will be determined by RECIST v1.1.
Through study completion, an average of 3 years

Collaborators and Investigators

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

Sponsor

OncoAtlas LLC

Collaborators

N.N. Blokhin National Medical Research Center of Oncology
Moscow MultidisciplinaryClinical Center Kommunarka

Investigators

  • Principal Investigator: Maxim Ivanov, PhD, OncoAtlas LLC

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)

June 1, 2022

Primary Completion (Estimated)

July 1, 2025

Study Completion (Estimated)

July 1, 2026

Study Registration Dates

First Submitted

May 7, 2024

First Submitted That Met QC Criteria

May 13, 2024

First Posted (Actual)

May 16, 2024

Study Record Updates

Last Update Posted (Actual)

May 16, 2024

Last Update Submitted That Met QC Criteria

May 13, 2024

Last Verified

May 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • BLOOMSI
  • 22-75-10154 (Other Grant/Funding Number: Russian Science Foundation)

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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