Identification of Biomarkers That Are Predictive of Early Ibrutinib Treatment Failure in High Risk TP53 Mutated Chronic Lymphocytic Leukemia

November 14, 2025 updated by: Oncology Institute of Southern Switzerland

Prospective, Observational, Multi-centred, Non-interventional Study on the Identification of Biomarkers That Are Predictive of Early Ibrutinib Treatment Failure in High Risk TP53 Mutated Chronic Lymphocytic Leukemia

The general aim of the project is the identification of dynamic molecular markers that can help the early and real time prediction of sustained benefit or no benefit from ibrutinib treatment in CLL harboring TP53 mutations. Specific aims of the project include: 1) Assess whether clearance of TP53 mutated clones translates into a predictive biomarker of long term benefit from ibrutinib treatment in CLL. 2) Assess whether plasma cell free DNA represents a sensitive tool that can early and dynamically inform on the development of ibrutinib resistant mutations in CLL.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

In the chemoimmunotherapy era, TP53 mutations defined a subgroup of high risk chronic lymphocytic leukemia (CLL) patients in whom allogeneic stem cell transplantation had to be strongly considered. As a result of the accumulating favorable outcome data reported for new biological drugs, including ibrutinib, in high risk CLL harboring TP53 mutations, there is concern about whether these patients should continue to be offered allogeneic stem cell transplantation. Despite their improved outcome, a proportion of high risk CLL harboring TP53 mutations is going to develop ibrutinib resistance, which in turns translate in a very poor survival. On these bases, in the setting of ibrutinib treatment, novel biomarkers are required to re-define high risk CLL patients candidate for consolidation strategies including allogeneic stem cell transplantation. Our working hypotheses are that: i) clearance of high risk TP53 mutated clones upon treatment with ibrutinib may associate with long progression free survival (PFS), while conversely, the persistence or increase of high risk TP53 mutated subclones under ibrutinib may associate with acquisition of resistance and disease progression; and ii) plasma cell free DNA represents an accessible source of tumor DNA for the early and sensitive identification of mutations causing resistance to ibrutinib. By using highly sensitive ultra-deep next generation sequencing strategies to monitor molecular biomarkers potentially relevant for ibrutinib in DNA coming from both cellular and the plasma fractions of peripheral blood, the project has the chance of identifying new dynamic molecular markers that can help the early and real time prediction of sustained benefit from ibrutinib treatment vs imminent progression in TP53 mutated CLL patients. In the end, the results of this study will provide the bases to refine the current approach for treatment tailoring in TP53 mutated patients by allowing the identification of cases who, though being in clinical response under ibrutinib, will conceivably benefit from immediate switch to alternative options (i.e. novel drugs, allogeneic stem cell transplantation, or CART).

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
56

Contacts and Locations

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

Study Locations

  • Italy
      • Aviano, Italy, 33081
        • Onco Ematologia Clinico Sperimentale, I.R.C.C.S. Centro di Riferimento Oncologico
      • Milan, Italy, 20132
        • Ospedale San Raffaele
      • Milan, Italy, 20133
        • Dipartimento di Ematologia, Niguarda Cancer Center, Ospedale Niguarda
      • Modena, Italy, 41124
        • Department of Medical and Surgical Sciences, section of Hematology
      • Novara, Italy, 28100
        • Divisione di Ematologia, Universita' del Piemonte Orientale
      • Roma, Italy, 00168
        • Institute of Hematology, Catholic University S. Cuore
      • Rome, Italy, 00133
        • Department of Haematology, Tor Vergata Hospital
      • Udine, Italy, 33100
        • Clinica Ematologica, Centro Trapianti e Terapie Cellulari "Carlo Melzi"
      • Varese, Italy, 21100
        • Ematologia, Ospedale di Circolo e Fondazione Macchi
  • Switzerland
      • Basel, Switzerland, 4031
        • Division of Hematology, Department of Internal Medicine, Basel University Hospital
      • Lucerne, Switzerland, 6000
        • Hematology, Luzern Kantonsspital
      • Lugano, Switzerland, 6903
        • Clinica Luganese Moncucco
    • Switzerland
      • Bellinzona, Switzerland, Switzerland, 6500
        • Oncology Institute of Southern Switzerland

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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Probability Sample

Study Population

Adult CLL patients harboring TP53 genetic abnormalities, independent of whether treatment naïve or previously treated, who warrants treatment according to iwCLL 2008 criteria, and who is planned to receive ibrutinib at standard dose as per clinical practice

Description

Inclusion Criteria:

  • Male or female adults 18 years or older
  • Documented diagnosis of CLL, according to iwCLL 2008 criteria
  • Presence of TP53 mutation as demonstrated by sequencing at the local laboratory and/or presence of 17p deletion as demonstrated by fluorescence in situ hybridization (FISH) testing performed at the local laboratory
  • CLL that warrants treatment
  • Planned treatment with ibrutinib 420 mg quaque die
  • Willing and able to comply with scheduled visits, laboratory tests, and study procedures
  • Evidence of a signed informed consent

Exclusion Criteria:

  • Current or prior histological transformation from CLL to an aggressive lymphoma (ie, Richter transformation).
  • Prior treatment with ibrutinib or idelalisib

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

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
TP53 mutated CLL
Drug: Ibrutinib
Treatment with ibrutinib 420 mg quaque die in the clinical practice
Other Names:
  • PCI-32765

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Impact of clonal response on PFS
Time Frame: 2/2016-2/2021
To evaluate the impact of clonal response (namely clearance of TP53 mutated alleles in the peripheral blood (PB) CLL cells at Week 24 after treatment start) on PFS measured according to iwCLL guidelines (Hallek 2008) as the interval from ibrutinib treatment start to progression (event), death (event) or last follow-up (censoring). Progression will be defined as per investigator assessment.
2/2016-2/2021

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Proportion of clonal response at Week 24 after treatment start
Time Frame: 2/2016-2/2021
To evaluate the proportion of clonal response, defined as clearance (100% reduction compared to baseline) of TP53 mutated alleles in the PB CLL cells at Week 24 after treatment start
2/2016-2/2021
Cumulative proportion of clonal response
Time Frame: 2/2016-2/2021
To evaluate the cumulative proportion of clonal response, defined as clearance (100% reduction compared to baseline) of TP53 mutated alleles in the PB CLL cells at any time from treatment start
2/2016-2/2021
Impact of clonal response on overall survival
Time Frame: 2/2016-2/2021
To evaluate the impact of clonal response on overall survival (OS) measured according to iwCLL guidelines (Hallek 2008) as the interval from ibrutinib treatment start to death (event) or last follow-up (censoring)
2/2016-2/2021
Effect of clonal response on the cumulative incidence of acquisition of resistance-mutations
Time Frame: 2/2016-2/2021
To evaluate the effect of clonal response on the cumulative incidence of acquisition of resistance-mutations
2/2016-2/2021
Effect clonal response on the cumulative incidence of transformation to Richter syndrome
Time Frame: 2/2016-2/2021
To evaluate the effect of clonal response on the cumulative incidence of transformation to Richter syndrome defined as the interval between ibrutinib treatment start to histologically documented development of an aggressive lymphoma
2/2016-2/2021
Impact of treatment-emergent BTK and PLCγ2 resistance mutations on PFS
Time Frame: 2/2016-2/2021
To evaluate the impact of treatment-emergent BTK and PLCγ2 resistance mutations on PFS
2/2016-2/2021
Impact of treatment-emergent BTK and PLCγ2 resistance mutations on OS
Time Frame: 2/2016-2/2021
To evaluate the impact of treatment-emergent BTK and PLCγ2 resistance mutations on OS
2/2016-2/2021
Impact of treatment-emergent BTK and PLCγ2 resistance mutations on the cumulative incidence of transformation to Richter syndrome
Time Frame: 2/2016-2/2021
To evaluate the impact of treatment-emergent BTK and PLCγ2 resistance mutations on the cumulative incidence of transformation to Richter syndrome
2/2016-2/2021
Accuracy of plasma cell free DNA for the identification of BTK and PLCγ2 resistance mutations
Time Frame: 2/2016-2/2021
To evaluate the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of plasma cell free DNA vs tumor genomic DNA genotyping for the identification of BTK and PLCγ2 resistance mutations
2/2016-2/2021

Collaborators and Investigators

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

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Oncology Institute of Southern Switzerland

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Davide Rossi, MD, PhD, Oncology Institute of Southern Switzerland

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)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 1, 2016

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
August 31, 2021

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
May 16, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 6, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 6, 2016

First Posted (Estimated)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 11, 2016

Study Record Updates

Last Update Posted (Estimated)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
November 18, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 14, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
November 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • IOSI-EMA-001

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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