Chronic Lymphocytic LeukemiaNCT02827617
Identification of Biomarkers That Are Predictive of Early Ibrutinib Treatment Failure in High Risk TP53 Mutated Chronic Lymphocytic Leukemia
An observational study of Chronic Lymphocytic Leukemia, run by Oncology Institute of Southern Switzerland at 13 sites in 2 countries.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Chronic Lymphocytic Leukemia
- What is being tested?
- Ibrutinib
- How many people
- 56 participants
- Where
- 13 sitesin 2 countries
- Study dates
- 1 Jun 2016to 16 May 2024
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
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
Who may be able to join
- 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
Who cannot join
- Current or prior histological transformation from CLL to an aggressive lymphoma (ie, Richter transformation).
- Prior treatment with ibrutinib or idelalisib
Trial locations and contacts
13 sites in 2 countries.
13 sites in 2 countries
Italy9 sites
Onco Ematologia Clinico Sperimentale, I.R.C.C.S. Centro di Riferimento Oncologico
Aviano, 33081
Ospedale San Raffaele
Milan, 20132
Dipartimento di Ematologia, Niguarda Cancer Center, Ospedale Niguarda
Milan, 20133
Department of Medical and Surgical Sciences, section of Hematology
Modena, 41124
Divisione di Ematologia, Universita' del Piemonte Orientale
Novara, 28100
Institute of Hematology, Catholic University S. Cuore
Roma, 00168
Department of Haematology, Tor Vergata Hospital
Rome, 00133
Clinica Ematologica, Centro Trapianti e Terapie Cellulari "Carlo Melzi"
Udine, 33100
Ematologia, Ospedale di Circolo e Fondazione Macchi
Varese, 21100
Switzerland4 sites
Division of Hematology, Department of Internal Medicine, Basel University Hospital
Basel, 4031
Oncology Institute of Southern Switzerland
Bellinzona, Switzerland, 6500
Hematology, Luzern Kantonsspital
Lucerne, 6000
Clinica Luganese Moncucco
Lugano, 6903
About this study
Official title: 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.
Read the 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).
- Conditions
- Chronic Lymphocytic Leukemia
- Being tested
- Ibrutinib
- Keywords
- Ibrutinib, TP53, Chronic lymphocytic leukemia
- Medical subject headings
- Leukemia, Lymphocytic, Chronic, B-Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IbrutinibDrug
Also called PCI-32765
Treatment with ibrutinib 420 mg quaque die in the clinical practice
| Study group | Role | What they receive |
|---|---|---|
| TP53 mutated CLL | Not described Receives: Drug: Ibrutinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Impact of clonal response on PFS
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.
Measured: 2/2016-2/2021
Secondary outcomes (9)
Proportion of clonal response at Week 24 after treatment start
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
Measured: 2/2016-2/2021
Cumulative proportion of clonal response
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
Measured: 2/2016-2/2021
Impact of clonal response on overall survival
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)
Measured: 2/2016-2/2021
Effect of clonal response on the cumulative incidence of acquisition of resistance-mutations
To evaluate the effect of clonal response on the cumulative incidence of acquisition of resistance-mutations
Measured: 2/2016-2/2021
Effect clonal response on the cumulative incidence of transformation to Richter syndrome
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
Measured: 2/2016-2/2021
Impact of treatment-emergent BTK and PLCγ2 resistance mutations on PFS
To evaluate the impact of treatment-emergent BTK and PLCγ2 resistance mutations on PFS
Measured: 2/2016-2/2021
Impact of treatment-emergent BTK and PLCγ2 resistance mutations on OS
To evaluate the impact of treatment-emergent BTK and PLCγ2 resistance mutations on OS
Measured: 2/2016-2/2021
Impact of treatment-emergent BTK and PLCγ2 resistance mutations on the cumulative incidence of transformation to Richter syndrome
To evaluate the impact of treatment-emergent BTK and PLCγ2 resistance mutations on the cumulative incidence of transformation to Richter syndrome
Measured: 2/2016-2/2021
Accuracy of plasma cell free DNA for the identification of BTK and PLCγ2 resistance mutations
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
Measured: 2/2016-2/2021
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jul 2016 (estimated)
- Study start1 Jun 2016
- Primary completion31 Aug 2021
- Study completion16 May 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Chronic Lymphocytic LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 56 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Oncology Institute of Southern Switzerland
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Davide Rossi, MD, PhD, Principal investigator, Oncology Institute of Southern Switzerland
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02827617
- Sponsor's protocol ID
- IOSI-EMA-001
- Status last verified
- Nov 2025
- First submitted
- 6 Jul 2016
- Last updated
- 18 Nov 2025
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Nov 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT02827617
- Acronym / sponsor ID
- IOSI-EMA-001
- Conditions
- Chronic Lymphocytic Leukemia
- Keywords
- Ibrutinib, TP53, Chronic lymphocytic leukemia
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 56 participants (estimated)
- Lead sponsor
- Oncology Institute of Southern SwitzerlandUniversity, hospital or other
- Study start
- 1 Jun 2016 (actual)
- Primary completion
- 31 Aug 2021 (actual)
- Study completion
- 16 May 2024 (actual)
- First posted
- 11 Jul 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| TP53 mutated CLL | – | Drug: Ibrutinib |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- 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
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (2 listed)
- Current or prior histological transformation from CLL to an aggressive lymphoma (ie, Richter transformation).
- Prior treatment with ibrutinib or idelalisib
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IbrutinibAlso: PCI-32765Treatment with ibrutinib 420 mg quaque die in the clinical practice | Drug | TP53 mutated CLL |
Primary outcome
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.
9 secondary outcomes
Proportion of clonal response at Week 24 after treatment start
Time frame: 2/2016-2/2021
Cumulative proportion of clonal response
Time frame: 2/2016-2/2021
Impact of clonal response on overall survival
Time frame: 2/2016-2/2021
Effect of clonal response on the cumulative incidence of acquisition of resistance-mutations
Time frame: 2/2016-2/2021
Effect clonal response on the cumulative incidence of transformation to Richter syndrome
Time frame: 2/2016-2/2021
Impact of treatment-emergent BTK and PLCγ2 resistance mutations on PFS
Time frame: 2/2016-2/2021
Impact of treatment-emergent BTK and PLCγ2 resistance mutations on OS
Time frame: 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
Accuracy of plasma cell free DNA for the identification of BTK and PLCγ2 resistance mutations
Time frame: 2/2016-2/2021
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Nov 2025.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Davide Rossi, MD, PhD principal investigator
Oncology Institute of Southern Switzerland
13 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Chronic Lymphocytic Leukemia, run by Oncology Institute of Southern Switzerland at 13 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 13 sites in Italy, Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Impact of clonal response on PFS (time frame: 2/2016-2/2021). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Nov 2025.