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

Study Overview
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Brief Summary
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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
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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).

Official Title
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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

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Ibrutinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| TP53 mutated CLL<br> | Drug: Ibrutinib<br>* Treatment with ibrutinib 420 mg quaque die in the clinical practice<br>* Other names: PCI-32765;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 2/2016-2/2021 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | 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) | 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 | 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 | 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 | 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 | 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 | 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 | 2/2016-2/2021 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ibrutinib, TP53, Chronic lymphocytic leukemia